Окисляющий/нетрозирующий стресс, апоптоз и сигнализация " Redox " : основные игроки в нейродегенеративных заболеваниях.

Abbreviations

3‐nitrotyrosine

Alzheimer's disease

amyotrophic lateral sclerosis

β‐Amiloid

ban brain barrier

tetrahydrobiopterin

catalase

cyclic guanosine monophosphate

central nervous system

cyclooxygenase

cerebrospinal fluid

endothelial NOS

endoplasmic reticulum

electron transport chain

flavin adenine dinucleotide

flavin mononucleotide

glutathione peroxidase

glutathione

hydrogen peroxide

huntington's disease

peroxynitrous acid

inducible NOS

c‐Jun N‐terminal kinase

multiple sclerosis

mitochondrial DNA

mitochondrial NOS

dinitrogen trioxide

nicotinamide adenine dinucleotide

nicotinamide adenine dinucleotide phosphate

nuclear factor kappa B

neuronal NOS

nitric oxide

nitrogen dioxide

nitrite

nitrate

nitric oxide synthase

NADPH oxidase

nitrosative stress

superoxide

peroxynitrite

oxidative stress

parkinson's disease

reactive nitrogen species

reactive oxygen species

superoxide dismutase

tumor necrosis factor receptor

ubiquinone

ubiquinol

ubisemiquinone

xanthine oxidase

nitroxyl radical

hydroxyl radical

Introduction

There is a significant increase in the prevalence of neurodegenerative diseases with the rise in the average age worldwide [ 1 ]. Alzheimer's disease, which is directly related to the increase in the elderly population and dementia, stands out as the most common neurodegenerative disease. In contrast, Parkinson's disease, characterized by motor dysfunction, and Multiple Sclerosis, characterized by chronic inflammation, rank second and third, respectively [ 1 , 2 ]. The complex pathophysiological processes of these diseases limit the effectiveness of therapeutic interventions to halt disease progression [ 3 ]. This situation increases the importance of studies to elucidate the molecular mechanisms of neurodegenerative diseases and identify new pharmacological targets [ 4 ]. In particular, determining the role of ROS, RNS, and apoptosis mechanisms in neurodegenerative diseases is crucial for better understanding molecular abnormalities and developing innovative treatment strategies [ 5 ].

The brain's neurons, glial cells, and endothelial cells rely on cellular energy, oxygen, and nitric oxide (NO) to maintain normal function [ 6 ]. ATP, oxygen, and NO play crucial roles in supporting synaptic transmission, astrocyte function, myelin production, blood flow, and vascular regulation, thus contributing to brain health and function. However, an imbalance in NO and the production of free radicals during the oxidative phosphorylation process in mitochondria can increase the risk of neurodegenerative diseases. This imbalance disrupts cellular functions and leads to neuronal cell death, accompanied by an increase in reactive oxygen species (ROS) and reactive nitrogen species (RNS) [ 7 , 8 ].

The brain is uniquely vulnerable to oxidative and nitrosative stress. However, the involvement of oxygen‐derived free radicals in critical functions through redox signaling and the enhancement of synaptic activity through NO introduces a complex dynamic. These compounds can have dual effects, promoting neurodegeneration or providing neuroprotection [ 8 , 9 ]. The effects of these compounds on neurological mechanisms are complex but depend on their physiological levels and persistence. Neuronal susceptibility results from the sequential reactions and interplay of the formed reactive radicals and the dynamic nature of different physiological processes, all contributing to increased stress factors [ 10 ].

Reactive oxygen and nitrogen species production increases when enzymes and proteins acting as antioxidants cannot eliminate these radicals [ 11 ]. This process is associated with the pathogenesis of five major neurodegenerative diseases: the accumulation of misfolded β‐amyloid proteins in Alzheimer's disease, the formation of α‐synuclein, the accumulation of Lewy bodies and loss of dopaminergic neurons in Parkinson's disease, the demyelination in Multiple sclerosis, SOD1 gene mutation in Amyotrophic lateral sclerosis, and the accumulation of mutated huntingtin in Huntington's disease [ 12 ]. These pathological conditions are likely to be promoted by increased mitochondrial and cytosolic ROS and RNS, which can cause oxidative damage to proteins, DNA, and lipids [ 13 ]. In this context, in this review, the molecular mechanisms underlying the increase of ROS and RNS in neurodegenerative diseases, redox processes, and the mechanisms involved in neuronal apoptosis are discussed in light of recent research. In addition, given the interconnected and intertwined interactions of multiple mechanistic pathways in neurodegeneration, an in‐depth understanding of the relationships between ROS, RNS, and apoptosis mechanisms and their cumulative effects is aimed.

Mechanism of Superoxide, ROS Formation, and NOX‐Mediated Damage

Oxidative stress (OS) arises from an imbalance between oxidants and antioxidants in biological systems, resulting in the excessive formation of ROS and an inadequate antioxidant system [ 14 ]. This phenomenon has been implicated in many diseases, with multiple mechanisms by which oxidants contribute to cellular damage during the OS process [ 15 ]. Although the impact of OS on disease pathology varies, it is known that enhancing antioxidant defense mechanisms can provide significant benefits in managing certain diseases [ 16 ].

OS involves the chemistry of reactions involving reactive species derived from oxygen and nitrogen. Compounds that act as sources of RNS include nitrogen oxides like peroxynitrite (ONOO − ), nitric oxide (NO), and nitrogen dioxide (NO 2 ). Compounds that serve as sources of ROS include oxygen‐derived molecules such as superoxide (O 2 •− ), hydrogen peroxide (H 2 O 2 ), hydroxyl radical (•OH), ozone, and singlet oxygen. Of particular importance is O 2 •− , which is a crucial type of ROS generated through electron leakage from ubisemiquinone (QH •− ) in the mitochondrial respiratory chain and through one‐electron reduction of oxygen in the NADPH oxidase (NOX) enzyme system [ 11 , 17 , 18 ]. Thus, the primary sources of intracellular ROS are mitochondria, with NOX enzymes playing a central and pivotal role in ROS production (7). Nitric oxide synthase (NOS), cytochrome P450, Xanthine oxidase (XO), the endoplasmic reticulum, and cyclooxygenases (8) are all additional sources of ROS [ 19 ].

NOS is an enzyme containing heme that can produce free radicals when encountering a specific substrate. When l ‐arginine binds, NOS produces NO. At low substrate concentrations, NOS generates O 2 •− and H 2 O 2 [ 20 ]. Cytochrome P450 facilitates monooxygenation reactions when it binds to a substrate and uses an oxygen molecule to create the oxy complex. NADPH electron transfer reduces the oxy complex to a peroxide complex, capturing adjacent hydrogen atoms in the substrate to generate ROS [ 21 ]. XO facilitates the oxidative hydroxylation of hypoxanthine to xanthine and xanthine to uric acid in human purine metabolism. XO rapidly transfers electrons during the oxidation of hypoxanthine and xanthine, producing O 2 •− and H 2 O 2 [ 22 ]. The production of cellular ROS in eukaryotic cells is attributed to the endoplasmic reticulum, with endoplasmic reticulum oxidoreductase‐1 (ERO1) as the primary source of ROS [ 23 ]. The cyclooxygenase (COX) enzyme contributes to ROS production by participating in the metabolism of arachidonic acid and generating prostaglandin precursors [ 24 ]. In general, the production of compounds that contribute to the pool of ROS occurs in cellular organelles such as mitochondria and the endoplasmic reticulum, as well as through enzyme mechanisms involving NOX, NOS, XO, COX, and cytochrome P450. This intricate ROS production network underscores oxidative stress's complexity in biological systems.

Electron Transport Chain‐Mediated Superoxide (O 2 •− ) Production

The formation of potentially harmful superoxide (O 2 •− ) takes place in mitochondria along the Electron transport chain (ETC) [ 25 ]. In complex I of the ETC, electrons are transferred from Nicotinamide adenine dinucleotide (NADH) to Flavin mononucleotide (FMN) and then to Ubiquinone (UQ), catalyzed by Fe‐S in the complex, resulting in reduced Ubiquinol (UQH 2 ). It is well‐established that two reactions occurring in specific parts of the respiratory chain lead to oxygen reduction to O 2 •− [ 26 ]. These reactions include the formation of O 2 •− by NADH dehydrogenase in complex I through the autooxidation of reduced FMN [ 27 ] and the formation of O 2 •− in complex III through the autooxidation of Ubisemiquinone (UQ •− ) [ 28 ] and reduced cytochrome b [ 29 ]. Electrons are also introduced into the ETC through Complex II. Complex II, also known as succinate dehydrogenase, converts succinate to fumarate while oxidizing Flavin adenine dinucleotide (FAD) into FADH 2 . The electrons from FADH 2 are then transferred to UQ sequentially through the Fe‐S cluster of Complex II [ 30 ]. Complex I and II transfer electrons to UQ, which is then reduced to UQH 2 [ 31 ] (Figure 1 ).

Complex III facilitates a sequence of electron transfer reactions from UQH 2 to cytochrome c, called the Q cycle [ 32 ], wherein UQH 2 is directly oxidized. Electrons are moved to Complex III and cytochrome c during the Q cycle. The Rieske iron‐sulfur protein (RISP) of complex III takes one electron from UQH 2 , while the complex transfers the second electron to cytochrome b. Following this, the electron is transferred from cytochrome b to a second Q molecule located on the matrix side of the complex, generating UQ •− . This region is recognized as the primary site of O 2 •− production in complex III [ 33 ]. When cytochrome c is reduced, it transfers electrons from complex III to complex IV (cytochrome c oxidase). At complex IV, molecular oxygen binds and is transformed into water [ 34 ]. Therefore, generating O 2 •− in mitochondria along the ETC is a cellular OS production component. During the process of OS, oxidative damage to cellular macromolecules involved in anabolic mechanisms, such as neurogenesis, becomes inevitable, thereby predisposing to neuropathogenesis (Figure 1 ).

NADPH Oxidase Mediated Superoxide (O 2 •− ) Generation

Previously, it was known that NOX activity was limited to phagocytes implicated in bacterial elimination [ 35 ]. However, subsequent studies have revealed that NOXs are also present in non‐phagocytic cells, and the NOX family now comprises seven isoforms [ 36 ]. Besides their function in the immune response, these enzymes have been found to engage in various physiological and pathological functions. They are a group of enzymes that produce ROS during the catalytic metabolism of oxygen [ 37 ]. All NOX isoforms are membrane‐bound enzymes that rely on Nicotinamide adenine dinucleotide phosphate (NADPH) for their activity [ 38 ]. The NOX enzyme's active site comprises a C‐terminal cytoplasmic region interacting with NADPH and N‐terminal transmembrane segments, including two heme groups producing superoxide (O 2 •− ) [ 39 ]. NOX enzymes have a catalytic center comprising flavin adenine dinucleotide (FAD), two heme cofactors, and a transmembrane domain [ 40 ]. The mechanism of O 2 •− production is by the transfer of electrons from NADPH to molecular oxygen via Fe(III) ions of the heme group of NOX isoforms and subsequent reduction to O 2 •− [ 41 ]. In the NOX‐catalyzed reaction, a hydride is transferred from NADPH to FAD after a single electron transfer from reduced FAD to hemes, ultimately reducing molecular oxygen to O 2 •− [ 7 ]. This electron transfer pathway, which leads to O 2 •− formation from NADPH, is thermodynamically straightforward [ 42 ]. The transmembrane domain allows NOX to transport electrons across the membrane. While NADPH oxidation happens on one side of the membrane, O 2 •− formation with reduction occurs on the other. This process effectively transports electrons from cytosolic NADPH to molecular oxygen in the membrane, where reduction occurs [ 43 ]. The involvement of NADPH oxidase in neurodegeneration is also related to this transmembrane O 2 •− formation. When antioxidant defenses such as Superoxide Dismutase (SOD) and Glutathione (GSH) are insufficient, the increase of O 2 •− mediated ROS leads to neuronal damage [ 9 ].

Synthesis of Nitric Oxide, Formation of RNS, and Mechanism of RNS Damage

In biological systems, Nitric oxide (NO) is a gasotransmitter synthesized by various isoforms of the enzyme Nitric oxide synthase (NOS). NO, which is synthesized by nNOS (neuronal NOS), eNOS (endothelial NOS), iNOS (inducible NOS), and mtNOS (mitochondrial NOS), plays a crucial role in numerous biological processes [ 44 ]. These processes encompass vasodilation, neurotransmission regulation, modulation of immune responses, and cellular signaling [ 8 ]. Physiologically, low NO concentrations regulate neurotransmitter release, influence synapse plasticity, and modulate the activity of nerve and retinal cells [ 12 , 45 ]. Additionally, low NO concentrations effectively suppress inflammation in response to environmental factors and facilitate tissue oxygen and nutrient uptake by increasing blood flow. This mechanism aids tissues such as the brain, liver, lung, kidney, and heart to maintain their optimal function [ 46 ]. However, endothelial dysfunction, ischemia‐reperfusion injury, neurodegenerative diseases, oxidative stress, inflammatory conditions, and infectious conditions can lead to overstimulation of NOS isoforms and the production of high concentrations of NO [ 8 , 12 , 47 ]. Dysregulated regulation and uncontrolled production of NO trigger the formation of Nitrosative stress (NS). Due to the high reactivity of NO, it can cause harm to proteins, lipids, and nucleic acids through oxidation and nitrosylation, leading to an increase in intracellular superoxide (O 2 •− ) and S‐nitrosylated compounds, thereby exacerbating NS [ 48 , 49 ].

Under physiological conditions, multiple cofactors, activators, regulators, and substrates interact to generate NO from NOS isoenzymes, resulting in a complex regulatory mechanism. For instance, cofactors such as tetrahydrobiopterin (BH4), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and Nicotinamide adenine dinucleotide phosphate (NADPH) are involved. Activators include calmodulin and calcium ions, while regulators include iron and zinc. Substrates include l ‐arginine and molecular oxygen. These components collectively stimulate and regulate the catalytic activity of NOS isoenzymes [ 47 , 50 ]. Calcium ions and calmodulin complex facilitate the formation of NOS monomers into dimeric enzyme complexes. This dimerization process is necessary for initiating NO synthesis.

BH4, as a cofactor, catalyzes the modification of l ‐arginine to NO and l ‐citrulline during the oxidative deamination process. Molecular oxygen serves as another substrate in this reaction. The resulting NO can mediate eight critical cellular reactions (Figure 2 ). One such reaction involves the interaction between NO and O 2 •− anions, forming the exceedingly reactive Peroxynitrite (ONOO − ) [ 51 ]. ONOO− is considered both a reactive nitrogen derivative and a reactive oxygen derivative, and it can cause damage to biological molecules through oxidative and nitrosative stress at high concentrations. The damages include various cellular effects such as modification of amino acids, lipid peroxidation, modification of DNA bases, and mitochondrial damage [ 52 ].

Additionally, ONOO− can oxidize iron‐containing hemoproteins (hemoglobin, myoglobin, cytochromes) in their ferric form, disrupting essential biological processes like oxygen transport, electron transfer, and cellular respiration [ 53 ]. One of the molecular targets of NO is cysteine residues or thiol groups in proteins. This reaction leads to an increase in S‐nitrosothiol and S‐nitrosated compounds in the cell. Consequently, proteins undergo modification through nitrosylation, resulting in changes in cellular signaling and enzymatic activity [ 54 ]. In particular, the modification of cysteine residues in the structure of Glutathione (GSH), an important antioxidant compound in the cell, by NO, and the formation of S‐nitroso GSH may disrupt redox homeostasis by reducing the intracellular GSH pool [ 55 ]. Another NO target in biological systems is tyrosine residues in proteins [ 56 ]. Nitrogen‐derived free radicals, primarily NO and ONOO − , perform a nitrotyrosination reaction by transferring the ‐NO 2 group to the phenolic structure of tyrosine. This modification leads to the formation of nitrotyrosine compounds and significant changes in the protein's three‐dimensional structure and conformation, resulting in mistargeting and functional abnormalities [ 57 ]. The redox reactions involving metalloproteins are another category of reactions in which NO exhibits reactivity. NO can engage in reduction‐oxidation reactions by forming complexes with proteins bound to metal ions, particularly those containing iron and copper. NO binding to metal ions can occur in physiological and pathological circumstances [ 58 ]. The interaction of NO with hemoglobin may affect oxygen delivery to cells and the regulation of oxygen levels in tissues.

Furthermore, NO can bind to iron atoms in ferrous heme and Fe‐S proteins, such as cytochrome oxidase and catalase. This binding results in the formation of iron nitrosyl bonds, which then modulate the metabolic pathways in which these proteins are involved. As a result, these interactions have the potential to impact critical metabolic processes such as cellular energy production, antioxidant defense mechanisms, and redox balancing [ 58 , 59 ].

NO can modify proteins through nitration and nitrosylation reactions and affect other cellular macromolecules, such as DNA and lipids, through nitroxidative modifications. The overproduction of NO, the main initiator of RNS, leads to the formation of ONOO− and 8‐nitroguanine, a marker of nitrosative DNA damage [ 60 ]. Apurinic sites formed as a result of depurination have the potential to induce erroneous base pairings during DNA replication, leading to the formation of mutagenic DNA lesions [ 61 ]. Secondary products derived from NO, such as ONOO− and NO radicals, can interact with double bonds in fatty acids, forming nitrofatty acids (Figure 2 ) . These nitroxidation adducts result from cellular nitrosative and oxidative stress effects on lipid components [ 62 ]. Accumulation of nitro fatty acids in cell membranes can reduce their elasticity, impair their permeability, and disrupt antioxidant defense mechanisms within the cell, leading to increased free radical damage [ 63 ].

RNS are accountable for numerous biological effects linked to the excessive production of NO or the presence of its by‐products. Mainly, reactive derivatives of NO, like ONOO − , can induce cellular damage by causing nitrative and oxidative modifications of DNA, proteins, and lipids. This can lead to various pathological conditions associated with deviations from the normal physiological functions of NO [ 46 ]. These pathological conditions, which are connected to increased nitrosative‐oxidative stress, encompass significant health issues, particularly inflammatory diseases, neurodegenerative disorders, and tissue damage. The cellular‐level effects of RNS can profoundly disrupt the homeostasis of biological systems and have substantial implications on tissue functionality. Hence, preventing or reducing cellular damage caused by uncontrolled RNS production and associated ROS has emerged as a potential strategy for treating numerous pathological conditions [ 64 ].

Additionally, NO can engage in redox reactions by binding to iron and copper ions found in metalloproteins. The NO‐mediated RNS can react with unsaturated fatty acids and deoxyguanosine, forming nitro fatty acids and initiating nitrosative DNA damage. In the presence of oxygen, NO can also generate nitrogen dioxide (NO 2 ) and dinitrogen trioxide (N 2 O 3 ), which can further contribute to the formation of other RNS. These resultant products can eventually be converted into nitrite and nitrate in aqueous environments, triggering nitrosative‐oxidative stress processes. Proteins, lipids, and DNA undergo structural modifications due to their interactions with NO (Figure 2 ).

Crosstalk Relationship of Reactive Oxygen Species and Reactive Nitrogen Species

Considerable literature exists concerning the etiology of elevated levels of ROS and RNS at the cellular level. ROS and RNS can arise as byproducts of normal cellular metabolic processes or due to deficiencies in the antioxidant defense system [ 11 , 65 ]. Cellular organelles such as mitochondria, peroxisomes, and the endoplasmic reticulum are potential oxidative and nitrosative compound sources. At the same time, enzymes like NOX, Xanthine oxidase, and unbound NOS contribute to the generation of oxidant radicals and peroxynitrite (ONOO − ) [ 66 ] (Figure 3 ). NOXs, as part of the ROS‐generating mechanisms, are a transmembrane protein complex spanning both sides of the cell membrane [ 67 ]. Notably, NOX plays a crucial role in immune cells (e.g., neutrophils, macrophages, and dendritic cells) by instigating ROS production to combat bacteria [ 68 ]. The activated NOX complex converts extracellular molecular oxygen into the highly reactive superoxide radical (O 2 •− ). The enzyme superoxide dismutase 3 (SOD3) regulates extracellular ROS and converts the O 2 •− anion into hydrogen peroxide (H 2 O 2 ) molecules. H 2 O 2 generated outside the cell can traverse the cell membrane and source intracellular ROS production [ 69 ]. Due to its involvement in energy production and oxidative metabolism, mitochondria remain the primary cellular organelle responsible for ROS production. While mitochondria facilitate cellular energy production through the continuous metabolism of molecular oxygen, they also contribute to ROS and RNS production [ 70 ]. Electrons within the multisubunit enzyme complex in the inner mitochondrial membrane partake in redox reactions while transported toward oxygen. Specifically, electrons that leak from complexes I and III, which cannot be transferred to other complexes, monovalently react with oxygen to form O 2 •− [ 71 ]. The SOD2 enzyme, responsible for regulating mitochondrial ROS, converts this primary free radical into H 2 O 2 . Mitochondrial defense mechanisms, such as antioxidant enzymes (catalase and glutathione peroxidase), can be employed to counterbalance the detrimental effects of H 2 O 2 , or the presence of ionic iron can lead to the formation of secondary free radicals, such as hydroxyl radical (•OH) [ 72 ]. Furthermore, molecular oxygen and arginine may combine with mitochondrial NOS, producing NO. The NO molecule can react with the O 2 •− radical to form ONOO − , the primary constituent of mitochondrial nitrosative stress, or other NO reactions can generate a series of byproducts, such as nitroxyl radical (•NO 2 ), peroxynitrous acid (HNO 3 ), nitrate (NO 3 − ), and nitrite (NO 2 − ) [ 73 ] (Figure 3 ). Increased levels of highly reactive species, including H 2 O 2 , ONOO − and •OH, within the mitochondria harm mitochondrial proteins, enzymes, and mitochondrial DNA (mtDNA). Elevated oxidative stress and nitrosative stress lead to protein and enzyme damage within the electron transport chain, disruption of mitochondrial membrane integrity, and mtDNA mutations, ultimately impacting cellular energy production [ 74 , 75 ].

After interacting with the nitrogenous bases of DNA, •OH and ONOO − can cause various forms of DNA damage, including cross‐linking, point mutations, and DNA breaks. These damages can disrupt the genetic integrity of cells and result in a range of health issues [ 76 , 77 ]. In addition to mitochondria, peroxisomes are another cellular organelle that can generate oxidative and nitrosative stress [ 78 ]. Specifically, peroxisomes facilitate the production of oxidant molecules such as O 2 •− and H 2 O 2 through XO activation, which contributes to the formation of RNS like ONOO − via the action of the NOS enzyme [ 79 , 80 ]. Apart from mitochondria and peroxisomes, the endoplasmic reticulum (ER) can also contribute to the accumulation of H 2 O 2 within the cell. In conditions such as ER stress or disrupted calcium homeostasis, heightened levels of H 2 O 2 can be detected in the ER lumen [ 81 ].

In general, the enzymes NOX, XO, and NOS, as well as the organelles ER, mitochondria, and peroxisomes, serve as direct or indirect sources of intracellular H 2 O 2 and ONOO − accumulation [ 82 ]. The accumulation of these oxidant and nitrogen compounds can increase oxidative and nitrosative stress within the cell, thereby triggering redox signals regulating numerous physiological processes. Cells have evolved mechanisms to protect against cellular damage caused by these compounds, employing both enzymatic and nonenzymatic antioxidant systems to counteract the elevated levels of free radicals, oxidants, and nitrogen compounds [ 83 ]. Under normal physiological conditions, enzymatic defense systems such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), as well as nonenzymatic defense systems like glutathione (GSH), are activated in the cytoplasm and organelles to regulate the excessive production of reactive oxygen and nitrogen species [ 84 , 85 ]. However, when the antioxidant defense mechanisms are overwhelmed, an intracellular redox imbalance arises, and ROS and RNS are overpopulated. This leads to alterations in the structure and function of cellular organelles, disruption of mitochondrial biogenesis, and decreased efficiency of energy‐dependent cellular processes [ 86 ]. These changes may ultimately result in cell death and the development of age‐related neurodegenerative disorders. Furthermore, they predispose individuals to various pathological conditions associated with diseases such as Alzheimer's, Parkinson's, and Multiple Sclerosis (MS) [ 87 ].

The Relationship Between the Formation of Reactive Oxygen Species and Reactive Nitrogen Species and Apoptosis

The induction of cellular apoptosis can occur through the activation of death receptors (extrinsic pathway) by ROS or through the stimulation of mitochondrial apoptogenic factors (intrinsic pathway) by both ROS and RNS [ 88 , 89 ]. Death receptors such as TNFR1, FAS, and TRAIL‐R, which activate the extrinsic apoptosis pathway, are located on the cell membrane and mediate intracellular protein‐protein activations following specific ligand‐receptor binding [ 90 ]. The direct role of ROS in inducing apoptosis is explained by the combined processes of increased extracellular ROS via NOX, receptor clustering, and lipid raft formation, which trigger death receptor activation [ 91 ]. However, further research is required to elucidate the molecular mechanisms that mediate receptor activation in ROS‐receptor interaction compared to classical ligand‐death receptor interaction. Moreover, ROS may modulate the action of death receptor ligands (such as TNF‐alpha, Fas, and TRAIL) and indirectly enhance cell death signaling [ 92 ]. Therefore, ROS's direct and indirect effects on death receptor activation and ligand modulation have been identified as components of the complex mechanisms that regulate cell death (Figure 4 ).

Tumor necrosis factor receptor (TNFR) is a death receptor that belongs to the TNF superfamily, and its primary biological functions are mediated by tumor necrosis factor‐alpha (TNF‐α). Upon TNF‐α binding to the receptor, the TNF‐R‐associated death domain adapter protein (TRADD) accumulates in the cytoplasmic region [ 93 ]. This results in two distinct complexes that activate survival or apoptosis pathways. RIP and TNF‐associated factor‐2 (TRAF2) are recruited to TRADD in complex I formation. This structure may regulate the inflammatory response of nuclear factor kappa B (NF‐κB) [ 91 ] or promote cell survival by increasing the synthesis of antiapoptotic proteins (such as Bcl‐XL, XIAP, FLIP), reducing oxidative/nitrosative stress through antioxidants such as manganese superoxide dismutase (MnSOD) [ 88 , 94 ]. On the other hand, complex II formation involves FAS‐associated death domain (FADD) and procaspase‐8, which are associated with TRADD. This structure promotes the cell death pathway by triggering the formation of the cell death‐initiating signaling complex (DISC) [ 91 , 95 ] (Figure 4 ).

Other receptors that play a pivotal role in the death receptor signaling pathway include FAS and TRAIL‐R. Upon ligand binding to these receptors and subsequent receptor activation, FADD and procaspase‐8 merge within the cytosol [ 67 , 91 , 96 ]. This association triggers the formation of the DISC and initiates the activation of procaspase‐8. The caspase cascade activation amplifies the apoptotic signal, expediting programmed cell death [ 97 , 98 ]. The activation of procaspase‐8 is crucial in instigating mitochondrial apoptotic processes. The level of caspase‐8 activation within the DISC determines the mechanisms by which apoptosis proceeds. A proficient activation of caspase‐8 can directly incite apoptosis through caspase‐3 (pathway 1). However, low levels of caspase‐8 activation can induce apoptosis by following an amplification pathway (pathway 2) that involves the participation of mitochondrial proteins [ 99 ]. In pathway 2, caspase‐8 activates tBID. Activated tBID interacts with proapoptotic proteins like Bax and Bak, disrupting the integrity of the mitochondrial outer membrane [ 97 , 100 ]. In addition, ROS and RNS facilitate the translocation of Bax and Bak to the outer membrane of mitochondria by damaging mitochondrial membrane lipids and proteins or through protein oxidation. The activation of Bax/Bak and the increase in mitochondrial ROS/RNS prompts the release of cytochrome c by augmenting the permeability of the mitochondrial outer membrane [ 74 , 96 , 101 , 102 , 103 ]. Cytochrome c, in turn, initiates the release of other proapoptotic factors, such as apoptosis‐inducing factor (AIF) and Smac/Diablo, thereby intensifying apoptosis signaling [ 104 ] (Figure 4 ). Apaf‐1 combines with cytochrome c released into the cell, forming the apoptosome complex and converting procaspase‐9 into active caspase‐9 [ 100 , 105 ]. Active caspase‐9 then triggers the activation of other effector caspase enzymes (caspase‐3, ‐6, ‐7), which are essential for the progression of apoptosis. Once activated, caspases cleave cellular proteins, ensuring the completion of apoptosis [ 97 , 100 , 105 ]. In summary, ROS and RNS play a crucial role in apoptosis regulation by activating receptor‐mediated apoptosis and activating intracellular apoptosis regulators.

Apoptosis Induction and Formation of Reactive Oxygen/Nitrogen Species in Neurodegenerative Diseases

Reactive oxygen and nitrogen species are naturally occurring chemical compounds in cellular metabolism processes [ 106 , 107 ]. They serve as crucial signaling molecules for neuronal cells and regulate various cellular functions when present at normal levels. However, elevated levels of ROS and RNS can generate toxic substances that harm neurons, disrupting their function and structure [ 9 , 108 ]. Under such circumstances, physiological apoptosis (programmed cell death) eliminates damaged neuronal cells with increased toxic load and facilitates cell regeneration and tissue repair [ 109 ]. Accumulating evidence suggests that ROS and RNS compounds play a role in the pathogenesis of common neurodegenerative diseases such as Alzheimer's, Parkinson's, Multiple sclerosis, Amyotrophic lateral sclerosis, and Huntington's [ 10 , 12 ]. Understanding the molecular mechanisms associated with the rise in NO and Hydrogen peroxide (H 2 O 2 ) levels in neuronal cells and the subsequent neurotoxicity‐induced apoptosis is paramount in comprehending the pathology of neurodegenerative diseases. Therefore, comprehending the interplay between apoptosis induction and the generation of ROS and RNS, as well as the cumulative effect of these processes, is crucial in understanding and preventing the progression of neurodegenerative diseases.

The Role of the Nitric Oxide/Nitric Oxide Synthase System in the Pathogenesis of Alzheimer's Disease

The primary role of NO lies in its presence as an endothelial derivative in blood vessels, aiding vasodilation. Furthermore, NO, synthesized by nNOS, functions at the neuronal level and contributes to various processes associated with nerve conduction. The NO/NOS system is a fundamental biological mechanism that governs diverse processes, such as neurogenesis and neurodevelopment, by influencing the generation of action potentials and neurotransmission. Studies investigating the involvement of the NO/NOS system in neurodegenerative processes have concentrated on three mechanisms. The first mechanism involves S‐Nitrosylation of cysteine residues in proteins, the second mechanism involves nitration of tyrosine residues, and the third mechanism involves cellular signaling and regulation through the cyclic guanosine monophosphate (cGMP) pathway.

NO formation and S‐Nitrosylation of proteins have been implicated in tau protein aggregation in neurons in Alzheimer's disease (AD). Cieślik et al. conducted animal models to investigate the impact of NO on memory impairment in AD. The study demonstrated a direct correlation between NO signaling pathways and l ‐arginine levels, NOS activity, protein S‐Nitrosylation, and ROS/RNS production. Impaired l ‐arginine metabolism, abnormal protein nitrosylation, and elevated endothelial NOS (eNOS) monomer content have been identified as among the various effects of NO in the pathology of AD [ 110 ]. It has been reported that β‐Amyloid (Aβ) formation, tau aggregation, and NO production‐mediated nitrosative stress exhibit a triangular interaction, which may lead to synapse loss and neurodegeneration [ 111 ] (Figure 5 ). Sen et al. reported in a study conducted on brain tissues of mice and cultured cortical neurons that increased levels of NO result in the S‐Nitrosylation of GAPDH, thereby promoting tau and amyloid pathology in AD [ 111 ]. Furthermore, an investigation performed on an AD transgenic mouse model revealed the presence of S‐Nitrosylation‐modified proteins in the brains and synaptosomes of the animals, which were found to be involved in axon guidance and neuronal signaling processes [ 112 ].

In AD, tyrosine residues' nitration, which occurs through nitrative and oxidative modifications, has been linked to tau polymerization. Reynolds et al. reported that nitrative and oxidative damage play a mechanistic role in neurodegeneration and that peroxynitrite (ONOO − ) mediated nitrogen and oxygen‐derived molecules influence tau polymerization. According to their study, ONOO − causes 3‐nitrotyrosine (3‐NT) modification by reacting with tyrosine residues in proteins. This protein nitration may promote tau accumulation in AD [ 113 ]. Additionally, it has been observed that the cross‐linking of ONOO − to proteins through the formation of a tyrosyl radical leads to protein misfolding. This, in turn, increases the levels of 3‐NT and 3,3’‐dithyrosine in the hippocampus region of individuals with AD [ 114 ]. Ahmed et al. reported that protein nitration, oxidation, and glycation adducts might have a biochemical role in AD. Increased concentrations of 3‐NT, N‐carboxymethyl‐lysine, and 3‐deoxyglucosone derivatives were observed in patients' cerebrospinal fluid (CSF) samples. It has been suggested that these oxidation and nitration adducts impact the functioning of neuronal cells in AD, leading to cognitive impairment [ 115 ].

The cGMP pathway is a crucial mechanism that transmits the cellular effects of NO signaling in neurons. NO triggers the synthesis of cGMP, which acts as a secondary messenger in neurons [ 116 ]. Consequently, a reduced cGMP concentration may impair neurotransmission and decrease AD neuronal function as individuals age [ 117 ]. Tropea et al. observed that the effects of NO can differ based on its cellular concentration and contribute to mechanisms associated with synaptic plasticity and memory by activating the NO/cGMP pathway under normal physiological conditions. Conversely, they noted that when NO is released at high concentrations from glial cells as an immune response, it leads to the formation of RNS and neurotoxic effects [ 118 ]. Studies have indicated that NO enhances synaptic activity in neurons, supports synaptic plasticity by fostering communication between neurons, and boosts cGMP production by activating the guanylate cyclase enzyme in postsynaptic cells [ 119 ]. It has been suggested that cGMP could be a critical mechanism in forming long‐term memory by modulating the NO/cGMP/PKG pathway in cellular signaling [ 120 ]. Puzzo et al. reported that elevated levels of Aβ in AD disrupt NO production and cGMP molecular signaling, thereby affecting synaptic mechanisms and resulting in cognitive impairment [ 121 ].

The increased oxidized and nitrated compound levels in pathological conditions have been reported as a neuro‐destruction indicator. Conversely, under low oxidative stress levels in physiological conditions, oxidative modifications like S‐Nitrosylation may indicate neuroprotection and normal signal transduction conditions [ 122 ]. It has been suggested that physiologic concentrations of NO could effectively inhibit Aβ aggregation, a crucial aspect of AD pathogenesis. Thus, preclinical studies propose that increasing NO and cGMP signaling at a particular level could be an appropriate strategy for AD treatment. Chuang et al. examined the neuronal effects of a dinitrosyl iron complex that prolongs the half‐life of NO in the biological system. This complex has been shown to protect neuronal cells from Aβ‐induced cytotoxicity by degrading neuronal Aβ and enhancing neuronal functions [ 123 ]. Qin et al. investigated the effects of synthesized methylthiazoles and NO‐chimeras on improving synaptic function and exerting neuroprotective effects in AD transgenic mice. The study reported that NO‐chimeras improved in vivo learning and memory functions, provided neuroprotection and neurorestoration through their NO‐mimetic activity, and thus could be considered a prototype AD drug [ 124 ].

Several observations can be made when considering the role of NO in the pathogenesis of AD. Firstly, it is evident that NO plays a crucial role in regulating neuronal functions at physiological levels. However, when cells accumulate NO, it can produce reactive nitrogen and oxygen species, resulting in neurotoxic effects. The divergent effects of NO, which can either promote neurotoxicity or activate neuroprotective mechanisms, necessitate the exploration of various strategies for AD treatment. Therefore, given the concentration‐dependent effects of NO, using NO‐mediated systems should be considered a potential therapeutic approach for AD.

ROS/RNS Generation and Apoptosis in the Pathogenesis of Alzheimer's Disease

In treating Alzheimer's disease, there has been a focus on drugs that target the formation of β‐Amyloid (Aβ) plaques [ 125 ]. However, other potential targets, such as the abnormal accumulation of tau proteins in neurons, neurotransmitter imbalance, inflammation, ROS/RNS generation, and apoptosis, have also been considered for AD [ 126 ]. These factors illustrate the complexity and multiple causes of the disease, expanding the potential areas for new treatment strategies. In this context, it is essential to target processes that lead to the loss of nerve cells, including apoptosis and ROS/RNS generation, as a crucial step toward developing innovative and effective therapies to mitigate the effects of AD [ 126 , 127 ]. Several ROS‐sensitizing prodrugs have been developed and evaluated for their potential to reduce the production of oxidant molecules, target inflammation and apoptosis, and improve the pathological symptoms of AD. Studies have shown that these prodrugs, which can penetrate the blood‐brain barrier, exhibit neuroprotective effects in neuroblastoma cells when exposed to Hydrogen peroxide (H 2 O 2 ). They also regulate apoptosis‐related proteins such as Bax, Bcl‐2, and cleaved caspase‐3 in microglial cells, improve cognitive deficits, and support memory development in AD mouse models [ 128 ]. Another study reported that BAD, one of the proapoptotic proteins, plays an essential role in the pathogenesis of AD by increasing neuronal apoptosis, triggering neuroinflammation, and suppressing microglial phagocytosis of Aβ plaques. Moreover, BAD has been found to mediate the formation of oxidized mitochondrial DNA and neuronal death by promoting an increase in mitochondrial ROS. Hence, molecular approaches targeting BAD may offer potential therapeutic benefits in AD [ 129 ]. Apart from ROS and regulators of apoptosis, the activation of the cyclic guanosine monophosphate (cGMP) pathway is considered one of the primary mechanisms for NO‐mediated neuronal activity. Numerous studies have indicated that reduced cGMP levels can inhibit synaptogenesis, decrease interactions between neurons and glial cells, and impair NO‐mediated antiapoptotic responses [ 12 , 130 ]. Moreover, low cGMP concentrations have been observed to diminish the antiapoptotic effect by affecting the phosphorylation of proteins participating in apoptosis regulation and promoting the production of RNS by increasing NO and peroxynitrite (ONOO − ) [ 130 ]. Additionally, Monte et al. investigated the correlation between the catalytic activity of NOS‐III and apoptosis and cerebrovascular disease in AD. The study reported an association between decreased levels of NOS‐III in cerebral vessels and increased levels of p53 in endothelial cells, which subsequently induced apoptosis. Furthermore, it was found that low levels of cerebrovascular NO and NOS‐III led to Aβ accumulation, impaired vasodilation responses, and cerebral hypoperfusion [ 131 ]. Wang et al. elucidated the relationship between biometal homeostasis, ROS, RNS, and neuronal death in AD. The study revealed that imbalances in AD biometal levels result in increased brain tissue oxidant and nitrogen compounds. This, in turn, causes the oxidation of cellular components, particularly DNA and proteins [ 132 ]. Oxidized compounds disrupt the integrity of plasma membranes, causing their release from the cell and affecting mitochondrial function, ultimately triggering apoptosis [ 132 , 133 ]. Consequently, it has been established that increased ROS and RNS, coupled with disturbed biometal balance, contribute to the pathology of AD, manifested through the formation of neurofibrillary tangles, an increase in Aβ plaques, and ultimately neurodegeneration [ 132 ]. Using findings from human autopsy and animal model experiments, Ekundayo et al. elucidated the roles of ER stress, oxidative stress, and apoptosis in the progression of AD [ 126 ]. The study reported that ROS, ER stress, and apoptosis activate interconnected mechanisms that contribute to the pathogenesis of AD. These mechanisms include the extracellular accumulation of Aβ, protein misfolding, and regulation of apoptotic factors. It was emphasized that these mechanisms may significantly impact clinical symptoms such as neuronal loss, cognitive impairments, and memory loss observed in the later stages of AD [ 126 ]. Obulesu et al. provided a comprehensive overview of the role of mitochondria and ER‐mediated cell death processes in the intricate etiology of AD [ 134 ]. Apoptosis mechanisms involved in the elimination of damaged cells in normal physiological processes are abnormally activated in Alzheimer's disease, accelerating neuron loss and leading to cognitive impairment [ 135 ]. In particular, it has been stated that various factors such as reactive species (ROS/RNS), nitrated proteins, Bax, Caspase‐9, and p55 affect the disruption of the apoptosis process. The authors highlight the significance of Caspase‐9 activation in the mitochondrial apoptosis pathway, as well as the activation of Caspase‐3 (an effector caspase) and p55 (a component of the tumor necrosis factor receptor) as critical modulators leading to neuronal apoptosis [ 134 ]. In a study by Buizza et al., OS biomarkers were examined to investigate the progression of AD and the association between changes in the tertiary structure of the p53 protein and oxidative imbalance. Immortalized B lymphocytes obtained from patients with early‐onset AD and those with ADmut mutation were utilized in the investigation. Both patient groups exhibited increased expression of unfolded and nitrated p53, along with decreased activity of SOD, GPx, and GRD enzymes, which are indicative of antioxidant capacity. Notably, 4‐hydroxynonenal and 3‐nitrotyrosine (3‐NT) OS marker levels were significantly elevated in the ADmut mutation patient group. These results indicate that alterations in the conformation of the redox‐sensitive p53 protein are closely associated with oxidative/nitrosative stress. Accordingly, unfolded p53 may be an early marker for oxidative/nitrosative damage and apoptosis in AD [ 136 ].

Studies on the treatment of AD have predominantly centered around investigating its etiology, progression, and pathogenesis. Various factors, including inflammation, ROS/RNS, and apoptosis, have significantly influenced the disease progression by promoting the abnormal build‐up of Aβ plaques and tau proteins. As a result, medications aimed at mitigating ROS/RNS generation and modulating apoptosis hold promise in alleviating the symptoms associated with AD.

The Nitric Oxide/Nitric Oxide Synthase System in the Pathogenesis of Parkinson's Disease (PD)

Parkinson's disease (PD) is a prominent age‐related neurodegenerative disease characterized by the loss of dopaminergic neurons, accumulation of Lewy bodies, and hypertrophy of the subthalamic nucleus [ 137 ]. While clinical symptoms of PD have been described, the underlying biological processes contributing to disease progression are not fully understood [ 138 ]. Although the mechanisms of neuronal loss and the accumulation of alpha‐synuclein protein in PD are not fully elucidated, various evidence, including mitochondrial dysfunctions, mitochondrial bioenergetic crisis, dopamine oxidation, neuroinflammation, gene polymorphisms, and environmental factors, suggests that endogenous factors may contribute to the loss of dopaminergic neurons [ 139 , 140 , 141 ].

Studies have suggested that NO, synthesized by neuronal Nitric oxide synthase, exerts opposing effects through neuroprotective or neurodegenerative mechanisms in PD. Experimental animal and cell studies have highlighted the benefits of low doses of NO, which improve motor functions by increasing dopamine release and enhancing blood flow to the brain through its vasodilating effect [ 142 , 143 , 144 ]. Moreover, experimental evidence suggests that physiological concentrations of NO exhibit neuroprotective properties [ 145 ]. Physiological levels of NO can react with endogenously produced oxidant compounds, converting them into harmless nitrites and nitrates and potentially reducing the harmful effects of cellular ROS [ 146 ]. The distribution of NOS in the brain is closely associated with dopaminergic neuronal pathways, proposing that NO plays a critical role in regulating its role in the dopaminergic system [ 147 , 148 , 149 ] (Figure 5 ). It has been proposed that NO may slow down ROS generation by regulating uncontrolled oxidative reactions, thereby delaying neuronal death and postponing the onset of dopaminergic cell death [ 146 , 150 , 151 ]. Consequently, NO has been suggested as a possible molecular target for halting the progression of PD.

The alternative perspective suggesting that NO has a neurodegenerative effect on the brain has been thoroughly examined based on evidence from post‐mortem examinations, clinical observations, and experimental models [ 152 ]. Böckelmann et al. analyzed the putamen regions of post‐mortem brains from patients with PD and control subjects to explore the involvement of NO in the mechanisms underlying PD pathology. Their study revealed a significant decrease in the proportion of neurons stained positively with the nicotinamide adenine dinucleotide phosphate (NADPH)‐diaphorase technique in PD brains, indicating the involvement of NO and NOS positive elements in degenerative processes in PD [ 153 ]. Hunot et al. conducted an immunohistochemical analysis of NOS isoforms involved in NO production and NADPH‐diaphorase activity in mesencephalic tissue samples from PD patients. The findings demonstrated a proliferation in NADPH‐diaphorase‐positive glial cell density in dopaminergic cell groups, and the presence of NOS‐expressing glial cells was directly correlated with the loss of dopaminergic neurons in PD [ 154 ]. Levecque et al. performed a case‐control study investigating the association between polymorphisms in the inducible NOS and neuronal NOS genes and PD. Three variants were identified in exon 29, exon 18, and exon 22 of nNOS and iNOS, respectively. The study highlighted that these variants may impact the progression of PD by altering the structure of the encoded proteins and rendering individuals more susceptible to the disease [ 155 ]. Aras et al. utilized nNOS and NOS inhibitors, 7‐Nitroindazole and S‐methylisothiourea, to examine their impacts on dopaminergic neurons in an animal model of PD induced by MPTP. The study reported that these inhibitors reduced PD‐associated symptoms such as dopaminergic cell death and impaired motor activity while also decreasing the levels of oxidized forms of NO, such as nitrate/nitrite [ 156 ].

Furthermore, it has been documented that NOS inhibitors, when administered in conjunction with antioxidants, may attenuate dopaminergic neuron damage in the substantia nigra and slow the progression of PD [ 157 , 158 , 159 ]. Broom et al. investigated the impact of the iNOS inhibitor GW27415022 on microglial activation in an animal model of PD induced by 6‐OHDA. The study indicated that the iNOS inhibitor decreased nigrostriatal dopaminergic neurons, reduced reactive microglia and MMP‐9 immunopositive cells, and mediated neuroprotection. These findings suggest that iNOS inhibitors could serve as a therapeutic approach for PD by mitigating the adverse effects of NO on dopaminergic neurons and inflammation [ 160 ].

Numerous investigations have extensively studied the effects of NO and NOS on the physiological system and thoroughly investigated their role in the pathophysiology of neurodegenerative disorders. It has been emphasized that this gasotransmitter system plays a crucial role in the beginning and progression of PD, indicated by the reduced survival of dopaminergic neurons.

Generation of ROS/RNS and Apoptosis in the Pathogenesis of Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by movement disorders and primarily associated with the deterioration of dopaminergic neurons and a reduction in brain dopamine levels [ 152 ]. Although the molecular mechanisms underlying neuronal degeneration have not been completely elucidated, it is believed that oxidative stress, caused by an increase in free radicals, is one of the potential mechanisms triggering apoptosis in nerve cells. Research has demonstrated that the superoxide (O 2 •− ) anion and NO damage nervous tissue through the formation of reactive compounds like hydrogen peroxide (H 2 O 2 ) and peroxynitrite (ONOO − ), which are produced during the process of oxidative/nitrosative stress (OS/NS), leading to damage in substantia nigra neurons [ 161 , 162 ]. Therefore, the development of PD is associated with increased OS/NS and the induction of apoptosis within the brain. Reactive oxygen species/reactive nitrogen species have been reported to disrupt the function of the mitochondrial respiratory chain, leading to apoptosis and subsequent neuronal cell death [ 163 , 164 ]. Nunes et al. reported that NO and dopamine metabolism affect mitochondrial functions that regulate cellular energy production. ROS/RNS production interferes with the electron transport chain's complex I and IV functions, causing mitochondrial dysfunction. They also reported that increased nitroxidative stress, decreased levels of Glutathione (GSH), and mitochondrial dysfunction might influence dopamine metabolism through a common mechanism of neurodegeneration, ultimately contributing to cell death [ 165 ].

ROS and RNS play a role in apoptosis by activating caspases, increasing p53 expression, and causing DNA damage in different cell types. Several mechanisms are essential in regulating apoptosis, including ROS‐mediated oxidative modifications, NO‐mediated S‐nitrosylation, and DNA oxidation‐mediated caspase activation [ 166 , 167 ]. The catalytic site of the caspase enzyme contains cysteine, which can undergo nitrosylation or nitration when it interacts with NO derivatives. This interaction reorganizes the enzyme's activity and functions [ 168 ]. Both NO and H 2 O 2 have been shown to modulate caspase activity in apoptosis through death receptor‐dependent and receptor‐independent pathways. However, the specific mechanisms by which reactive radical compounds contribute to apoptosis induced by automatic procaspase‐8 activation and direct caspase‐9 activation have yet to be fully explored [ 88 , 147 , 168 , 169 ]. Research suggests that reactive nitrogen compounds may play a significant role in dopaminergic neuron degeneration by contributing to OS and initiating apoptosis through various mechanisms [ 147 ]. The parkin protein is known to support the health of nerve cells in neurodegenerative diseases. However, it has been discovered that oxidative posttranslational modifications of parkin can lead to neuronal cell death and neurodegeneration by upregulating p53 gene expression. Sunico and colleagues have reported that S‐nitrosylation of parkin protein results in p53‐mediated neuronal cell death, contributing to sporadic PD progression [ 170 ]. Additionally, their study has found a correlation between increased expression levels of nitrosylated parkin (SNO‐parkin) and p53 in the brains of postmortem PD patients, highlighting the critical role of reactive nitrogen species in the pathogenesis of PD [ 170 ].

The mechanisms underlying DNA damage induction and repair inhibition are actively being investigated in initiating apoptosis triggered by ROS and RNS. Studies examining the pathogenesis of PD have reported that 6‐hydroxydopamine affects p53 and DNA damage repair pathways, activates the unfolded protein response (UPR) and OS pathways, triggers the release of cytochrome‐c from mitochondria, activates modulator caspases, and induces ROS‐induced apoptosis in dopaminergic cells [ 171 , 172 ]. ROS and RNS species may contribute to the progression of PD pathology by directly interacting with DNA, inhibiting DNA repair mechanisms, or increasing the production of genotoxic species [ 147 ]. Mandir et al. reported that nuclear proteins dependent on NO in substantia nigra neurons affect DNA repair mechanisms through PARP activation in an animal model of PD induced by MPTP [ 173 ]. Studies have shown that oxidative/nitrosative DNA lesions, especially 8‐oxoguanine and 8‐nitroguanine, may accumulate in nuclear and mitochondrial genomes during aging. These lesions compromise the integrity of single‐stranded DNA by causing increased oxidative damage to nucleic acids. DNA strand damage leads to indirect effects such as the activation of PARP, a nuclear enzyme that can stimulate p53 and promote apoptosis, the process of cellular death [ 147 , 173 , 174 ].

Although the etiology of PD is not entirely comprehended, factors such as ROS, RNS, DNA damage, and mitochondrial dysfunction, which increase due to genetic and environmental influences during the aging process, are considered the main mechanisms that accelerate the death of dopaminergic neuronal cells. Therefore, research suggests that comprehending the molecular mechanisms involved in the genesis and progression of PD may provide insights into potential strategies for preventing or treating the disease.

The Nitric Oxide/Nitric Oxide Synthase System in the Pathogenesis of Multiple Sclerosis

Multiple sclerosis (MS) is widely recognized as a chronic autoimmune disease impacting the central nervous system (CNS), with a solid correlation to demyelination [ 175 ]. In this pathological process, the immune system initiates an autoimmune response against the myelin sheath surrounding nerve fibers—this and inflammation damage myelin‐associated proteins, impaired nerve communication, and cognitive impairment [ 176 ]. Consequently, white and gray matter lesions can manifest within the brain and spinal cord. Although autoimmune reactions are the primary cause of this condition, factors such as inflammation, oxidative and nitrosative stress (OS and NS) are believed to be initiating factors for this immune response [ 177 ].

NO is a crucial signaling molecule produced by various cell types in the CNS system, including neurons, astrocytes, and microglia [ 108 ] (Figure 5 ). However, studies have shown that elevated NO and peroxynitrite (ONOO − ) production levels contribute to neurotoxic effects in MS [ 178 ]. Two recent meta‐analyses examined the relationship between NO levels and metabolites in MS patients and the disease stage [ 177 , 179 ]. Förster et al. compared nitrate/nitrite levels in serum and cerebrospinal fluid (CSF) samples from MS patients, patients with other neurological disorders, and healthy controls. The meta‐analysis findings revealed increased levels of NO and its metabolites in the CSF and plasma of MS patients, suggesting that NS molecules could serve as potential biomarkers for MS [ 179 ]. In another meta‐analysis by Silva et al., the relationship between NO and metabolite levels in the relapse/remission stages of MS patients and their disability status was investigated. The study confirmed that nitrite/nitrate levels were directly proportional to the disease stage in MS patients, as evaluated by the extended disability status scale [ 177 ]. Fominykh et al. explored the association between spinal cord lesions and NS metabolites in different MS subtypes. The study reported increased NOX levels in relapsing‐remitting MS patients, while S‐nitrosothiol concentrations increased in both relapsing‐remitting and secondary progressive MS patients. S‐nitrosothiol levels were closely related to spinal cord damage [ 180 ]. Liu et al. conducted a comprehensive investigation to determine which cell types induce iNOS in MS lesions, the relationship between iNOS and blood‐brain barrier (BBB) damage, and the distribution of ONOO − in active MS lesions using postmortem tissues from MS patients. The results revealed increased NO metabolism in various cell types, including astrocytes, microglia, and endothelial cells, in progressive MS lesions. The study also observed elevated iNOS mRNA and protein expression and increased nitrotyrosine immunoreactivity in most MS lesions.

Moreover, considering the proximity of astrocytes to the BBB, the study suggested that increased levels of astrocyte‐derived iNOS and NO might regulate inflammatory responses and contribute to BBB damage [ 181 ]. Acar et al. assessed the utility of NO as an indicator of disease activity by measuring nitrite and nitrate levels in CSF and serum samples from MS patients during relapse and remission periods. The study reported a correlation between increased levels of NO metabolites and the IgG index and active lesions detected by brain magnetic resonance imaging (MRI). These findings suggest that the elevation of NO may play a significant role in the pathogenesis of MS [ 182 ].

Numerous studies have investigated serum/plasma samples, CSF, and postmortem tissue samples to gain insights into the intricate connection between NO metabolites and iNOS levels in MS pathophysiology. Furthermore, meta‐analyses have been conducted to assess the association between NO metabolites and disability and the relapse/remission phases of the disease through comprehensive reviews of the existing literature. The research on the involvement of NO in MS and autoimmune response supports novel therapeutic approaches that aim to inhibit NO production in the treatment of MS.

ROS/RNS Generation and Apoptosis in the Pathogenesis of Multiple Sclerosis

The neuropathological findings of multiple sclerosis are strongly associated with inflammatory demyelination and damage to the axons in the central nervous system (CNS). These findings encompass demyelinating lesions, loss of oligodendrocytes, periventricular lesions, degeneration of axons, and neuronal loss [ 183 ]. Various observations indicate that mitochondrial dysfunction, the overproduction of ROS/RNS, and the upregulation of p53 are closely linked to the destruction of myelin and the loss of oligodendrocytes in MS [ 183 , 184 ] (Figure 5 ). Although ROS and RNS are generated in different organelles within the cells through various mechanisms, mitochondria are considered the direct source of these species and the central regulators of cell viability. Consequently, antioxidants that suppress oxidative/nitrative stress (OS/NS) and counteract reactive species demonstrate beneficial effects with the potential to mitigate the formation of lesions in MS [ 185 , 186 ].

In oligodendrocytes, mitochondrial energy is utilized for lipid synthesis, which plays a crucial role in forming the myelin sheath. However, mitochondrial damage induced by ROS and RNS can disrupt energy metabolism in oligodendrocytes. This contributes to the initiation of demyelination processes, oligodendrocyte death, and, ultimately, the progression of MS pathogenesis [ 187 ]. Particularly, mitochondrial DNA (mtDNA) plays a significant role in various mitochondrial signaling pathways associated with cellular energy homeostasis, mitochondrial respiratory chain activity, and apoptosis of neurons and oligodendrocytes in MS [ 178 , 188 ]. To uncover the role of mtDNA deletions in the pathogenesis of MS, Graham et al. examined cerebral cortex and subcortical white matter samples from patients with secondary progressive MS. They discovered the presence of multiple mtDNA deletions and defects in complex IV/complex II‐mediated mitochondrial respiratory chain activity. These findings prove that mtDNA deletions result in neurons with respiratory deficiency, leading to the loss of neurological function in MS [ 188 ]. Dutta et al. investigated mitochondrial respiratory functions and axon degeneration by examining the motor cortex of postmortem MS patients. They detected decreased mitochondrial gene expression and reduced functional activity of complexes I and III in the MS cortex. The decrease in mitochondrial ATP production and cell viability contributed to the demyelination of motor neuron axons in MS patients [ 189 ]. Fischer et al. studied the formation of oxidative and nitrosative reagents for developing the demyelination process in MS. They assessed the expression levels of genes and proteins involved in mitochondrial function and ROS/RNS formation in lesion samples obtained from MS patients. They demonstrated that potential tissue damage in MS is initiated as a result of increased oxidative damage in activated microglia and macrophages, and the NOX complex and related proteins are implicated in this process. They determined that oxidative/nitrosative damage disrupts mitochondrial respiratory chain functions, causing cellular energy deficiency and accelerating the demyelination process in MS by increasing ROS and RNS production [ 190 ]. Mitochondrial energy deficiency, an essential component of neurodegeneration observed in MS, and the production of oxygen/nitrogen radicals in activated microglia impact the course of the disease by promoting inflammatory response in nervous tissue and accelerating myelin degeneration [ 191 ]. Given the significant role of OS/NS and mitochondrial dysfunction in the pathogenesis of MS, mitochondria‐targeted antioxidant therapies have been investigated to prevent neuronal cell death [ 192 , 193 ]. Mao et al. explored the beneficial effects of MitoQ on inflammation and OS mechanisms in an experimental encephalomyelitis mouse model that reflects MS symptoms. The study highlighted that MitoQ treatment exhibited protective effects on neurons by inhibiting axonal inflammation, reducing OS, and decreasing neuronal cell loss [ 194 ].

In the literature, MS mechanisms have been supported by studies investigating both internal and external apoptotic pathways, OS/NS, and mitochondrial energy deficiency. Wosik and colleagues conducted a study investigating the effects of Fas and TRAIL‐mediated apoptosis signaling on p53‐driven cell death in human oligodendrocytes. They discovered that Fas and TRAIL ligands were present in the inflammatory media of active MS lesions, and there was an increase in p53 expression in lesions where cell loss was observed. This increase in p53 expression induced caspase cascade‐mediated apoptosis by triggering the upregulation of Fas, DR4, and DR5 in oligodendrocytes [ 195 ].

Kuhlmann et al. examined the relationship between apoptosis‐related oligodendrocyte loss and sequence variations in Bax, Bcl‐2, Bcl‐x, and p53 proteins in MS patients. They analyzed the sequences to compare the genetic differences in these proteins, which regulate apoptosis, between relapsing‐remitting MS patients and healthy controls. Spesific polymorphisms were found in the p53 and Bax genes in the patient group, and it was reported that these polymorphisms may affect susceptibility to MS [ 196 ].

Hagman et al. investigated the potential of molecules associated with apoptosis as predictive markers in the progressive stages of MS. They analyzed the gene profile of relapsing‐remitting MS patients and observed an increase in the expression of proapoptotic genes such as BAD, BIK, BCLG, BOK, FADD, PUMA, and TNFRSF25. They also found increased expression levels of the CASP1 gene associated with the caspase cascade. Additionally, they reported increased expression levels of genes belonging to the NF‐κB family, which promote inflammation and weaken antioxidant defense. The study highlighted that intrinsic proapoptotic mechanisms play a significant role in relapsing‐remitting MS, and proapoptotic markers may help monitor MS development [ 197 ].

In summary, various studies have substantiated the active involvement of apoptotic transcripts, as well as proteins and enzymes associated with ROS and RNS, in the demyelination and neurodegeneration processes underlying the pathogenesis of MS. Numerous investigations have demonstrated the correlation between OS mechanisms, mitochondrial damage, neuronal and oligodendrocyte cell loss, and myelin and tissue damage during the progression of MS. Oxidative and nitrosative compounds are known to disrupt mitochondrial membrane integrity and respiratory chain function, thereby depleting cellular energy and triggering the activation of signal transduction pathways related to apoptosis. Consequently, these studies emphasize the significance of neuroprotective therapies that enhance endogenous antioxidant enzyme levels or mitigate demyelination, as they may serve a crucial role in thwarting oxidative damage in patients with MS.

Nitric Oxide/Nitric Oxide Synthase System in the Pathogenesis of Amyotrophic Lateral Sclerosis and Huntington's Disease

Amyotrophic lateral sclerosis (ALS) is a disease described by pathological brain and spinal cord processes, including neuronal damage, abnormal protein accumulation (such as TDP‐43 and FUS), and excessive activation of astrocytes and microglia [ 198 ]. Genetic factors and mutations have also been implicated in ALS. Specifically, ALS's most common genetic mutation affects the SOD1 gene [ 199 ]. Mutations in SOD1 disrupt the normal function of this enzyme, which is involved in cellular antioxidant activity, making the cell susceptible to reactive species. SOD1 mutations can enhance inflammatory responses, activate iNOS, and increase the production of NO (Figure 5 ). This accelerates the progression of ALS by causing neurotoxicity and neurodegeneration of motor neurons [ 198 , 200 ]. Studies supporting this hypothesis have been conducted in ALS patients and animal models of ALS. Beckman et al. reported that SOD1 mutations observed in familial ALS patients reduce the capacity of neurons to scavenge superoxide (O 2 •− ), resulting in increased formation of peroxynitrite (ONOO − ) and elevated levels of nitration in cellular targets [ 201 ]. Chen et al. linked the buildup of SOD1 aggregates in mutant SOD1 transgenic mice to the generation of reactive nitrogen species (RNS) and the S‐nitrosylation of protein disulfide isomerase (PDI). They reported that the increase in iNOS and NO levels during the disease led to increased S‐nitrosylation of PDI, and this increase in reactive nitrogen compounds contributed to the accumulation of mutant SOD1 aggregates in ALS [ 202 ]. Lewis et al. investigated the expression of Arginase 1 and iNOS in microglial changes from the early symptomatic period of the disease to advanced stages in mouse spinal cord samples carrying the mutant SOD transgene. They suggested that Arginase 1 and iNOS showed increased expression in microglia as the disease progressed and that evaluating the cytokine profile could provide a deeper understanding of the Arginase 1/iNOS balance in motor neurons [ 199 ].

Huntington's disease (HD) is a fatal genetic neurodegenerative disorder characterized by an uncommon development of the CAG repeats of the HTT gene [ 203 ]. While the evidence supporting the role of iNOS‐mediated NO production mechanisms in disease pathology in HD is not as conclusive as in other neurodegenerative diseases, several mechanisms have been suggested to describe the involvement of the NO molecule in HD's neurodegenerative process [ 198 ]. One such mechanism is the increased release of glutamate at synapses, which is linked to the excitotoxic effect of glutamate and the heightened nitrosative/oxidative damage caused by nNOS [ 203 ]. Another hypothesis suggests that NO may be neuroprotective in the initial phase of HD but can have neurotoxic effects as the disease progresses. Studies supporting this hypothesis indicate that reduced nNOS activity may indicate neuroprotective properties of NO, whereas increased nNOS activity may contribute to neurodegeneration [ 204 ]. Additionally, it has been reported that enhancing the availability and antioxidative effects of NO in HD may hinder the progressive neurodegenerative process, particularly by inhibiting ONOO − production [ 203 ]. These findings suggest that manipulating NO levels could potentially be a strategy for disease management in HD.

In conclusion, the intricate nature of the biological effects of NO necessitates further investigations to explore the stimulation or inhibition of different aspects of NO‐dependent mechanisms in diseases like ALS and HD and gain a deeper understanding of disease progression.

ROS/RNS Generation and Apoptosis in the Pathogenesis of Amyotrophic Lateral Sclerosis and Huntington's Disease

The etiology of amyotrophic lateral sclerosis is highly complex, with the SOD1 mutation standing out prominently [ 205 ]. The SOD1 mutation leads to the accumulation of superoxide (O 2 •− ) and peroxynitrite (ONOO − ) radicals, causing oxidative and nitrosative stress and damage to cellular macromolecules. Additionally, this mutation disrupts cellular redox homeostasis by allowing other substrates to enter the active site of the SOD1 enzyme [ 206 ]. Due to the accumulation of radicals, the resulting stress environment leads to abnormalities in energy metabolism, ATP production in mitochondria, and the modulation of apoptosis [ 207 ]. In the context of ALS, the SOD1 mutation is suggested to directly trigger the generation of ROS, RNS, and mitochondrial dysfunction. Turner et al. reported increased biochemical markers indicating oxidant damage to proteins, lipids, and DNA in postmortem tissue samples from sporadic and SOD1‐related familial ALS patients [ 208 ]. Another study by Chang et al. focused on transgenic mutant SOD1 mice using postmortem tissue samples from ALS patients. This study revealed that mRNA oxidation was a common mechanism in both subject groups. Changes in the expression of specific proteins corresponding to oxidized mRNA species have been linked to motor neuron impairment in ALS [ 209 ]. In a study on mutant SOD1 transgenic mice to understand the pathophysiology of ALS, Martin et al. examined the fundamental mechanisms of motor neuron toxicity. The study demonstrated the role of factors such as mitochondrial toxicity, NO production, and ONOO − in the pathophysiological processes of ALS. Observations have shown that motor neuron degeneration is associated with activating p53 and p73 and abnormalities in mitochondrial enzymes. The higher levels of oxidative/nitrosative reagents and protein nitration in motor neurons of mutant SOD1 mice compared to the control group suggest that mitochondrial pathology and OS/NS contribute to neurodegeneration caused by the SOD mutation [ 207 ]. Another experimental animal model study examined the effects of the Fas death receptor pathway and oxidative/nitrosative damage on motor neuron apoptosis. Motor neurons were protected from apoptosis in mice lacking the Fas receptor and ligand. However, after neuronal injury, an increase in Fas protein levels dependent on p53 and induction of apoptosis through caspase‐8 activation were observed. Furthermore, increased levels of NOS and DNA damage mediated by NO and O 2 •− were detected in mice carrying mutant SOD1. These findings suggest that the Fas receptor‐mediated death pathway and NOS mechanisms are essential in apoptosis‐mediated neurodegeneration [ 210 ].

Numerous studies have extensively investigated the association between caspase activation and neurodegenerative processes in Huntington's disease (HD). It has been observed that the activation of caspases and the accumulation of nuclear Huntingtin protein in the brains of HD patients contribute to neuropathological changes [ 211 , 212 , 213 , 214 , 215 ]. An increase in the active form of caspase‐3 has been identified in astroglial cells during both early and advanced stages of HD [ 213 ]. These findings have laid the groundwork for exploring the potential utilization of different caspase activations as markers of HD and their correlation with disease progression. Investigations conducted on human subjects and in vivo HD models have demonstrated that the increased activated caspase‐3 is evident in early and advanced HD patients. However, it has been reported that caspase‐6 activation precedes the onset of motor abnormalities in the early stages of HD pathogenesis, occurring even before caspase‐3 activation [ 214 ]. These findings indicate that caspase‐6 might have an essential function in the early stages of HD [ 214 , 215 ].

Furthermore, one of the possible mechanisms of toxicity caused by mutant Huntington's protein involves alterations in the activity of transcription factors that regulate apoptosis and neurogenesis. Wetzel et al. focused on these alterations and proposed that changes in the activity of factors such as p53 and CREB‐binding protein might have a crucial role in the pathogenesis of HD [ 216 ]. Considering that p53 influences genes involved in mitochondrial functions, it has been suggested that elevated levels of p53 may lead to enhanced expression of Bax and Puma, resulting in mitochondrial dysfunction and neuronal loss [ 216 , 217 ].

At the cellular level, protein aggregation, impaired mitochondrial mechanisms, and oxidative/nitrosative damage contribute to HD, a polyglutamine disorder [ 218 ]. In HD, the mechanisms, such as CAG repeat sequences in the Huntington gene causing abnormal protein elongation and increased nerve cell stress sensitivity to free radical levels, underlie possible toxic effects [ 219 ] (Figure 5 ). Hands et al. investigated the causal relationship between cellular protein aggregation, OS, and neurotoxicity by studying HD models in vitro and in vivo. It was reported that protein aggregation leads directly to free radical production, and the increase in ROS is associated with an increase in toxic polyglutamine oligomers. Maintaining redox homeostasis in HD has been shown as a potential target for treating polyglutamine disorders [ 220 ]. Siddiqui et al. investigated the mechanisms of development of mitochondrial dysfunctions in postmortem striatal samples of HD and in the STHdhQ111 and STHdhQ7 in vitro striatal model depending on the levels of oxidative damage. It was reported that increased mitochondrial ROS and mitochondrial DNA lesions indicated OS and impaired bioenergetically mediated damage in HD [ 221 ]. Furthermore, NS and mitochondrial dysfunctions have been reported as critical factors for developing neuropathological mechanisms and neuronal cell death in HD [ 222 , 223 ].

Overall, previous studies in postmortem tissues, in vivo animal models, and cultured neurons have consistently shown that ROS, RNS, and apoptotic cascades play a crucial role in neuronal deterioration. The association of nitroxidative damage with apoptosis in ALS and HD has been reported to be multifaceted, triggering the neurodegeneration process through genetic mutations, mitochondrial dysfunction, and macromolecular disorders.

Innovative and Potential Approaches in the Treatment of Neurodegenerative Diseases

Recently, approaches have been proposed to treat neurodegenerative diseases by targeting key neuropathology dynamics involved in disease pathology, such as abnormal protein accumulation, genetic mutations, inflammation, impaired bioenergetics, oxidative stress, and mitochondrial dysfunction [ 224 , 225 ]. In this direction, significant innovations and improvements have been made in targeted protein digestion techniques, antisense oligonucleotides, RNA interference technologies, tandem affinity systems, and stem cell‐based treatment models [ 226 ]. As a result of many years of research by scientists, drugs such as Aduhelm (aducanumab), Lecanemab, Riluzole, and Edaravone have been introduced into clinical use as therapeutic options. Among these therapeutic options, Aduhelm (aducanumab) and Lecanemab are antibodies targeting β‐amyloid aggregates and oligomers in Alzheimer's disease [ 227 ]. Riluzole effectively delays motor neuron death in ALS by reducing synaptic glutamate accumulation [ 228 ]. In addition, antisense drug development is ongoing for genes encoding Tau, LRRK2, HTT, and SOD1 proteins [ 226 ].

In addition to targeting specific proteins and genes, targeting mitochondria has also been evaluated as a potential therapeutic strategy in treating neurodegenerative diseases [ 4 ]. Neurons with high energy requirements are exposed to ROS accompanying energy production, as they meet this need primarily through mitochondrial oxidative phosphorylation. Therefore, to reduce mitochondrial stress and ROS levels, using antioxidants that suppress mitochondria‐induced oxidative stress production has been an alternative to suppressing neurodegeneration. In particular, drugs and lipogenic antioxidants that neutralize free radicals and promote mitochondrial biogenesis, such as Edaravone (Radicava), MitoTEMPOL, CoQ10, MitoQ, MitoApocynin, SkQ1, MitoSOD, MitoVitE, and EPI‐589 show neuroprotective effects [ 225 , 229 , 230 ]. Among these, Edaravone (Radicava) was approved by the Food and Drug Administration (FDA) in 2017 and included in clinical applications in line with its effects on slowing the loss of motor function in ALS patients [ 230 ]. In clinical studies, Ederavone was reported to increase overall survival in ALS patients by reducing oxidative stress and preventing neuronal damage [ 231 ]. In phase I and II studies on the tolerability and clinical benefits of CoQ10 in Parkinson's disease patients, CoQ10 was reported to provide clinical benefits by demonstrating a safety and tolerability profile [ 232 ]. However, in phase III studies, it was reported that it did not have the potential to change the progression of the disease [ 233 , 234 ]. The safety, tolerability, and pharmacokinetic profiles of EPI‐589, which stands out with its radical scavenging activity, were evaluated, and in line with the findings obtained, it was suggested that it could be a potential treatment for ALS patients [ 235 ]. In addition, it was revealed that the percentage of oxidized/total coenzyme Q (CoQ) was associated with the early stage of Alzheimer's disease (AD) pathogenesis by analyzing cerebrospinal fluid (CSF) samples of patients with AD [ 236 ]. In another randomized clinical trial, patients with Alzheimer's disease were given coenzyme Q, α‐tocopherol, vitamin C, and α‐lipoic acid daily for 16 weeks (E/C/ALA), and it was reported that E/C/ALA treatment reduced the oxidative stress levels of CSF [ 237 ]. These studies reveal that improving oxidative stress, redox imbalance, and pathological processes in mitochondrial energy metabolism are promising in treating neurodegenerative diseases.

Identifying molecular targets that regulate mitochondrial dynamics and developing pharmacological agents that interfere with oxidative stress mechanisms are emerging as an innovative strategy for treating neurodegenerative diseases [ 226 ]. Although current studies have shown promising results for these agents, it has been emphasized that their dose–response relationships and pharmacokinetic and pharmacodynamic properties should be studied in detail in vivo and in vitro environments to understand their neuroprotective effects better [ 238 ]. It has been reported that determining the most appropriate dose regimens and pharmacokinetic effects in preclinical applications will play an important role in formulating clinical treatment strategies [ 238 ]. Accordingly, more comprehensive studies evaluating the clinical efficacy of neuroprotective agents targeting mitochondrial biogenesis and ROS‐related mechanisms will contribute to developing future treatment protocols.

Conclusion

This review presents a comprehensive analysis of oxidative stress, nitrosative stress, redox signaling, mitochondrial targets, and apoptosis induction in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Amyotrophic lateral sclerosis, and Huntington's disease. The evidence gathered strongly supports the notion that neurophysiological systems regulate the survival or demise of brain cells through the influence of various molecules, including ROS, RNS, caspases, apoptotic proteins, and mitochondrial effectors. The accumulation of oxygen/nitrogen‐derived free radicals and the disruption of redox balance are directly linked to the activation of apoptotic signaling pathways. This phenomenon is believed responsible for the clinical heterogeneity observed in different neurodegenerative diseases, influencing genetic interactions and the accumulation of disease‐specific proteins. Given that ROS and RNS play a pivotal role in redox signaling and contribute to neurological cell death, there is increasing interest in understanding redox mechanisms and exploring novel neurotherapeutic strategies for the future.

Author Contributions

Nuray Üremiş conceived and designed the review. Nuray Üremiş and Muhammed Mehdi Üremiş wrote the manuscript and drawn pictures. Both authors contributed to this manuscript and approved the submitted version.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

This research was supported by the Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (grant number: TUB1).

Data Availability Statement

The authors have nothing to report.

References

1. Mayne K., White J. A., McMurran C. E., Rivera F. J., and de la Fuente A. G., “Aging and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe?,” Frontiers in Aging Neuroscience 12 (2020): 572090.

2. Fereshtehnejad S. M., Vosoughi K., Heydarpour P., et al., “Burden of Neurodegenerative Diseases in the Eastern Mediterranean Region, 1990‐2016: Findings From the Global Burden of Disease Study 2016,” European Journal of Neurology 26, no. 10 (2019): 1252–1265.

3. Rekatsina M., Paladini A., Piroli A., Zis P., Pergolizzi J. V., and Varrassi G., “Pathophysiology and Therapeutic Perspectives of Oxidative Stress and Neurodegenerative Diseases: A Narrative Review,” Advances in Therapy 37, no. 1 (2020): 113–139.

4. de la Fuente A. G., Pelucchi S., Mertens J., Di Luca M., Mauceri D., and Marcello E., “Novel Therapeutic Approaches to Target Neurodegeneration,” British Journal of Pharmacology 180, no. 13 (2023): 1651–1673.

5. Kumar A. and Singh A., “A Review on Mitochondrial Restorative Mechanism of Antioxidants in Alzheimer's Disease and Other Neurological Conditions,” Frontiers in Pharmacology 6 (2015): 206.

6. Watts M. E., Pocock R., and Claudianos C., “Brain Energy and Oxygen Metabolism: Emerging Role in Normal Function and Disease,” Frontiers in Molecular Neuroscience 11 (2018): 216.

7. Natarajan S. K. and Becker D. F., “Role of Apoptosis‐Inducing Factor, Proline Dehydrogenase, and NADPH Oxidase in Apoptosis and Oxidative Stress,” Cell Health Cytoskeleton 2012, no. 4 (2012): 11–27.

8. Steinert J. R., Chernova T., and Forsythe I. D., “Nitric Oxide Signaling in Brain Function, Dysfunction, and Dementia,” The Neuroscientist 16, no. 4 (2010): 435–452.

9. Cobley J. N., Fiorello M. L., and Bailey D. M., “13 Reasons Why the Brain Is Susceptible to Oxidative Stress,” Redox Biology 15 (2018): 490–503.

10. Picón‐Pagès P., Garcia‐Buendia J., and Muñoz F. J., “Functions and Dysfunctions of Nitric Oxide in Brain,” Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease 1865, no. 8 (2019): 1949–1967.

11. Üremiş M. M., Gültekin S., Üremiş N., et al., “Protective Role of Vitamin E Against Acrylamide‐Induced Testicular Toxicity From Pregnancy to Adulthood: Insights Into Oxidative Stress and Aromatase Regulation,” Naunyn‐Schmiedeberg's Archives of Pharmacology 397, no. 2 (2024): 829–841.

12. Iova O. M., Marin G. E., Lazar I., et al., “Nitric Oxide/Nitric Oxide Synthase System in the Pathogenesis of Neurodegenerative Disorders‐An Overview,” Antioxidants 12, no. 3 (2023): 753.

13. Bhat A. H., Dar K. B., Anees S., et al., “Oxidative Stress, Mitochondrial Dysfunction and Neurodegenerative Diseases; A Mechanistic Insight,” Biomedicine & Pharmacotherapy 74 (2015): 101–110.

14. Singh A., Kukreti R., Saso L., and Kukreti S., “Oxidative Stress: A Key Modulator in Neurodegenerative Diseases,” Molecules 24, no. 8 (2019): 1583.

15. Valko M., Leibfritz D., Moncol J., Cronin M. T. D., Mazur M., and Telser J., “Free Radicals and Antioxidants in Normal Physiological Functions and Human Disease,” The International Journal of Biochemistry & Cell Biology 39, no. 1 (2007): 44–84.

16. Ghezzi P., Jaquet V., Marcucci F., and Schmidt H. H. H. W., “The Oxidative Stress Theory of Disease: Levels of Evidence and Epistemological Aspects,” British Journal of Pharmacology 174, no. 12 (2017): 1784–1796.

17. Weidinger A. and Kozlov A., “Biological Activities of Reactive Oxygen and Nitrogen Species: Oxidative Stress Versus Signal Transduction,” Biomolecules 5, no. 2 (2015): 472–484.

18. Akbulut S., Uremis M. M., Sarici K. B., et al., “Measurement of Oxidant and Antioxidant Levels in Liver Tissue Obtained From Patients With Liver Transplantation: A Case‐Control Study,” Transplant Immunology 75 (2022): 101697.

19. de Almeida A. J. P. O., de Oliveira J. C. P. L., da Silva Pontes L. V., et al., “Ros: Basic Concepts, Sources, Cellular Signaling, and Its Implications in Aging Pathways,” Oxidative Medicine and Cellular Longevity 2022 (2022): 1–23.

20. Porasuphatana S., Tsai P., and Rosen G. M., “The Generation of Free Radicals by Nitric Oxide Synthase,” Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 134, no. 3 (2003): 281–289.

21. Hrycay E. G. and Bandiera S. M., “Monooxygenase, Peroxidase and Peroxygenase Properties and Reaction Mechanisms of Cytochrome P450 Enzymes,” Advances in Experimental Medicine and Biology 851 (2015): 1–61.

22. Liu N., Xu H., Sun Q., et al., “The Role of Oxidative Stress in Hyperuricemia and Xanthine Oxidoreductase (XOR) Inhibitors,” Oxidative Medicine and Cellular Longevity 2021 (2021): 1470380.

23. Zeeshan H., Lee G., Kim H. R., and Chae H. J., “Endoplasmic Reticulum Stress and Associated ROS,” International Journal of Molecular Sciences 17, no. 3 (2016): 327.

24. Bourens M., Fontanesi F., Soto I. C., Liu J., and Barrientos A., “Redox and Reactive Oxygen Species Regulation of Mitochondrial Cytochrome C Oxidase Biogenesis,” Antioxidants & Redox Signaling 19, no. 16 (2013): 1940–1952.

25. Wang Y. and Hekimi S., “Understanding Ubiquinone,” Trends in Cell Biology 26, no. 5 (2016): 367–378.

26. F. Turrens J., Alexandre A., and L. Lehninger A., “Reprint Of: Ubisemiquinone Is the Electron Donor for Superoxide Formation by Complex III of Heart Mitochondria,” Archives of Biochemistry and Biophysics 726 (2022): 109232.

27. Pryde K. R. and Hirst J., “Superoxide Is Produced by the Reduced Flavin in Mitochondrial Complex I,” Journal of Biological Chemistry 286, no. 20 (2011): 18056–18065.

28. Turrens J. F., “Mitochondrial Formation of Reactive Oxygen Species,” The Journal of Physiology 552, no. Pt 2 (2003): 335–344.

29. Dröse S. and Brandt U., “The Mechanism of Mitochondrial Superoxide Production By the Cytochrome bc1 Complex,” Journal of Biological Chemistry 283, no. 31 (2008): 21649–21654.

30. Zhao R. Z., Jiang S., Zhang L., and Yu Z. B., “Mitochondrial Electron Transport Chain, ROS Generation and Uncoupling (Review),” International Journal of Molecular Medicine 44, no. 1 (2019): 3–15.

31. Nolfi‐Donegan D., Braganza A., and Shiva S., “Mitochondrial Electron Transport Chain: Oxidative Phosphorylation, Oxidant Production, and Methods of Measurement,” Redox Biology 37 (2020): 101674.

32. Jarmuszkiewicz W., Dominiak K., Budzinska A., Wojcicki K., and Galganski L., “Mitochondrial Coenzyme Q Redox Homeostasis and Reactive Oxygen Species Production,” Frontiers in Bioscience‐Landmark 28, no. 3 (2023): 61.

33. Malinska D., Kulawiak B., Kudin A. P., et al., “Complex III‐Dependent Superoxide Production of Brain Mitochondria Contributes to Seizure‐Related Ros Formation,” Biochimica et Biophysica Acta (BBA) ‐ Bioenergetics 1797, no. 6–7 (2010): 1163–1170.

34. Noodleman L., Han Du W. G., McRee D., Chen Y., Goh T., and Götz A. W., “Coupled Transport of Electrons and Protons in a Bacterial Cytochrome C Oxidase‐DFT Calculated Properties Compared to Structures and Spectroscopies,” Physical Chemistry Chemical Physics 22, no. 46 (2020): 26652–26668.

35. Fraga C. G., Oteiza P. I., Hid E. J., and Galleano M., “PolyPhenols and the Regulation of NADPH Oxidases,” Redox Biology 67 (2023): 102927.

36. Schröder K., “Nadph Oxidases: Current Aspects and Tools,” Redox Biology 34 (2020): 101512.

37. Taylor J. P. and Tse H. M., “The Role of NADPH Oxidases in Infectious and Inflammatory Diseases,” Redox Biology 48 (2021): 102159.

38. Crosas‐Molist E. and Fabregat I., “Role of NADPH Oxidases in the Redox Biology of Liver Fibrosis,” Redox Biology 6 (2015): 106–111.

39. Bedard K. and Krause K. H., “The NOX Family of ROS‐Generating Nadph Oxidases: Physiology and Pathophysiology,” Physiological Reviews 87, no. 1 (2007): 245–313.

40. Geiszt M. and Leto T. L., “The Nox Family of NAD(P)H Oxidases: Host Defense and Beyond,” Journal of Biological Chemistry 279, no. 50 (2004): 51715–51718.

41. Feschyan S. M., Simonyan R. M., Simonyan G. M., Simonyan M. A., and Manukyan A. L., “NADPH Containing Superoxide‐Producing Thermostable Complex From Raspberry, Apricot, Grape, and Grape Seeds: Isolation, Purification, and Properties,” Plant Methods 19, no. 1 (2023): 1.

42. Iyanagi T., “Molecular Mechanism of Metabolic NAD(P)H‐Dependent Electron‐Transfer Systems: The Role of Redox Cofactors,” Biochimica et Biophysica Acta (BBA) ‐ Bioenergetics 1860, no. 3 (2019): 233–258.

43. Magnani F. and Mattevi A., “Structure and Mechanisms of ROS Generation by Nadph Oxidases,” Current Opinion in Structural Biology 59 (2019): 91–97.

44. Pérez‐Torres I., Manzano‐Pech L., Rubio‐Ruíz M. E., Soto M. E., and Guarner‐Lans V., “Nitrosative Stress and Its Association With Cardiometabolic Disorders,” Molecules 25, no. 11 (2020): 2555.

45. Takır S., Gürel‐Gürevin E., Toprak A., Demirci‐Tansel C., and Uydeş‐Doğan B. S., “The Elevation of Intraocular Pressure is Associated With Apoptosis and Increased Immunoreactivity for Nitric Oxide Synthase in Rat Retina Whereas the Effectiveness of Retina Derived Relaxing Factor Is Unaffected,” Experimental Eye Research 145 (2016): 401–411.

46. Yoon S., Eom G. H., and Kang G., “Nitrosative Stress and Human Disease: Therapeutic Potential of Denitrosylation,” International Journal of Molecular Sciences 22, no. 18 (2021): 9794.

47. Fernando V., Zheng X., Walia Y., Sharma V., Letson J., and Furuta S., “S‐Nitrosylation: An Emerging Paradigm of Redox Signaling,” Antioxidants 8, no. 9 (2019): 404.

48. Kurutas E. B., “The Importance of Antioxidants Which Play the Role in Cellular Response Against Oxidative/Nitrosative Stress: Current State,” Nutrition Journal 15, no. 1 (2016): 71.

49. Eleuteri E., et al, “Role of Oxidative and Nitrosative Stress Biomarkers in Chronic Heart Failure,” Frontiers in Bioscience 14(2009): 2230–2237.

50. Tegeder I., “Nitric Oxide Mediated Redox Regulation of Protein Homeostasis,” Cellular Signalling 53 (2019): 348–356.

51. Piacenza L., Zeida A., Trujillo M., and Radi R., “The Superoxide Radical Switch in the Biology of Nitric Oxide and Peroxynitrite,” Physiological Reviews 102, no. 4 (2022): 1881–1906.

52. Jomova K., Raptova R., Alomar S. Y., et al., “Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging,” Archives of Toxicology 97, no. 10 (2023): 2499–2574.

53. Pacher P., Beckman J. S., and Liaudet L., “Nitric Oxide and Peroxynitrite in Health and Disease,” Physiological Reviews 87, no. 1 (2007): 315–424.

54. Silva M. P., Cedraz‐Mercez P. L., and Varanda W. A., “Effects of Nitric Oxide on Magnocellular Neurons of the Supraoptic Nucleus Involve Multiple Mechanisms,” Brazilian Journal of Medical and Biological Research 47, no. 2 (2014): 90–100.

55. Barnett S. D. and Buxton I. L. O., “The Role of S‐Nitrosoglutathione Reductase (GSNOR) in Human Disease and Therapy,” Critical Reviews in Biochemistry and Molecular Biology 52, no. 3 (2017): 340–354.

56. Yanar K., Atayik M. C., Simsek B., and Çakatay U., “Novel Biomarkers for the Evaluation of Aging‐Induced Proteinopathies,” Biogerontology 21, no. 5 (2020): 531–548.

57. Ahsan H., “3‐Nitrotyrosine: A Biomarker of Nitrogen Free Radical Species Modified Proteins in Systemic Autoimmunogenic Conditions,” Human Immunology 74, no. 10 (2013): 1392–1399.

58. Cooper C. E., “Nitric Oxide and Iron Proteins,” Biochimica et Biophysica Acta (BBA) ‐ Bioenergetics 1411, no. 2–3 (1999): 290–309.

59. Kim S. and Ponka P., “Nitric Oxide‐Mediated Modulation of Iron Regulatory Proteins: Implication for Cellular Iron Homeostasis,” Blood Cells, Molecules, and Diseases 29, no. 3 (2002): 400–410.

60. Hu C. W., Chang Y. J., Hsu Y. W., Chen J. L., Wang T. S., and Chao M. R., “Comprehensive Analysis of the Formation and Stability of Peroxynitrite‐Derived 8‐nitroguanine by LC‐MS/MS: Strategy for the Quantitative Analysis of Cellular 8‐Nitroguanine,” Free Radical Biology and Medicine 101 (2016): 348–355.

61. Bhamra I., Compagnone‐Post P., O'Neil I. A., Iwanejko L. A., Bates A. D., and Cosstick R., “Base‐Pairing Preferences, Physicochemical Properties and Mutational Behaviour of the DNA Lesion 8‐Nitroguanine,” Nucleic Acids Research 40, no. 21 (2012): 11126–11138.

62. Melo T., Montero‐Bullón J. F., Domingues P., and Domingues M. R., “Discovery of Bioactive Nitrated Lipids and Nitro‐Lipid‐Protein Adducts Using Mass Spectrometry‐Based Approaches,” Redox Biology 23 (2019): 101106.

63. Girotti A. W. and Korytowski W., “Nitric Oxide Inhibition of Chain Lipid Peroxidation Initiated by Photodynamic Action in Membrane Environments,” Cell Biochemistry and Biophysics 78, no. 2 (2020): 149–156.

64. Sołtan M., Bartusik‐Aebisher D., and Aebisher D., “The Potential of Oxygen and Nitrogen Species‐Regulating Drug Delivery Systems in Medicine,” Frontiers in Bioengineering and Biotechnology 10 (2022): 973080.

65. Che Z., Zhou Z., Li S. Q., Gao L., Xiao J., and Wong N. K., “ROS/RNS As Molecular Signatures of Chronic Liver Diseases,” Trends in Molecular Medicine 29, no. 11 (2023): 951–967.

66. Trombetti S., Cesaro E., Catapano R., et al., “Oxidative Stress and ROS‐Mediated Signaling in Leukemia: Novel Promising Perspectives to Eradicate Chemoresistant Cells in Myeloid Leukemia,” International Journal of Molecular Sciences 22, no. 5 (2021): 2470.

67. Checa J. and Aran J. M., “Reactive Oxygen Species: Drivers of Physiological and Pathological Processes,” Journal of Inflammation Research 13 (2020): 1057–1073.

68. Dupré‐Crochet S., Erard M., and Nüβe O., “ROS Production in Phagocytes: Why, When, and Where?,” Journal of Leukocyte Biology 94, no. 4 (2013): 657–670.

69. Burtenshaw D., Hakimjavadi R., Redmond E., and Cahill P., “Nox, Reactive Oxygen Species and Regulation of Vascular Cell Fate,” Antioxidants 6, no. 4 (2017): 90.

70. Espinosa A., Casas M., and Jaimovich E., “Energy (And Reactive Oxygen Species Generation) Saving Distribution of Mitochondria for the Activation of ATP Production in Skeletal Muscle,” Antioxidants 12, no. 8 (2023): 1624.

71. Duong Q. V., Levitsky Y., Dessinger M. J., Strubbe‐Rivera J. O., and Bazil J. N., “Identifying Site‐Specific Superoxide and Hydrogen Peroxide Production Rates From the Mitochondrial Electron Transport System Using a Computational Strategy,” Function 2, no. 6 (2021): zqab050.

72. Baek J. I., Kim Y. R., Lee K. Y., and Kim U. K., “Mitochondrial Redox System: A Key Target of Antioxidant Therapy to Prevent Acquired Sensorineural Hearing Loss,” Frontiers in Pharmacology 14 (2023): 1176881.

73. Dai W., Deng Y., Chen X., et al., “A Mitochondria‐Targeted Supramolecular Nanoplatform for Peroxynitrite‐Potentiated Oxidative Therapy of Orthotopic Hepatoma,” Biomaterials 290 (2022): 121854.

74. Bhatti J. S., Bhatti G. K., and Reddy P. H., “Mitochondrial Dysfunction and Oxidative Stress in Metabolic Disorders ‐ A Step Towards Mitochondria Based Therapeutic Strategies,” Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease 1863, no. 5 (2017): 1066–1077.

75. Larsen F. J., Schiffer T. A., Weitzberg E., and Lundberg J. O., “Regulation of Mitochondrial Function and Energetics By Reactive Nitrogen Oxides,” Free Radical Biology and Medicine 53, no. 10 (2012): 1919–1928.

76. Butterfield D. A. and Boyd‐Kimball D., “Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease,” Antioxidants 9, no. 9 (2020): 818.

77. Vrettou S. and Wirth B., “S‐Glutathionylation and S‐Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases,” International Journal of Molecular Sciences 23, no. 24 (2022): 15849.

78. Sandalio L. M., Serrano M. R., Puertas M. C. R., and Rio L. A., “Role of Peroxisomes As a Source of Reactive Oxygen Species (ROS) Signaling Molecules,” Sub–Cellular Biochemistry 69 (2013): 231–255.

79. Corpas F. J., del Río L. A., and Palma J. M., “Impact of Nitric Oxide (NO) on the ROS Metabolism of Peroxisomes,” Plants 8, no. 2 (2019): 37.

80. Del Rio L. A. and Lopez‐Huertas E., “ROS Generation in Peroxisomes and Its Role in Cell Signaling,” Plant and Cell Physiology 57, no. 7 (2016): 1364–1376.

81. Bhandary B., Marahatta A., Kim H. R., and Chae H. J., “An Involvement of Oxidative Stress in Endoplasmic Reticulum Stress and Its Associated Diseases,” International Journal of Molecular Sciences 14, no. 1 (2012): 434–456.

82. Lismont C., Nordgren M., Van Veldhoven P. P., and Fransen M., “Redox Interplay Between Mitochondria and Peroxisomes,” Frontiers in Cell and Developmental Biology 3 (2015): 35.

83. Chaudhary P., Janmeda P., Docea A. O., et al., “Oxidative Stress, Free Radicals and Antioxidants: Potential Crosstalk in the Pathophysiology of Human Diseases,” Frontiers in Chemistry 11 (2023): 1158198.

84. Aslan M., Gürel E., Üremiş N., Üremiş M. M., and Taşlıdere E., “Anti‐Inflammatory and Antioxidative Effects of Dexpanthenol on Nicotine‐Induced Lung Injury in Rats,” Toxicology and Environmental Health Sciences 15, no. 3 (2023): 303–313.

85. Jena A. B., Samal R. R., Bhol N. K., and Duttaroy A. K., “Cellular Red‐Ox System in Health and Disease: The Latest Update,” Biomedicine & Pharmacotherapy 162 (2023): 114606.

86. James A. M. and Murphy M. P., “How Mitochondrial Damage Affects Cell Function,” Journal of Biomedical Science 9, no. 6 Pt 1 (2002): 475–487.

87. Vazquez‐Villasenor I., Garwood C. J., Simpson J. E., Heath P. R., Mortiboys H., and Wharton S. B., “Persistent DNA Damage Alters the Neuronal Transcriptome Suggesting Cell Cycle Dysregulation and Altered Mitochondrial Function,” European Journal of Neuroscience 54, no. 9 (2021): 6987–7005.

88. Redza‐Dutordoir M. and Averill‐Bates D. A., “Activation of Apoptosis Signalling Pathways By Reactive Oxygen Species,” Biochimica et Biophysica Acta (BBA) ‐ Molecular Cell Research 1863, no. 12 (2016): 2977–2992.

89. Baek M. W., Seong K. J., Jeong Y. J., et al., “Nitric Oxide Induces Apoptosis in Human Gingival Fibroblast Through Mitochondria‐Dependent Pathway and JNK Activation,” International Endodontic Journal 48, no. 3 (2015): 287–297.

90. Diaz Arguello O. A. and Haisma H. J., “Apoptosis‐Inducing TNF Superfamily Ligands for Cancer Therapy,” Cancers 13, no. 7 (2021): 1543.

91. Circu M. L. and Aw T. Y., “Reactive Oxygen Species, Cellular Redox Systems, and Apoptosis,” Free Radical Biology and Medicine 48, no. 6 (2010): 749–762.

92. Shen H. M. and Pervaiz S., “TNF Receptor Superfamily‐Induced Cell Death: Redox‐Dependent Execution,” The FASEB Journal 20, no. 10 (2006): 1589–1598.

93. Li Z., Yuan W., and Lin Z., “Functional Roles in Cell Signaling of Adaptor Protein TRADD From a Structural Perspective,” Computational and Structural Biotechnology Journal 18 (2020): 2867–2876.

94. Blaser H., Dostert C., Mak T. W., and Brenner D., “TNF and ROS Crosstalk in Inflammation,” Trends in Cell Biology 26, no. 4 (2016): 249–261.

95. Han J. H., Park J., Kang T. B., and Lee K. H., “Regulation of Caspase‐8 Activity at the Crossroads of Pro‐Inflammation and Anti‐Inflammation,” International Journal of Molecular Sciences 22, no. 7 (2021): 3318.

96. Uremis M. M., Turkoz Y., and Uremis N., “Investigation of Apoptotic Effects of Cucurbitacin D, I, and E Mediated by Bax/Bcl‐Xl, caspase‐3/9, and Oxidative Stress Modulators in HepG2 Cell Line,” Drug Development Research 85, no. 2 (2024): e22174.

97. Üremi̇ş N., Üremi̇ş M. M., Gül M., Özsoy E. N., and Türköz Y., “Protective Effects of Vitamin E Against Acrylamide‐Induced Hepatotoxicity and Nephrotoxicity From Fetal Development to Adulthood: Insights Into Akt/NF‐κB and Bcl‐xL/Bax Signaling Pathways,” Toxicology 502 (2024): 153729.

98. Üremiş M. M., Üremiş N., and Türköz Y., “Cucurbitacin E Shows Synergistic Effect With Sorafenib By Inducing Apoptosis in Hepatocellular Carcinoma Cells and Regulates Jak/Stat3, ERK/MAPK, PI3K/Akt/mTOR Signaling Pathways,” Steroids 198 (2023): 109261.

99. Kantari C. and Walczak H., “Caspase‐8 and Bid: Caught in the Act Between Death Receptors and Mitochondria,” Biochimica et Biophysica Acta (BBA) ‐ Molecular Cell Research 1813, no. 4 (2011): 558–563.

100. Uremis N., Aslan M., Taslidere E., and Gürel E., “Dexpanthenol Exhibits Antiapoptotic and Anti‐Inflammatory Effects Against Nicotine‐Induced Liver Damage By Modulating Bax/Bcl‐Xl, Caspase‐3/9, and Akt/Nf‐Kappab Pathways,” Journal of Biochemical and Molecular Toxicology 38, no. 1 (2024): e23622.

101. Aggarwal V., Tuli H., Varol A., et al., “Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements,” Biomolecules 9, no. 11 (2019): 735.

102. Roberts R. A., Smith R. A., Safe S., Szabo C., Tjalkens R. B., and Robertson F. M., “Toxicological and Pathophysiological Roles of Reactive Oxygen and Nitrogen Species,” Toxicology 276, no. 2 (2010): 85–94.

103. Chae I. H., Park K. W., Kim H. S., and Oh B. H., “Nitric Oxide‐Induced Apoptosis Is Mediated By Bax/Bcl‐2 Gene Expression, Transition of Cytochrome C, and Activation of Caspase‐3 in Rat Vascular Smooth Muscle Cells,” Clinica Chimica Acta 341, no. 1–2 (2004): 83–91.

104. Garrido C., Galluzzi L., Brunet M., Puig P. E., Didelot C., and Kroemer G., “Mechanisms of Cytochrome C Release From Mitochondria,” Cell Death & Differentiation 13, no. 9 (2006): 1423–1433.

105. Üremiş M. M., Gürel E., Aslan M., and Taşlıdere E., “Dexpanthenol Protects Against Nicotine‐Induced Kidney Injury by Reducing Oxidative Stress and Apoptosis Through Activation of the AKT/Nrf2/HO‐1 Pathway,” Naunyn‐Schmiedeberg's Archives of Pharmacology 397, no. 2 (2024): 1105–1114.

106. Altinoz E., Oner Z., Elbe H., Uremis N., and Uremis M., “Linalool Exhibits Therapeutic and Protective Effects in a Rat Model of Doxorubicin‐Induced Kidney Injury by Modulating Oxidative Stress,” Drug and Chemical Toxicology 45, no. 5 (2022): 2024–2030.

107. Aranda‐Rivera A. K., Cruz‐Gregorio A., Arancibia‐Hernández Y. L., Hernández‐Cruz E. Y., and Pedraza‐Chaverri J., “RONS and Oxidative Stress: An Overview of Basic Concepts,” Oxygen 2, no. 4 (2022): 437–478.

108. Chachlaki K. and Prevot V., “Nitric Oxide Signalling in the Brain and Its Control of Bodily Functions,” British Journal of Pharmacology 177, no. 24 (2020): 5437–5458.

109. Abdulhussein D., et al, “Chapter Nine ‐ Apoptosis in Health and Diseases of the eye and Brain.” in Advances in Protein Chemistry and Structural Biology, eds. Donev R.. Academic Press, 2021, 279–306).

110. Cieslik P., Siekierzycka A., Radulska A., et al., “Nitric Oxide‐Dependent Mechanisms Underlying MK‐801‐ or Scopolamine‐Induced Memory Dysfunction in Animals: Mechanistic Studies,” International Journal of Molecular Sciences 22, no. 22 (2021): 12282.

111. Sen T., Saha P., and Sen N., “Nitrosylation of GAPDH Augments Pathological Tau Acetylation Upon Exposure to Amyloid‐Β,” Science Signaling 11, no. 522 (2018): eaao6765.

112. Gu L. and Robinson R. A. S., “High‐Throughput Endogenous Measurement of S‐Nitrosylation in Alzheimer's Disease Using Oxidized Cysteine‐Selective CPILOT,” Analyst 141, no. 12 (2016): 3904–3915.

113. Reynolds M. R., Berry R. W., and Binder L. I., “Site‐Specific Nitration and Oxidative Dityrosine Bridging of the τ Protein by Peroxynitrite: Implications for Alzheimer's Disease,” Biochemistry 44, no. 5 (2005): 1690–1700.

114. Hensley K., Maidt M. L., Yu Z., Sang H., Markesbery W. R., and Floyd R. A., “Electrochemical Analysis of Protein Nitrotyrosine and Dityrosine in the Alzheimer Brain Indicates Region‐Specific Accumulation,” The Journal of Neuroscience 18, no. 20 (1998): 8126–8132.

115. Ahmed N., Ahmed U., Thornalley P. J., Hager K., Fleischer G., and Münch G., “Protein Glycation, Oxidation and Nitration Adduct Residues and Free Adducts of Cerebrospinal Fluid in Alzheimer's Disease and Link to Cognitive Impairment,” Journal of Neurochemistry 92, no. 2 (2005): 255–263.

116. Francis S. H., Busch J. L., and Corbin J. D., “CGMP‐Dependent Protein Kinases and CGmp Phosphodiesterases in Nitric Oxide and Cgmp Action,” Pharmacological Reviews 62, no. 3 (2010): 525–563.

117. Palmeri A., Ricciarelli R., Gulisano W., et al., “Amyloid‐β Peptide Is Needed for CGMP‐Induced Long‐Term Potentiation and Memory,” The Journal of Neuroscience 37, no. 29 (2017): 6926–6937.

118. Tropea M. R., Gulisano W., Vacanti V., Arancio O., Puzzo D., and Palmeri A., “Nitric Oxide/cGMP/CREB Pathway and Amyloid‐Beta Crosstalk: From Physiology to Alzheimer's Disease,” Free Radical Biology and Medicine 193, no. Pt 2 (2022): 657–668.

119. Acquarone E., Argyrousi E. K., van den Berg M., et al., “Synaptic and Memory Dysfunction Induced by Tau Oligomers Is Rescued By Up‐Regulation of the Nitric Oxide Cascade,” Molecular Neurodegeneration 14, no. 1 (2019): 26.

120. Ota K. T., Pierre V. J., Ploski J. E., Queen K., and Schafe G. E., “The NO‐CGMP‐PKG Signaling Pathway Regulates Synaptic Plasticity and Fear Memory Consolidation in the Lateral Amygdala via Activation of ERK/MAP Kinase,” Learning & Memory 15, no. 10 (2008): 792–805.

121. Puzzo D., Vitolo O., Trinchese F., Jacob J. P., Palmeri A., and Arancio O., “Amyloid‐β Peptide Inhibits Activation of the Nitric Oxide/CGMP/CAMP‐Responsive Element‐Binding Protein Pathway During Hippocampal Synaptic Plasticity,” The Journal of Neuroscience 25, no. 29 (2005): 6887–6897.

122. Dyer R. R., Ford K. I., and Robinson R. A. S., “The Roles of S‐Nitrosylation and S‐Glutathionylation in Alzheimer's Disease,” Methods in Enzymology 626 (2019): 499–538.

123. Chuang W. H., Chou Y. T., Chen Y. H., et al., “Neuroprotective Effect of NO‐Delivery Dinitrosyl Iron Complexes (DNICS) on Amyloid Pathology in the Alzheimer's Disease Cell Model,” ACS Chemical Neuroscience 14, no. 16 (2023): 2922–2934.

124. Qin Z., Luo J., VandeVrede L., et al., “Design and Synthesis of Neuroprotective Methylthiazoles and Modification as No‐Chimeras for Neurodegenerative Therapy,” Journal of Medicinal Chemistry 55, no. 15 (2012): 6784–6801.

125. Awasthi M., Singh S., Pandey V. P., and Dwivedi U. N., “Alzheimer's Disease: An Overview of Amyloid Beta Dependent Pathogenesis and Its Therapeutic Implications Along With in Silico Approaches Emphasizing the Role of Natural Products,” Journal of the Neurological Sciences 361 (2016): 256–271.

126. Ekundayo B. E., Obafemi T. O., Adewale O. B., Obafemi B. A., Oyinloye B. E., and Ekundayo S. K., “Oxidative Stress, Endoplasmic Reticulum Stress and Apoptosis in the Pathology of Alzheimer's Disease,” Cell Biochemistry and Biophysics 82 (2024): 457–477.

127. Griñán‐Ferré C., Bellver‐Sanchis A., Izquierdo V., et al., “The Pleiotropic Neuroprotective Effects of Resveratrol in Cognitive Decline and Alzheimer's Disease Pathology: From Antioxidant to Epigenetic Therapy,” Ageing Research Reviews 67 (2021): 101271.

128. Liu Z., Zhang B., Xia S., Fang L., and Gou S., “ROS‐Responsive and Multifunctional Anti‐Alzheimer Prodrugs: Tacrine‐Ibuprofen Hybrids via a Phenyl Boronate Linker,” European Journal of Medicinal Chemistry 212 (2021): 112997.

129. Zhang L., Qian Y., Li J., et al., “BAD‐Mediated Neuronal Apoptosis and Neuroinflammation Contribute to Alzheimer's Disease Pathology,” iScience 24, no. 9 (2021): 102942.

130. Bobba A., Atlante A., Moro L., Calissano P., and Marra E., “Nitric Oxide Has Dual Opposite Roles During Early and Late Phases of Apoptosis in Cerebellar Granule Neurons,” Apoptosis 12, no. 9 (2007): 1597–1610.

131. de la Monte S. M., Sohn Y. K., Etienne D., Kraft J., and Wands J. R., “Role of Aberrant Nitric Oxide Synthase‐3 Expression in Cerebrovascular Degeneration and Vascular‐Mediated Injury in Alzheimer's Disease,” Annals of the New York Academy of Sciences 903 (2000): 61–71.

132. Wang W. T., Tailor B. A., Cohen D. S., and Huang X., “Alzheimer's Pathogenesis, Metal‐Mediated Redox Stress, and Potential Nanotheranostics,” EC pharmacology and toxicology 7, no. 7 (2019): 547–558.

133. Mielke M. M. and Lyketsos C. G., “Lipids and the Pathogenesis of Alzheimer's Disease: Is There a Link?,” International Review of Psychiatry 18, no. 2 (2006): 173–186.

134. Obulesu M. and Lakshmi M. J., “Apoptosis in Alzheimer's Disease: an Understanding of the Physiology, Pathology and Therapeutic Avenues,” Neurochemical Research 39, no. 12 (2014): 2301–2312.

135. Goel P., Chakrabarti S., Goel K., Bhutani K., Chopra T., and Bali S., “Neuronal Cell Death Mechanisms in Alzheimer's Disease: An Insight,” Frontiers in Molecular Neuroscience 15 (2022): 937133.

136. Buizza L., Cenini G., Lanni C., et al., “Conformational Altered p53 As an Early Marker of Oxidative Stress in Alzheimer's Disease,” PLoS One 7, no. 1 (2012): e29789.

137. Berg D., Borghammer P., Fereshtehnejad S. M., et al., “Prodromal Parkinson Disease Subtypes ‐ Key to Understanding Heterogeneity,” Nature Reviews Neurology 17, no. 6 (2021): 349–361.

138. Savica R., Carlin J. M., Grossardt B. R., et al., “Medical Records Documentation of Constipation Preceding Parkinson Disease: A Case‐Control Study,” Neurology 73, no. 21 (2009): 1752–1758.

139. Yamamoto T., Maruyama W., Kato Y., et al., “Selective Nitration of Mitochondrial Complex I by Peroxynitrite: Involvement in Mitochondria Dysfunction and Cell Death of Dopaminergic SH‐SY5Y Cells,” Journal of Neural Transmission 109, no. 1 (2002): 1–13.

140. Tansey M. G., McCoy M. K., and Frank‐Cannon T. C., “Neuroinflammatory Mechanisms in Parkinson's Disease: Potential Environmental Triggers, Pathways, and Targets for Early Therapeutic Intervention,” Experimental Neurology 208, no. 1 (2007): 1–25.

141. Zaman V., Shields D. C., Shams R., et al., “Cellular and Molecular Pathophysiology in the Progression of Parkinson's Disease,” Metabolic Brain Disease 36, no. 5 (2021): 815–827.

142. Ciani E., Guidi S., Della Valle G., Perini G., Bartesaghi R., and Contestabile A., “Nitric Oxide Protects Neuroblastoma Cells From Apoptosis Induced by Serum Deprivation Through Camp‐Response Element‐Binding Protein (CREB) Activation,” Journal of Biological Chemistry 277, no. 51 (2002): 49896–49902.

143. Culmsee C., Gerling N., Landshamer S., et al., “Nitric Oxide Donors Induce Neurotrophin‐Like Survival Signaling and Protect Neurons Against Apoptosis,” Molecular Pharmacology 68, no. 4 (2005): 1006–1017.

144. Thippeswamy T., Mckay J. S., Morris R., Quinn J., Wong L. F., and Murphy D., “Glial‐Mediated Neuroprotection: Evidence for the Protective Role of the No‐CGMP Pathway via Neuron‐Glial Communication in the Peripheral Nervous System,” GLIA 49, no. 2 (2005): 197–210.

145. Laranjinha J., Santos R. M., Lourenço C. F., Ledo A., and Barbosa R. M., “Nitric Oxide Signaling in the Brain: Translation of Dynamics Into Respiration Control and Neurovascular Coupling,” Annals of the New York Academy of Sciences 1259 (2012): 10–18.

146. Tripathy D., Chakraborty J., and Mohanakumar K. P., “Antagonistic Pleiotropic Effects of Nitric Oxide in the Pathophysiology of Parkinson's Disease,” Free Radical Research 49, no. 9 (2015): 1129–1139.

147. Kavya R., Saluja R., Singh S., and Dikshit M., “Nitric Oxide Synthase Regulation and Diversity: Implications in Parkinson's Disease,” Nitric Oxide 15, no. 4 (2006): 280–294.

148. Stykel M. G. and Ryan S. D., “Nitrosative Stress in Parkinson's Disease,” NPJ Parkinson's Disease 8, no. 1 (2022): 104.

149. Solís O., Espadas I., Del‐Bel E. A., and Moratalla R., “Nitric Oxide Synthase Inhibition Decreases L‐Dopa‐Induced Dyskinesia and the Expression of Striatal Molecular Markers in Pitx3 − /− Aphakia Mice,” Neurobiology of Disease 73 (2015): 49–59.

150. Ju T. C., Chen S. D., Liu C. C., and Yang D. I., “Protective Effects of S‐Nitrosoglutathione Against Amyloid β‐peptide Neurotoxicity,” Free Radical Biology and Medicine 38, no. 7 (2005): 938–949.

151. Mohanakumar K. P., Thomas B., Sharma S. M., Muralikrishnan D., Chowdhury R., and Chiueh C. C., “Nitric Oxide: an Antioxidant and Neuroprotector,” Annals of the New York Academy of Sciences 962 (2002): 389–401.

152. Martins‐Pinge M. C., de Jager L., de Campos B. H., Bezerra L. O., Turini P. G., and Pinge‐Filho P., “Nitric Oxide Involvement in Cardiovascular Dysfunctions of Parkinson Disease,” Frontiers in Pharmacology 13 (2022): 898797.

153. Böckelmann R., Wolf G., Ransmayr G., and Riederer P., “NADPH‐Diaphorase/Nitric Oxide Synthase Containing Neurons in Normal and Parkinson's Disease Putamen,” Journal of Neural Transmission ‐ Parkinson's Disease and Dementia Section 7, no. 2 (1994): 115–121.

154. Hunot S., Boissière F., Faucheux B., et al., “Nitric Oxide Synthase and Neuronal Vulnerability in Parkinson's Disease,” Neuroscience 72, no. 2 (1996): 355–363.

155. Levecque C., Elbaz A., Clavel J., et al., “Association Between Parkinson's Disease and Polymorphisms in the Nnos and Inos Genes in a Community‐Based Case‐Control Study,” Human Molecular Genetics 12, no. 1 (2003): 79–86.

156. Aras S., Tanriover G., Aslan M., Yargicoglu P., and Agar A., “The Role of Nitric Oxide on Visual‐Evoked Potentials in MPTP‐Induced Parkinsonism in Mice,” Neurochemistry International 72 (2014): 48–57.

157. Madathil S. K., Karuppagounder S. S., and Mohanakumar K. P., “Sodium Salicylate Protects Against Rotenone‐Induced Parkinsonism in Rats,” Synapse 67, no. 8 (2013): 502–514.

158. Khan H., Singh T. G., Dahiya R. S., and Abdel‐Daim M. M., “α‐Lipoic Acid, an Organosulfur Biomolecule a Novel Therapeutic Agent for Neurodegenerative Disorders: An Mechanistic Perspective,” Neurochemical Research 47, no. 7 (2022): 1853–1864.

159. Tardiolo G., Bramanti P., and Mazzon E., “Overview on the Effects of N‐Acetylcysteine in Neurodegenerative Diseases,” Molecules 23, no. 12 (2018): 3305.

160. Broom L., Marinova‐Mutafchieva L., Sadeghian M., Davis J. B., Medhurst A. D., and Dexter D. T., “Neuroprotection by the Selective iNOS Inhibitor GW274150 in a Model of Parkinson Disease,” Free Radical Biology and Medicine 50, no. 5 (2011): 633–640.

161. Dias V., Junn E., and Mouradian M. M., “The Role of Oxidative Stress in Parkinson's Disease,” Journal of Parkinson's Disease 3, no. 4 (2013): 461–491.

162. Tieu K., Ischiropoulos H., and Przedborski S., “Nitric Oxide and Reactive Oxygen Species in Parkinson's Disease,” IUBMB Life 55, no. 6 (2003): 329–335.

163. Sivagurunathan N., Gnanasekaran P., and Calivarathan L., “Mitochondrial Toxicant‐Induced Neuronal Apoptosis in Parkinson's Disease: What We Know so Far,” Degenerative Neurological and Neuromuscular Disease 13 (2023): 1–13.

164. Brahadeeswaran S., Lateef M., and Calivarathan L., “An Insight Into the Molecular Mechanism of Mitochondrial Toxicant‐Induced Neuronal Apoptosis in Parkinson's Disease,” Current molecular medicine 23, no. 1 (2023): 63–75.

165. Nunes C. and Laranjinha J., “Nitric Oxide and Dopamine Metabolism Converge via Mitochondrial Dysfunction in the Mechanisms of Neurodegeneration in Parkinson's Disease,” Archives of Biochemistry and Biophysics 704 (2021): 108877.

166. Nakamura T., Cho D. H., and Lipton S. A., “Redox Regulation of Protein Misfolding, Mitochondrial Dysfunction, Synaptic Damage, and Cell Death in Neurodegenerative Diseases,” Experimental Neurology 238, no. 1 (2012): 12–21.

167. Tsang A. H. K. and Chung K. K. K., “Oxidative and Nitrosative Stress in Parkinson's Disease,” Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease 1792, no. 7 (2009): 643–650.

168. Li C. Q. and Wogan G. N., “Nitric Oxide as a Modulator of Apoptosis,” Cancer Letters 226, no. 1 (2005): 1–15.

169. Zhuang S. and Simon G., “Peroxynitrite‐Induced Apoptosis Involves Activation of Multiple Caspases in HL‐60 Cells,” American Journal of Physiology‐Cell Physiology 279, no. 2 (2000): C341–C351.

170. Sunico C. R., Nakamura T., Rockenstein E., et al., “S‐Nitrosylation of Parkin as a Novel Regulator of p53‐mediated Neuronal Cell Death in Sporadic Parkinson's Disease,” Molecular Neurodegeneration 8 (2013): 29.

171. Holtz W. A., Turetzky J. M., Jong Y. J. I., and O'Malley K. L., “Oxidative Stress‐Triggered Unfolded Protein Response is Upstream of Intrinsic Cell Death Evoked By Parkinsonian Mimetics,” Journal of Neurochemistry 99, no. 1 (2006): 54–69.

172. Blum D., Torch S., Lambeng N., et al., “Molecular Pathways Involved in the Neurotoxicity of 6‐OHDA, Dopamine and MPTP: Contribution to the Apoptotic Theory in Parkinson's Disease,” Progress in Neurobiology 65, no. 2 (2001): 135–172.

173. Mandir A. S., Przedborski S., Jackson‐Lewis V., et al., “Poly(ADP‐Ribose) Polymerase Activation Mediates 1‐methyl‐4‐phenyl‐1, 2,3,6‐tetrahydropyridine (MPTP)‐Induced Parkinsonism,” Proceedings of the National Academy of Sciences 96, no. 10 (1999): 5774–5779.

174. Nakabeppu Y., Tsuchimoto D., Yamaguchi H., and Sakumi K., “Oxidative Damage in Nucleic Acids and Parkinson's Disease,” Journal of Neuroscience Research 85, no. 5 (2007): 919–934.

175. Walton C., King R., Rechtman L., et al., “Rising Prevalence of Multiple Sclerosis Worldwide: Insights From the Atlas of MS, Third Edition,” Multiple Sclerosis Journal 26, no. 14 (2020): 1816–1821.

176. Üremiş M. M., Üremiş N., Gül M., et al., “Acrylamide, Applied During Pregnancy and Postpartum Period in Offspring Rats, Significantly Disrupted Myelination by Decreasing the Levels of Myelin‐Related Proteins: MBP, MAG, and MOG,” Neurochemical Research 49, no. 3 (2024): 617–635.

177. Silva B., Viero F. T., Rodrigues P., and Trevisan G., “Nitric Oxide Involvement in the Disability and Active Disease of Multiple Sclerosis: Systematic Review and Meta‐Analysis,” Nitric Oxide 145 (2024): 8–20.

178. Lan M., Tang X., Zhang J., and Yao Z., “Insights in Pathogenesis of Multiple Sclerosis: Nitric Oxide May Induce Mitochondrial Dysfunction of Oligodendrocytes,” Reviews in the Neurosciences 29, no. 1 (2017): 39–53.

179. Förster M., Nelke C., Räuber S., et al., “Nitrosative Stress Molecules in Multiple Sclerosis: A Meta‐Analysis,” Biomedicines 9, no. 12 (2021): 1899.

180. Fominykh V., Onufriev M. V., Vorobyeva A., et al., “Increased S‐Nitrosothiols Are Associated With Spinal Cord Injury in Multiple Sclerosis,” Journal of Clinical Neuroscience 28 (2016): 38–42.

181. Liu J. S. H., Zhao M. L., Brosnan C. F., and Lee S. C., “Expression of Inducible Nitric Oxide Synthase and Nitrotyrosine in Multiple Sclerosis Lesions,” The American Journal of Pathology 158, no. 6 (2001): 2057–2066.

182. Acar G., Idiman F., Diman E., Kirkali G., Cakmakci H., and Ozakbas S., “Nitric Oxide As an Activity Marker in Multiple Sclerosis,” Journal of Neurology 250, no. 5 (2003): 588–592.

183. Ghafourifar P., Mousavizadeh K., Parihar M. S., et al., “Mitochondria in Multiple Sclerosis,” Frontiers in Bioscience 13 (2008): 3116–3126.

184. Signorile A., Ferretta A., Ruggieri M., et al., “Mitochondria, Oxidative Stress, cAMP Signalling and Apoptosis: A Crossroads in Lymphocytes of Multiple Sclerosis, a Possible Role of Nutraceutics,” Antioxidants (Basel) 10, no. 1 (2020): 21.

185. Miller E. and Wachowicz B., “Advances in Antioxidative Therapy of Multiple Sclerosis,” Current Medicinal Chemistry 20, no. 37 (2013): 4720–4730.

186. Miller E. D., Dziedzic A., Saluk‐Bijak J., and Bijak M., “A Review of Various Antioxidant Compounds and Their Potential Utility as Complementary Therapy in Multiple Sclerosis,” Nutrients 11, no. 7 (2019): 1528.

187. Haider L., “Inflammation, Iron, Energy Failure, and Oxidative Stress in the Pathogenesis of Multiple Sclerosis,” Oxidative Medicine and Cellular Longevity 2015 (2015): 1–10.

188. Campbell G. R., Ziabreva I., Reeve A. K., et al., “Mitochondrial DNA Deletions and Neurodegeneration in Multiple Sclerosis,” Annals of Neurology 69, no. 3 (2011): 481–492.

189. Dutta R., McDonough J., Yin X., et al., “Mitochondrial Dysfunction as a Cause of Axonal Degeneration in Multiple Sclerosis Patients,” Annals of Neurology 59, no. 3 (2006): 478–489.

190. Fischer M. T., Sharma R., Lim J. L., et al., “NADPH Oxidase Expression in Active Multiple Sclerosis Lesions in Relation to Oxidative Tissue Damage and Mitochondrial Injury,” Brain 135, no. Pt 3 (2012): 886–899.

191. Lassmann H. and van Horssen J., “The Molecular Basis of Neurodegeneration in Multiple Sclerosis,” FEBS Letters 585, no. 23 (2011): 3715–3723.

192. Mirshafiey A. and Mohsenzadegan M., “Antioxidant Therapy in Multiple Sclerosis,” Immunopharmacology and Immunotoxicology 31, no. 1 (2009): 13–29.

193. Theodosis‐Nobelos P. and Rekka E. A., “Efforts Towards Repurposing of Antioxidant Drugs and Active Compounds for Multiple Sclerosis Control,” Neurochemical Research 48, no. 3 (2023): 725–744.

194. Mao P., Manczak M., Shirendeb U. P., and Reddy P. H., “MitoQ, a Mitochondria‐Targeted Antioxidant, Delays Disease Progression and Alleviates Pathogenesis in an Experimental Autoimmune Encephalomyelitis Mouse Model of Multiple Sclerosis,” Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease 1832, no. 12 (2013): 2322–2331.

195. Wosik K., Antel J., Kuhlmann T., Brück W., Massie B., and Nalbantoglu J., “Oligodendrocyte Injury in Multiple Sclerosis: A Role for P53,” Journal of Neurochemistry 85, no. 3 (2003): 635–644.

196. Kuhlmann T., Glas M., zum Bruch C., et al., “Investigation of Bax, bcl‐2, bcl‐x and p53 Gene Polymorphisms in Multiple Sclerosis,” Journal of Neuroimmunology 129, no. 1–2 (2002): 154–160.

197. Hagman S., Kolasa M., Basnyat P., et al., “Analysis of Apoptosis‐Related Genes in Patients With Clinically Isolated Syndrome and Their Association With Conversion to Multiple Sclerosis,” Journal of Neuroimmunology 280 (2015): 43–48.

198. Boje M. K., “Nitric Oxide Neurotoxicity in Neurodegenerative Diseases,” Frontiers in Bioscience 9 (2004): 763–776.

199. Lewis K. E., Rasmussen A. L., Bennett W., et al., “Microglia and Motor Neurons During Disease Progression in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis: Changes in Arginase1 and Inducible Nitric Oxide Synthase,” Journal of Neuroinflammation 11 (2014): 55.

200. Chabrier P. E., Demerlé‐Pallardy C., and Auguet M., “Nitric Oxide Synthases: Targets for Therapeutic Strategies in Neurological Diseases,” Cellular and Molecular Life Sciences 55, no. 8–9 (1999): 1029–1035.

201. Beckman J. S., Carson M., Smith C. D., and Koppenol W. H., “ALS, SOD and Peroxynitrite,” Nature 364, no. 6438 (1993): 584.

202. Chen X., Zhang X., Li C., et al., “S‐Nitrosylated Protein Disulfide Isomerase Contributes to Mutant SOD1 Aggregates in Amyotrophic Lateral Sclerosis,” Journal of Neurochemistry 124, no. 1 (2013): 45–58.

203. Deckel A. W., “Nitric Oxide and Nitric Oxide Synthase in Huntington's Disease,” Journal of Neuroscience Research 64, no. 2 (2001): 99–107.

204. Pérez‐Severiano F., Escalante B., Vergara P., Ríos C., and Segovia J., “Age‐Dependent Changes in Nitric Oxide Synthase Activity and Protein Expression in Striata of Mice Transgenic for the Huntington's Disease Mutation,” Brain Research 951, no. 1 (2002): 36–42.

205. Grad L. I., Rouleau G. A., Ravits J., and Cashman N. R., “Clinical Spectrum of Amyotrophic Lateral Sclerosis (ALS),” Cold Spring Harbor Perspectives in Medicine 7, no. 8 (2017): a024117.

206. Barber S. C. and Shaw P. J., “Oxidative Stress in ALS: Key Role in Motor Neuron Injury and Therapeutic Target,” Free Radical Biology and Medicine 48, no. 5 (2010): 629–641.

207. Martin L. J., Liu Z., Chen K., et al., “Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis Mutant Superoxide Dismutase‐1 Transgenic Mice: Mechanisms of Mitochondriopathy and Cell Death,” Journal of Comparative Neurology 500, no. 1 (2007): 20–46.

208. Turner M. R., Bowser R., Bruijn L., et al., “Mechanisms, Models and Biomarkers in Amyotrophic Lateral Sclerosis,” Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 14, no. 0 1 (2013): 19–32.

209. Chang Y., Kong Q., Shan X., et al., “Messenger RNA Oxidation Occurs Early in Disease Pathogenesis and Promotes Motor Neuron Degeneration in ALA,” PLoS One 3, no. 8 (2008): e2849.

210. Martin L. J., Chen K., and Liu Z., “Adult Motor Neuron Apoptosis Is Mediated by Nitric Oxide and Fas Death Receptor Linked by DNA Damage and p53 Activation,” The Journal of Neuroscience 25, no. 27 (2005): 6449–6459.

211. Graham R. K., Slow E. J., Deng Y., et al., “Levels of Mutant Huntingtin Influence the Phenotypic Severity of Huntington Disease in YAC128 Mouse Models,” Neurobiology of Disease 21, no. 2 (2006): 444–455.

212. Van Raamsdonk J. M., Murphy Z., Slow E. J., Leavitt B. R., and Hayden M. R., “Selective Degeneration and Nuclear Localization of Mutant Huntingtin in the YAC128 Mouse Model of Huntington Disease,” Human Molecular Genetics 14, no. 24 (2005): 3823–3835.

213. Hermel E., Gafni J., Propp S. S., et al., “Specific Caspase Interactions and Amplification are Involved in Selective Neuronal Vulnerability in Huntington's Disease,” Cell Death & Differentiation 11, no. 4 (2004): 424–438.

214. Graham R. K., Deng Y., Carroll J., et al., “Cleavage at the 586 Amino Acid caspase‐6 Site in Mutant Huntingtin Influences caspase‐6 Activation in Vivo,” The Journal of Neuroscience 30, no. 45 (2010): 15019–15029.

215. Warby S. C., Doty C. N., Graham R. K., et al., “Activated caspase‐6 and caspase‐6‐cleaved Fragments of Huntingtin Specifically Colocalize in the Nucleus,” Human Molecular Genetics 17, no. 15 (2008): 2390–2404.

216. Bossy‐Wetzel E., Petrilli A., and Knott A. B., “Mutant Huntingtin and Mitochondrial Dysfunction,” Trends in Neurosciences 31, no. 12 (2008): 609–616.

217. Bae B. I., Xu H., Igarashi S., et al., “p53 Mediates Cellular Dysfunction and Behavioral Abnormalities in Huntington's Disease,” Neuron 47, no. 1 (2005): 29–41.

218. Zheng J., Winderickx J., Franssens V., and Liu B., “A Mitochondria‐Associated Oxidative Stress Perspective on Huntington's Disease,” Frontiers in Molecular Neuroscience 11 (2018): 329.

219. Abramov A. Y., Potapova E. V., Dremin V. V., and Dunaev A. V., “Interaction of Oxidative Stress and Misfolded Proteins in the Mechanism of Neurodegeneration,” Life 10, no. 7 (2020): 101.

220. Hands S., Sajjad M. U., Newton M. J., and Wyttenbach A., “In Vitro and in Vivo Aggregation of a Fragment of Huntingtin Protein Directly Causes Free Radical Production,” Journal of Biological Chemistry 286, no. 52 (2011): 44512–44520.

221. Siddiqui A., Rivera‐Sánchez S., Castro M. R., et al., “Mitochondrial Dna Damage is Associated With Reduced Mitochondrial Bioenergetics in Huntington's Disease,” Free Radical Biology and Medicine 53, no. 7 (2012): 1478–1488.

222. Akbar M., Essa M. M., Daradkeh G., et al., “Mitochondrial Dysfunction and Cell Death in Neurodegenerative Diseases Through Nitroxidative Stress,” Brain Research 1637 (2016): 34–55.

223. Kim J., Moody J. P., Edgerly C. K., et al., “Mitochondrial Loss, Dysfunction and Altered Dynamics in Huntington's Disease,” Human Molecular Genetics 19, no. 20 (2010): 3919–3935.

224. Moren C., Souza R. M., Giraldo D. M., and Uff C., “Antioxidant Therapeutic Strategies in Neurodegenerative Diseases,” International Journal of Molecular Sciences 23, no. 16 (2022): 9328.

225. Shinn L. J. and Lagalwar S., “Treating Neurodegenerative Disease With Antioxidants: Efficacy of the Bioactive Phenol Resveratrol and Mitochondrial‐Targeted MitoQ and SKQ,” Antioxidants 10, no. 4 (2021): 573.

226. Kumar D., Md Ashraf G., Bilgrami A. L., and Imtaiyaz Hassan M., “Emerging Therapeutic Developments in Neurodegenerative Diseases: A Clinical Investigation,” Drug Discovery Today 27, no. 10 (2022): 103305.

227. Cummings J., Osse A. M. L., Cammann D., Powell J., and Chen J., “Anti‐Amyloid Monoclonal Antibodies for the Treatment of Alzheimer's Disease,” BioDrugs 38, no. 1 (2024): 5–22.

228. Miller R. G., Mitchell J. D., and Moore D. H., “Riluzole for Amyotrophic Lateral Sclerosis (ALS)/Motor Neuron Disease (MND),” Cochrane Database of Systematic Reviews 2012, no. 3 (2012): Cd001447.

229. Fields M., Marcuzzi A., Gonelli A., Celeghini C., Maximova N., and Rimondi E., “Mitochondria‐Targeted Antioxidants, an Innovative Class of Antioxidant Compounds for Neurodegenerative Diseases: Perspectives and Limitations,” International Journal of Molecular Sciences 24, no. 4 (2023): 3739.

230. Cruz M. P., “Edaravone (Radicava): A Novel Neuroprotective Agent for the Treatment of Amyotrophic Lateral Sclerosis,” P & T: A Peer‐Reviewed Journal for Formulary Management 43, no. 1 (2018): 25–28.

231. Brooks B. R., Berry J. D., Ciepielewska M., et al., “Intravenous Edaravone Treatment in ALS and Survival: An Exploratory, Retrospective, Administrative Claims Analysis,” eClinicalMedicine 52 (2022): 101590.

232. Shults C. W., Oakes D., Kieburtz K., et al., “Effects of Coenzyme Q10 in Early Parkinson Disease: Evidence of Slowing of the Functional Decline,” Archives of Neurology 59, no. 10 (2002): 1541–1550.

233. Beal M. F., Oakes D., Shoulson I., et al., “A Randomized Clinical Trial of High‐Dosage Coenzyme Q10 in Early Parkinson Disease: No Evidence of Benefit,” JAMA Neurology 71, no. 5 (2014): 543–552.

234. Negida A., Menshawy A., El Ashal G., et al., “Coenzyme Q10 for Patients With Parkinson's Disease: A Systematic Review and Meta‐Analysis,” CNS & Neurological Disorders ‐ Drug Targets 15, no. 1 (2016): 45–53.

235. Noda N., Hamatani T., Shibue Y., et al., “Phase 1 Study to Investigate the Safety, Tolerability, and Pharmacokinetics of EPI‐589 in Healthy Participants,” Clinical Pharmacology in Drug Development 11, no. 10 (2022): 1136–1146.

236. Isobe C., Abe T., and Terayama Y., “Increase in the Oxidized/Total Coenzyme Q‐10 Ratio in the Cerebrospinal Fluid of Alzheimer's Disease Patients,” Dementia and Geriatric Cognitive Disorders 28, no. 5 (2009): 434–439.

237. Galasko D. R., Peskind E., Clark C. M., et al., “Antioxidants for Alzheimer Disease: A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures,” Archives of Neurology 69, no. 7 (2012): 836–841.

238. Jin H., Kanthasamy A., Ghosh A., Anantharam V., Kalyanaraman B., and Kanthasamy A. G., “Mitochondria‐Targeted Antioxidants for Treatment of Parkinson's Disease: Preclinical and Clinical Outcomes,” Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease 1842, no. 8 (2014): 1282–1294.

Associated Data

Data Availability Statement

The authors have nothing to report.