Роль альфа-рецептора, активированного пероксидисом, в нейродегенеративных заболеваниях и других неврологических расстройствах: перспективы клинического применения.

Introduction

Neurodegenerative diseases are increasingly recognized as a pressing global health issue. The significant socioeconomic burden associated with these diseases inidcates the urgent need for innovative treatment strategies. As the global population ages, this burden is expected to escalate, highlighting the critical necessity for effective interventions. The pathophysiological mechanisms underlying neurodegenerative diseases are complex, involving inflammation, oxidative stress, and apoptosis (Abramov, 2022; Teleanu et al., 2022; Zhang et al., 2024). Current drug treatments are largely ineffective and often come with considerable side effects. Therefore, there is an urgent demand for new therapies to improve the onset, progression, and prognosis of neurodegenerative diseases. Peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor that belongs to the NR1C nuclear receptor subfamily, which also includes PPARγ and PPARβ/δ. PPARα plays a crucial role in various physiological processes, including lipid metabolism, glucose homeostasis, and cell differentiation (Montaigne et al., 2021; Riaz et al., 2023). In recent years, extensive research has focused on the role of PPARα in immune cells, where it is known to differentiate and expand various immune cell types (Christofides et al., 2021). Recent studies have also shown the potential role of PPARα in neuroprotection, neuroregeneration, metabolic regulation, and neuroinflammatory responses (Moreno and Cerù, 2015; Pérez-Segura et al., 2023; Ivraghi et al., 2024). PPARα operates at the intersection of immune regulation, energy balance, and inflammation, making it a promising target for treating neuroinflammatory diseases. While the role of PPARα in neurodegenerative diseases has garnered significant attention, further research and review are warranted. This article comprehensively outlines the relationship between PPARα and various neurodegenerative diseases, examines the possible mechanisms by which PPARα may contribute to their treatment, and emphasizes the potential of PPARα as a therapeutic target in these diseases.

Search Strategy

The articles cited in this review were primarily published between 2010 and 2024 and were retrieved from the PubMed and Google Scholar databases. In addition, we included some classic theories published prior to 2010. The following search keywords were used: PPARα, PPARα agonists, neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, neuroinflammation, and metabolites. Our search strategy used these specific keywords and their combinations. Articles with high relevance were screened based on the content of each article’s title and abstract.

Peroxisome Proliferator-Activated Receptor Alpha Expression Profile

At the outset of research on PPARα, Kersten (2014) indicated that this receptor is expressed at elevated levels in organs that primarily rely on fatty acids for energy metabolism, such as the heart, kidney, and liver. Additionally, PPARα is expressed in various immune cells, including monocytes, macrophages, and lymphocytes (Lefebvre et al., 2006). It was later discovered that PPARα exhibits different distributions across various tissues in mammals (Braissant et al., 1996). During the embryonic stage in rats, PPARα is co-expressed in the central nervous system (CNS); however, the expression of PPARα decreases in the postnatal stage (Abbott, 2009). Although the distribution of PPARα in the human brain is limited, it is present and fully active in the human CNS (Moreno et al., 2004; Heneka and Landreth, 2007). Subsequently, Warden et al. (2016) identified PPARα as the only isoform among the PPARs that co-localizes with all cell types in the brain tissue of adult mice and humans, as demonstrated using double immunofluorescence microscopy. Notably, PPARα displays a strong neuronal characteristic, its co-localization with neurons being significantly greater than that with astrocytes or microglia. Some scholars found that astrocytes are the primary cell type expressing PPARα in the brain, although the expression level is very low (Basu-Modak et al., 1999; Santos et al., 2005).

PPARα is traditionally regarded as a nuclear receptor that primarily functions as a transcription factor within the nucleus, highlighting its subcellular localization (Feige et al., 2005). However, recent studies have found that in differentiated human macrophages, PPARα exhibits a different distribution pattern, primarily located in the cytoplasm (Chinetti et al., 1998; Abbott, 2009). This distribution suggests that PPARα’s function may extend beyond the nucleus and is regulated by a dynamic balance of shuttling between the cytoplasm and the nucleus. For example, hyodeoxycholic acid (HDCA) directly interacts with RAN protein to reduce the nuclear export of PPARα without affecting its import, leading to an accumulation of PPARα in the nucleus and enhanced transcriptional activity (Zhong et al., 2023). This mechanism has implications for the therapy of non-alcoholic fatty liver disease (NAFLD), as HDCA promotes the nuclear localization of PPARα and enhances fatty acid oxidation in the liver, alleviating symptoms of NAFLD in mice. Conversely, MEK1 can directly interact with PPARα, causing its ectopic relocation from the nucleus to the cytoplasm and inhibiting its transcriptional activity. This interaction occurs through the binding of MEK1 to the LXXLL motif of PPARα, and the inhibitory effect is independent of MEK1’s kinase activity, relying instead on its nuclear export function (El Azzouzi et al., 2012).

Hager et al. (2000) revealed that the compartmentalization and dynamic translocation of transcription factors, including nuclear receptors, are essential for their transcriptional regulatory functions. Kumar et al. (2006) indicated that nuclear receptors, such as glucocorticoid, vitamin D, and thyroid hormone receptors, constantly shuttle between the cytoplasm and the nucleus. In various cell types, ligand stimulation induces the redistribution of glucocorticoid receptors and vitamin D receptors from the cytoplasm to the nucleus (Kumar et al., 2006). In contrast, estrogen and retinoic acid receptors remain confined to the nucleus, regardless of whether they are activated by a ligand (Hager et al., 2000). While PPARα is predominantly localized in the nucleus, it also possesses multiple nuclear import/export pathways, enabling dynamic shuttling between the nucleus and the cytoplasm. This process may be regulated by internal or external cellular signals and requires a balance between nuclear localization signals (NLS) and nuclear export signals (NES) (Hager et al., 2000). Umemoto and Fujiki (2012) identified two NLS and two NES in PPARα. The NLS is located in the DNA binding domain (DBD) and the hinge domain; however, the DBD also contains a NES that can be recognized by calreticulin, while another NES is found in the activation function-2 (AF2) domain. Research has demonstrated that PPARα’s intracellular translocation is regulated by its ligand, with the NLS accumulating in the nucleus in a ligand-dependent manner. When WY14643 is added to the culture medium, the NLS sharply accumulates in the nucleus within 1 hour. In contrast, upon withdrawal of WY14643, the NLS redistributes to the cytoplasm within the same timeframe (Umemoto and Fujiki, 2012). These findings reveal the dynamic distribution and function of PPARα in cells and emphasize the importance of nucleocytoplasmic shuttling as a key regulatory mechanism for PPARα function.

Peroxisome Proliferator-Activated Receptor Alpha Protein Structure

PPARα is a transcription factor characterized by a typical nuclear receptor structure comprising four distinct functional domains that collectively determine its biological function and activity (Kota et al., 2005; Figure 1 ). The A/B domain, located at the N-terminus, is the least conserved among PPAR family members. It contains a ligand-independent activation function-1 (AF-1), which plays a role in the post-transcriptional modification of PPARα (Hi et al., 1999). This region, rich in acidic amino acids, exhibits low basal transcriptional activity. Notably, the A/B domain can exert its function without the need for ligand binding (Desvergne and Wahli, 1999). The DBD, also referred to as the C domain, features two zinc finger structures that enable PPARα to specifically bind to the peroxisome proliferation response element (PPRE) located in the promoter region of target genes (Hsu et al., 1998). PPARα forms an obligatory heterodimer with the retinoid X receptor (RXR) for DNA binding (Kliewer et al., 1992; Ye et al., 2022). PPARα binds to the 5′ motif of the PPRE, while RXR binds to the 3′ motif (Rigano et al., 2017). The consensus sequence of the PPRE is notable for its two AGGTCA-like sequences, which are oriented and aligned by a single nucleotide spacer (Tzeng et al., 2015). The hinge region (D domain) is a highly flexible domain connecting the DBD and the ligand-binding domain (LBD, also known as the E binding domain) and serving as a docking site for transcriptional cofactors (Desvergne and Wahli, 1999). The hinge region’s structural integrity is crucial for the interaction between PPARα and nuclear receptor corepressors, such as NCoR, in the absence of a ligand (Dowell et al., 1999). A study on a truncated form of PPARα, lacking part of the hinge region and LBD, suggests that this region may contain a nuclear localization signal (Gervois et al., 1999). The E domain, which possesses a ligand-dependent transcriptional AF-2, is structured as a 12-helix formation that creates a large Y-shaped hydrophobic pocket known as the ligand-binding pocket (Pawlak et al., 2015; Christofides et al., 2021). The ligand-binding pocket exhibits strong lipophilicity, enabling the molecule to bind both endogenous and exogenous lipophilic ligands (Xu et al., 2001). For example, 1-palmitoyl-glycerol and 2-palmitoyl-glycerol act as natural agonists of PPARα, binding through hydrogen bonds with H440 (H10/11), Y464 (H12), and S280 (H3) within the LBD (Depommier et al., 2021). Upon ligand binding, the AF-2 domain undergoes a ligand-dependent conformational change that directs various co-activators carrying LXXLL motifs to the hydrophobic cleft on the LBD surface, facilitating the assembly of an active transcription complex (Xu et al., 2001).

Structure and function of PPARα.

PPARα protein consists of four distinct functional domains, each contributing to various biological functions and activities. The figure was created with BioRender.com. AF-1: Activation function-1; AF-2: activation function-2; DBD: DNA-binding domain; LBD: ligand binding domain; PPARα: peroxisome proliferator-activated receptor alpha; PPRE: peroxisome proliferation response element; RXR: retinoid X receptor.

Therapeutic Effects of Peroxisome Proliferator-Activated Receptor Alpha on Neurodegenerative Diseases

Neurodegenerative diseases are a class of disorders characterized by neuronal dysfunction and death (Dugger and Dickson, 2017), which typically lead to chronic and progressive neurological decline, impacting cognitive, motor, and sensory abilities (Lyketsos et al., 2011; Hardiman et al., 2017). Examples of neurodegenerative diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, and amyotrophic lateral sclerosis (ALS) (Mortada et al., 2021; Figure 2 ). The global trend of population aging has contributed to an increasing prevalence of neurodegenerative diseases, placing a considerable burden on affected individuals, their families, and healthcare systems. Despite some progress in understanding these diseases, effective treatments remain limited, particularly for interventions in the disorders’ early stages. In this context, PPARα has emerged as a key player at the intersection of energy metabolism and immune regulation, garnering significant attention for its potential in treating neurodegenerative diseases. PPARα may influence the progression of these diseases by modulating neuroinflammation, responding to oxidative stress, regulating synaptic plasticity in the hippocampus, and affecting gut microbiota metabolism.

Pie chart illustrating the mechanisms of PPARα involvement in nervous system diseases.

PPARα enhances Aβ phagocytosis through the autophagy-lysosome pathway in Alzheimer’s disease. In Parkinson’s disease, PPARα stimulates astrocytes to secrete GDNF, which aids in the repair of dopamine neurons. In multiple sclerosis, PPARα facilitates the transformation of Th1 cells into Th2 cells. PPARα promotes the apoptosis of glioblastoma cells. Created with the Figdraw 2.0 (license code: WIORP22422). GDNF: Glial cell-derived neurotrophic factor; MBP: myelin basic protein; PPARα: peroxisome proliferator-activated receptor alpha; Th1: T helper 1 cells; Th2: T helper 2 cells.

Peroxisome proliferator-activated receptor alpha in Alzheimer’s disease

AD is a progressive condition with an insidious onset and is the most common cause of dementia in the elderly. While age is the primary known risk factor, family history, genetic factors such as apolipoprotein E (APOE) variations, and lifestyle factors also play significant roles. The neuropathological hallmarks of AD include the accumulation of amyloid-beta (Aβ) plaques and the formation of neurofibrillary tangles within the brain parenchyma (DeTure and Dickson, 2019). According to the amyloid cascade hypothesis, the abnormal accumulation and clearance of Aβ in the brain are the initial events in AD onset (Heppner et al., 2015). Consequently, reducing the load of amyloid plaques in the brain holds great therapeutic potential for treating AD. Recent studies have demonstrated that synthetic PPARα agonists such as gemfibrozil can significantly reduce levels of soluble and insoluble Aβ in the hippocampus and cortical tissues of AD model mice (Luo et al., 2020; Raha et al., 2021). This reduction facilitates the gathering of microglia and astrocytes around Aβ plaques, boosts the formation of autophagosomes, and encourages lysosomal development (Luo et al., 2020; Raha et al., 2021). Investigations of the downstream targets of PPARα-promoted lysosomal development have revealed a complex regulatory network involving PPARα and transcription factor EB (TFEB). TFEB, a member of the microphthalmia-transcription factor E (MiT/TFE) family (Rehli et al., 1999), coordinates the expression of lysosomal genes through coordinated lysosomal expression and regulation (CLEAR) elements (Sardiello et al., 2009; Palmieri et al., 2011). TFEB is a key orchestrator of autophagy, enhancing autophagosome formation and facilitating their fusion with lysosomes (Settembre et al., 2011). Notably, the mouse Tfeb promoter contains a PPARα response element (PPRE) and an RXRα binding site. Gemfibrozil (a known PPARα activator) and ATRA (an RXRα agonist) can synergistically upregulate TFEB in brain cells through PPARα/RXRα heterodimers, thereby influencing lysosomal biogenesis (Ghosh et al., 2015). Combination therapy with gemfibrozil and retinoic acid can shift the activation state of astrocytes from the neurotoxic A1 type to the neuroprotective A2 type, enhance the expression of low-density lipoprotein receptor in astrocytes, and promote the internalization of Aβ ( Figure 3 ). TFEB, lysosome-associated membrane protein 2, and tripeptidyl peptidase 1 were upregulated in astrocytes and neurons in the hippocampus of 5XFAD mice following this combined therapy, leading to accelerated degradation of Aβ in lysosomes (Raha et al., 2021). In astrocytes treated with PPARα agonists, cathepsin B and cathepsin D levels increased by two to three times (Raha et al., 2021). This is consistent with research indicating that cathepsin B and cathepsin D are direct substrates for TFEB and that heightened TFEB activity increases both the quantity and functionality of cathepsins (Carey et al., 2020). Additionally, we observed that the expression of insulin-degrading enzyme was significantly reduced in the hippocampus of 5×FAD mice, while gemfibrozil treatment increased the astrocytes’ levels of insulin-degrading enzyme—one of the main proteases responsible for Aβ degradation (Raha et al., 2021).

Aβ uptake and degradation in AD.

In the hippocampus of patients with AD, gemfibrozil treatment can recruit microglia and astrocytes to Aβ plaques and promote the endocytosis of Aβ in A2 astrocytes. Additionally, gemfibrozil enhances the degradation of Aβ in astrocytes through the autophagy-lysosome pathway. Created with BioRender.com. Aβ: Amyloid-beta; AD: Alzheimer’s disease; ADAM10: A disintegrin and metalloproteinase 10; APP: amyloid precursor protein; CtsB: cathepsin B; CtsD: cathepsin D; IDE: insulin-degrading enzyme; LAMP2: lysosome-associated membrane protein 2; LDLR: low-density lipoprotein receptor; RXRα: retinoid X receptor; sAPPα: soluble amyloid precursor protein alpha; TFEB: transcription factor EB; TPP1: tripeptidyl peptidase 1.

Corbett et al. (2015) found that the Adam10 promoter contains a PPAR response element; it is PPARα, rather than PPARβ or PPARγ, that regulates the expression of Adam10. ADAM10 can prevent the production of Aβ by cleaving the amyloid precursor protein (APP) near the membrane, resulting in the release of soluble APPα fragments (Corbett et al., 2015; Yuan et al., 2017). PPARα activation in neuronal cells prevents DNA damage and neuronal apoptosis by reducing the expression of apoptosis-inducing factor and endonuclease G (Endo G), as well as inhibiting their translocation to the nucleus (Cheng et al., 2015). Both Endo G and apoptosis-inducing factor function as mitochondrial nucleases that, upon cytoplasmic release, translocate to the nucleus and induce chromatin fragmentation into nucleosomal units (Hangen et al., 2010; Wang et al., 2024). Therefore, enhancing cellular clearance pathways, particularly through the induction of lysosomal biogenesis and function, is considered a viable therapeutic strategy for diseases characterized by the accumulation of toxic protein aggregates.

Peroxisome proliferator-activated receptor alpha in Parkinson’s disease

PD is the second most prevalent neurodegenerative disorder and is associated with movement disturbances. The primary pathological feature of PD is the loss of dopaminergic neurons in the substantia nigra (Surmeier, 2018). PD development and progression are believed to be driven by the abnormal aggregation of α-synuclein and the subsequent propagation of pathological changes between the enteric nervous system, the brainstem, and higher-order brain regions (Morris et al., 2024). Current pharmacological interventions for PD primarily focus on dopamine replacement therapies, such as levodopa and the use of dopamine receptor agonists (Gao et al., 2020). While these treatments are effective in alleviating symptoms, they do not address the underlying disease progression, underscoring the need for novel therapeutic approaches.

Emerging evidence suggests that PPARα may play a significant role in PD-associated pathological processes. PPARα influences PD by regulating lipid metabolism and reducing neuroinflammation. The dysregulation of PPAR expression has been implicated in disease initiation and progression, with PPARα being expressed in dopaminergic neurons within the substantia nigra-striatum circuit (Galan-Rodriguez et al., 2009). Additionally, PPARα-deficient mice exhibit a decrease in the number of dopaminergic neurons in the substantia nigra, indicating that PPARα is essential for the normal development and functional maintenance of this region (Gonzalez-Aparicio et al., 2011).

In exploring treatment options for PD, it was found that regular jogging can delay the spread of α-synuclein in the mouse brain (Feng et al., 2020). This effect may be closely related to PPARα activation (Dutta et al., 2022). Further studies revealed that treadmill exercise can upregulate TFEB expression through PPARα-dependent transcription, enhancing the autophagy-lysosome pathway (Dutta et al., 2022). Gemfibrozil, a PPARα activator, stimulates the expression of GDNF in astrocytes, reducing nigrostriatal pathology and motor dysfunction in PD mouse models (Gottschalk et al., 2021). GDNF is regarded as a neurotrophic factor, and decreased production of GDNF in the brain is known to play a significant role in nigrostriatal degeneration in PD (Allen et al., 2013; Gottschalk et al., 2021). Additionally, cinnamic acid has been shown to protect striatal fibers in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and to restore motor function in MPTP-intoxicated mice through PPARα activation (Prorok et al., 2019). In summary, PPARα may play a crucial role in PD pathogenesis, and its activators may offer new strategies for treatment. These findings provide fresh perspectives for addressing PD, particularly in regulating neurotrophic factors and alleviating neuroinflammation. The potential therapeutic effects of PPARα activators warrant further study and exploration.

Peroxisome proliferator-activated receptor alpha in multiple sclerosis

Multiple sclerosis (MS) is the most prevalent non-traumatic disabling neurological condition affecting young adults (Kobelt et al., 2017). The pathological features of MS are primarily characterized by the formation of multiple demyelinating plaques in the CNS, accompanied by the infiltration of inflammatory cells and axonal damage (Dendrou et al., 2015; Melchor et al., 2019). Myelin is synthesized in the CNS by oligodendrocytes, while it is produced by Schwann cells in the peripheral nervous system (Salzer, 2015; Kuhn et al., 2019). In MS, impaired myelin repair capacity is considered a key factor contributing to nerve damage, the onset of disease symptoms, and increased disability. Promoting the regeneration of myelin is hoped to restore nerve signal transmission, thereby restoring function, reducing disability, and preventing further nerve damage (Jana et al., 2012). Therefore, developing therapies that target CNS inflammation and remyelination is essential for promoting nerve repair and potentially preventing disease progression. A growing body of evidence suggests that resident CNS glial cells and neurons, in conjunction with peripheral immune cells, mediate cytokine- and chemokine-induced pro-inflammatory signaling cascades that contribute to myelin degradation and axonal damage while also playing a role in resolving inflammation during remyelination (Ramesh et al., 2013). Since the approval of interferon β-1b for the treatment of MS in 1993, most research on drug treatments has focused on immunomodulation to counteract and reduce the neuroinflammatory processes that induce demyelination (Scolding et al., 2017). Currently, the therapeutic options approved by the Food and Drug Administration for managing MS include anti-inflammatory β-interferons, immunomodulatory agents such as glatiramer acetate and fingolimod, and therapies designed to prevent immune cell infiltration into the CNS parenchyma, such as natalizumab (anti-VLA-4) (Derwenskus, 2011).

PPARα mRNA expression levels were notably downregulated in the cerebellum of mice with experimental autoimmune encephalomyelitis, in contrast to the increased expression of other PPAR isotypes (Dasgupta et al., 2007). Dasgupta et al. (2007) demonstrated that the PPARα agonist gemfibrozil consistently exerted inhibitory effects on both the expression and DNA binding activity of T-bet, a transcription factor crucial for regulating interferon-γ expression. Concurrently, gemfibrozil stimulated GATA3 expression and DNA binding activity, a key regulator of IL-4 production. The differential effects of gemfibrozil on T-bet and GATA3 expression were attributed to its inhibitory effect on nitric oxide production. The drug was shown to alter the myelin basic protein-induced differentiation of T cells from Th1 to Th2 phenotypes. Additionally, Dasgupta et al. (2007) demonstrated that gemfibrozil inhibited the infiltration of T-bet-positive T cells into the spinal cord parenchyma of experimental autoimmune encephalomyelitis model mice. These findings suggest that PPARα may modulate the immune response in MS. However, immunotherapy is generally ineffective in preventing disease progression, as these therapies cannot prevent or reverse the failure of myelin regeneration (Najm et al., 2015). Consequently, the focus of new treatments has gradually shifted from merely suppressing inflammation to promoting myelin regeneration. Jana et al. (2012) found that gemfibrozil stimulated the expression of myelin-specific genes such as myelin basic protein, 2′,3′-cyclic-nucleotide 3′-phosphodiesterase, myelin oligodendrocyte glycoprotein, and proteolipid protein in human primary oligodendrocytes, mixed glial cells, and spinal cord organ cultures. Another study indicated that fenofibrate and gemfibrozil can promote myelination in zebrafish by activating sterol regulatory element-binding proteins (Ashikawa et al., 2016). These findings suggest that gemfibrozil possesses myelinogenic properties. As an approved drug for treating human hyperlipidemia, gemfibrozil’s dual mechanism of action may offer breakthroughs in the treatment of MS.

Peroxisome proliferator-activated receptor alpha in other neurodegenerative diseases

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a relentless and ultimately fatal neurodegenerative disorder that affects children. It results from mutations in the CLN2 gene, leading to a deficiency or complete loss of function of the tripeptidyl peptidase 1 (TPP1) enzyme (Sohar et al., 1999; Ghosh et al., 2017). LINCL is traditionally distinguished from other forms of neuronal ceroid lipofuscinosis based on the age of symptom onset and cellular morphology. The typical clinical presentation includes the onset of visual impairment, seizures, and progressive dementia between the ages of 2 and 4 years, with death occurring between 8 and 15 years of age (Sohar et al., 1999). A study by Ghosh et al. (2017) found that treatment with gemfibrozil resulted in improvements in motor function, a reduction in neuronal apoptosis, and an increase in anti-inflammatory factor expression in the brains of LINCL mice. Specifically, gemfibrozil treatment reduced the burden of storage substances in the brains of Cln2 (–/–) mice, increased levels of anti-inflammatory factors such as SOCS3 and IL-1Ra, upregulated anti-apoptotic molecules like phospho-Bad, and decreased neuronal apoptosis. These findings suggest that gemfibrozil may be a promising therapeutic agent capable of extending the lifespan of LINCL patients.

ALS, also known as motor neuron disease, is a heterogeneous neurodegenerative disorder characterized by the degeneration of both upper motor neurons (which originate in the cerebral cortex and project to the brainstem and spinal cord) and lower motor neurons (which project from the brainstem or spinal cord to innervate peripheral muscles). This degeneration leads to muscle weakness and eventual paralysis (Wijesekera and Nigel Leigh, 2009; Hardiman et al., 2017). Continuous systemic administration of fenofibrate has been shown to improve ALS-like phenotypes and prolong survival in SOD1 G93A mice, a widely used preclinical model of ALS (Lee et al., 2021). Treatment with fenofibrate resulted in reduced spinal cord neuronal cell loss and less spinal cord gliosis in SOD1 G93A mice (Lee et al., 2021). It is believed that the therapeutic effects of fenofibrate are associated with the induction of PPARα expression and a reduction in pro-inflammatory molecules, such as iNOS and COX-2 (Lee et al., 2021).

Peroxisome proliferator-activated receptor alpha in other brain tumors

As mentioned above, PPARα is primarily expressed in astrocytes, and its expression levels can vary in certain neural tumor cells, such as astrocytic cells (Haynes et al., 2017). Some studies indicate that PPARα has an inhibitory effect on neural tumors. For instance, Urbanska et al. (2008 found that fenofibrate demonstrates potential therapeutic effects on medulloblastoma. In 12 of 13 clinical samples of medulloblastoma, PPARα expression was elevated in the nuclei of tumor cells (Urbanska et al., 2008). Pre-incubation of mouse and human medulloblastoma cell lines with fenofibrate attenuated IGF-I-induced phosphorylation events and inhibited clonal growth (Urbanska et al., 2008). Additionally, PPARα exhibits anti-tumor effects in gliomas by reducing cell proliferation and aerobic glycolysis (Shi et al., 2016). However, results regarding the role of PPARα in glioblastoma are conflicting. Haynes et al. (2017) showed that the overexpression of PPARα protein and PPARα mRNA is associated with increased malignancy of gliomas in glioblastoma. The PPARα antagonist GW6471 has been reported to reduce the proliferation of glioblastoma cells and inhibit neurosphere formation (Fidoamore et al., 2017). Conversely, other evidence suggests that PPARα activation inhibits the proliferation of human glioma cells, delays the cell cycle in the G1 phase (Gao et al., 2018), and induces apoptosis along with an accumulation of ROS in U87 cells (a human glioblastoma cell line) (Shi et al., 2014). Among the various PPARα agonists, fenofibrate has shown a more significant anti-cancer effect on glioblastoma than others (Wilk et al., 2015). Fenofibrate’s primary function is to activate PPARα transcriptional activity. Fenofibrate is first converted to fenofibric acid by blood and tissue esterases. Fenofibric acid activates PPARα, triggering fatty acid β-oxidation, subsequently inhibiting the expression of glycolytic enzymes (Grabacka et al., 2013). Since tumor cells rely more heavily on glycolysis for energy production and biosynthesis, this metabolic switch may lead to a decline in tumor cell energy metabolism (Dell’ Antone, 2012). Fenofibrate primarily affects complex I of the electron transport chain in glioblastoma mitochondria, leading to a severe inhibition of mitochondrial respiration and a transient increase in glycolysis in tumor cells (Wilk et al., 2015). Normal cells metabolize fenofibrate to fenofibric acid more efficiently than tumor cells; consequently, fenofibric acid does not inhibit mitochondrial respiration. In contrast, cancer cells are exposed to both unprocessed fenofibrate and fenofibric acid, which together impair mitochondrial respiration and glycolysis, triggering an energy catastrophe in glioblastoma cells (Wilk et al., 2015). Therefore, fenofibrate is preferentially toxic to tumor cells while exhibiting low systemic toxicity.

Neuroprotective Mechanisms of Peroxisome Proliferator-Activated Receptor Alpha in Neurodegenerative Diseases

Neuroinflammation is an immune response activated by glial cells in the central nervous system and is closely associated with the progression of various neurodegenerative diseases. Recent research has highlighted PPARα agonists’ potential therapeutic effects on these conditions (Titus et al., 2024). PPARα activation is involved in regulating several key processes, including the inflammatory response, synaptic plasticity, and metabolic function. This provides new insights into the mechanisms for treating neurodegenerative diseases. PPARα plays crucial roles in modulating neuroinflammatory responses, maintaining synaptic plasticity, and influencing metabolic pathways, all of which have significant implications for neuroprotection and disease progression ( Figure 4 ).

Mechanism of PPARα in neurodegenerative diseases.

PPARα agonists regulate neurodegenerative diseases by modulating neuroinflammation, hippocampal synaptic plasticity, and gut microbiota metabolites. Akt: Protein kinase B; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF: brain-derived neurotrophic factor; CREB: cAMP response element binding protein; iNOS: inducible nitric oxide synthase; KYNA: kynurenic acid; NF-κB: nuclear factor-kappa B; NMDAR: N-methyl-D-aspartate receptor; OEA: oleoylethanolamide; PEA: palmitoylethanolamide; PI3K: phosphatidylinositol 3-kinase; PPARα: peroxisome proliferator-activated receptor alpha; ROS: reactive oxygen species; SCFAs: short-chain fatty acids; TLR4: toll-like receptor 4; Treg: regulatory T cells.

Role of peroxisome proliferator-activated receptor alpha in neuroinflammation and oxidative stress

Studies on various neuroinflammatory diseases and animal models, including AD, PD, stroke, diabetic peripheral neuropathy, and traumatic brain and spinal cord injury, have confirmed PPARα’s neuroprotective effects (Esposito et al., 2012; D’Orio et al., 2018; Luo et al., 2020). Chronic neuroinflammation is recognized as a key driver of pathological progression in AD (Schwartz and Deczkowska, 2016). Venegas et al. (2017) reported that neuroinflammation can accelerate Aβ aggregation and increase microglial toxicity under AD-associated pathological conditions. This is due to the rise in inflammasome components, which may act as a seed for Aβ aggregation (Venegas et al., 2017; Friker et al., 2020).

PPARα serves as a key modulator in the regulation of inflammatory pathways. PPARα activation has been shown to suppress the expression of inflammatory response genes by repressing multiple signaling pathways, including NF-κB, activator protein-1 (AP-1), a signal transducer and transcription activator (Yang et al., 2016). Specifically, the downregulation of AP-1 following PPARα activation results in the inhibition of thrombin-induced endothelin-1 production in arterial endothelial cells, a potent vasoconstrictor associated with vascular inflammation (Delerive et al., 1999). Furthermore, this activation diminishes the production of the inflammatory mediators IL-6 and COX-2 in response to IL-1 and downregulates inducible nitric oxide synthase (iNOS) in macrophages (Fruchart et al., 1999).

PPARα activation has also been suggested as a therapeutic target in the context of ischemic stroke. In a study involving rats treated with fenofibrate or a vehicle after experiencing a stroke, transient middle cerebral artery occlusion followed by thrombolysis with tissue plasminogen activator demonstrated that PPARα agonism reduced infarct volume. This reduction was accompanied by decreased microglial activation and neutrophil infiltration within the infarcted area (Gautier et al., 2015).

Zhang et al. (2021) found that the PPARα agonist PEA alleviates apoptosis in the spinal cord neurons of rats with spinal cord injury by activating the PI3K/Akt signaling pathway. Additionally, it inhibits oxidative stress damage and promotes the recovery of motor function in SCI rats by activating the Raf-1/MEK/ERK signaling pathway. Other research has shown that PPARα has a significant therapeutic effect on obesity, as well as on paclitaxel-induced peripheral inflammatory hyperalgesia and cancer pain (Piomelli et al., 2006; Khasabova et al., 2012; Wang et al., 2014; Cristiano et al., 2022). For instance, PPARα can reverse and prevent paclitaxel-induced cold hypersensitivity and reduce neuroinflammation in the dorsal root ganglion (Caillaud et al., 2021). Furthermore, the PPARα agonist fenofibrate, when combined with oxaliplatin, tends to prevent the enhancement of thermal hyperalgesia in hind paw withdrawal and friction responses induced by oxaliplatin. The expressions of inflammatory markers interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), and IL-6 decreased significantly following fenofibrate treatment (Xu et al., 2006; Aliyah et al., 2023). PPARα agonists can also reduce inflammatory oxidative stress in the CNS. Fenofibrate has been shown to reduce oxidative stress in rats with traumatic brain injury, as evidenced by 3-nitrotyrosine and 4-hydroxynonenal staining, glutathione depletion, and an increased glutathione oxidation ratio (Chen et al., 2007). Additionally, PPARα activation prevents Aβ neurotoxicity by reducing the production of ROS and increasing catalase activity in hippocampal and cortical neurons (Gray et al., 2011).

Fenofibrate also improves inflammatory changes in CNS diseases by regulating immune function. Xu et al. (2007) demonstrated that fenofibrate can inhibit the secretion of IL-23, IL-12p40, IL-12p70, and IL-27p28 by microglia and astrocytes stimulated by lipopolysaccharide. Additionally, fenofibrate inhibits CD14/TLR expression in microglia, thereby regulating the production of pro-inflammatory molecules.

However, further studies have indicated that fenofibrate may exacerbate the inflammatory process (Dotson et al., 2016) and does not provide neuroprotective effects in female animal models (Dun et al., 2007; Dotson et al., 2016). In stroke treatment, fenofibrate can increase the expression of the M2 macrophage phenotype (CD206) in the ischemic hemisphere of men while promoting the expression of the M1 macrophage phenotype (TNF-α) and increasing gene expression of the pro-inflammatory cytokine IL-6 in the ischemic hemisphere of women (Dotson et al., 2016). The lower PPARα expression in the ischemic hemisphere may partially explain the poorer long-term stroke outcomes observed in women. Another study found that women with high low-density lipoprotein (LDL) cholesterol levels experienced increased visual memory loss when taking fenofibrate for more than 7 years (Ancelin et al., 2012). This effect may be attributable to the fact that, in older adult individuals without ApoE4 alleles, higher LDL cholesterol is associated with better memory function (West et al., 2008). Long-term use of fenofibrate may negatively affect visual memory by lowering LDL cholesterol levels. Dunn et al. (2007) found that PPARα is more abundant in male than female CD4 + T cells, and its expression is sensitive to androgen levels. Genetic ablation of PPARα selectively removes the regulatory brake on NF-κB and c-jun activity in male T lymphocytes, leading to higher production of interferon gamma (IFNγ) and tumor necrosis factor (TNF) (but not IL-17) and reduced production of T helper (Th) 2 cytokines. These findings suggest that males may be less susceptible to Th1-mediated autoimmunity due to their T cells expressing higher levels of PPARα.

Role of peroxisome proliferator-activated receptor alpha in synaptic plasticity

It is well known that the CNS and the immune system engage in strong bidirectional crosstalk. Modulation of synaptic plasticity by neuroinflammatory mediators can negatively affect the function of brain neuronal networks (Di Filippo et al., 2013). Neuroinflammatory diseases associated with cognitive function, such as PD and AD, may involve abnormalities in the induction, maintenance, and reversal of neuroplasticity (Di Filippo et al., 2008). In addition to its anti-inflammatory properties, PPARα may positively influence synaptic plasticity through multiple mechanisms. PPARα is implicated in the modulation of pain perception, potentially through its effects on glucocorticoid signaling pathways. Glucocorticoids, a class of steroid hormones, are secreted in response to acute or chronic physical and psychological stress and interact with the glucocorticoid receptor (GR), a distinct nuclear receptor. These hormones can traverse the blood–brain barrier and blood–spinal cord barrier. However, excessive glucocorticoid levels can adversely affect neuronal health, leading to synaptic degeneration, hippocampal atrophy, and cognitive impairments (Müller et al., 2001; Tata et al., 2006; Liston and Gan, 2011). In the CNS, glucocorticoid signaling is associated with the exacerbation of pain-like behaviors and exhibits upregulation that correlates with the surge in inflammatory cytokines following injury (Blackburn-Munro and Blackburn-Munro, 2003). PPARα activation interferes with GR-dependent gene expression by inhibiting glucocorticoid receptor alpha recruitment and blocking RNA polymerase II recruitment to glucocorticoid response elements on GR target gene promoters (Bougarne et al., 2009).

Recent research indicates that aspirin, a widely used analgesic, binds to the Tyr314 residue of the PPARα LBD. Aspirin enhances hippocampal plasticity by stimulating the transcriptional activation of cAMP response element-binding protein (CREB) through PPARα (Patel et al., 2018). Low-dose oral aspirin has been shown to upregulate brain-derived neurotrophic factor (BDNF), CREB, and other plasticity-related molecules, such as PSD95 and NR2A, while also increasing calcium influx in the hippocampus of mice (Patel et al., 2018). Additionally, it has been demonstrated that the protective effects of nonsteroidal anti-inflammatory drugs may arise from their ability to activate PPAR receptors and inhibit inflammatory responses in the brain (Landreth and Heneka, 2001).

Additionally, hexadecanamide is present in the hippocampus of normal mice as an endogenous ligand of PPARα (Roy et al., 2016). Oral administration of hexadecanamide can increase BDNF, PSD95, and neurotrophin-3 (NT3) levels in hippocampal neurons (Patel et al., 2020). Similar to BDNF, NT3 is known to regulate synaptic plasticity through the tropomyosin-related kinase B receptor (Chao, 2003; Patel et al., 2020). In AD, PPARα deficiency has been shown to affect the neuronal activity of cultured hippocampal neurons and synaptic plasticity in mice. The reduction in PPARα target gene expression may lead to hAPP-mediated silencing of cortical network synaptic transmission (Sáez-Orellana et al., 2021). Simvastatin, an HMG-CoA reductase inhibitor (Sanford and Curran, 2008), can increase BDNF levels in the hippocampus and cortex of AD mice, subsequently improving memory and learning abilities. However, simvastatin failed to stimulate BDNF production in CNS tissues or enhance memory and learning capabilities in FAD5X/PPARα-deficient mice (Roy et al., 2015). These findings indicate that PPARα plays a crucial role in the upregulation of neurotrophic factors in the CNS and in the preservation of memory during AD pathology.

A previous study reported that PPARα is essential for normal cognitive function, as deficits in spatial learning and long-term memory were observed in PPARα-knockout mice (D’Agostino et al., 2015). Additionally, PPARα deficiency impacts the expression of a group of synaptic proteins involved in excitatory neurotransmission and severely impairs hippocampal long-term potentiation, an activity-dependent enhancement of synaptic strength plays a critical role in memory processing (Bliss and Collingridge, 1993; Roy et al., 2013; Pierrot et al., 2019). Studies have demonstrated significant gender differences in hippocampal synaptic plasticity in mice, which are associated with variations in PPARα expression levels (Pierrot et al., 2019; Gall et al., 2023). Specifically, PPARα expression in male mice is twice as high as that in female mice. The enhancement of hippocampal synaptic plasticity mediated by PPARα is attributed to increased expression of the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, which triggers an AMPA response at excitatory synapses (Pierrot et al., 2019). The use of the PPARα antagonist GW6471 may influence both GluN2B and GluA1 expression and/or affect Cpt1c-mediated trafficking of GluA1, thereby regulating the synaptic activity of neurons (Gratacòs-Batlle et al., 2015; Sáez-Orellana et al., 2021).

Role of peroxisome proliferator-activated receptor alpha in metabolic regulation

Recently, intestinal microbes have become a focal point of research in various areas, including cancer, gastrointestinal diseases, and nervous system disorders. An abnormal composition and metabolites of intestinal microbes can lead to nerve damage by regulating immune responses, thereby contributing to neuroinflammatory diseases. PPARα plays a crucial role in regulating the homeostasis of commensal bacteria (Hasan et al., 2019). The PPARα pathway in innate immune cells coordinates intestinal mucosal immunity and commensal homeostasis by regulating the expression of interleukin-22 (IL-22) and antimicrobial peptides such as RegIIIβ, RegIIIγ, and calprotectin (Manoharan et al., 2016). PPARα deficiency in mice results in dysbiosis of intestinal commensal bacteria, leading to a microbiota-dependent increase in inflammatory cytokine expression (Manoharan et al., 2016). Recent studies have indicated that an abnormal composition of intestinal microbiota and their metabolites may contribute to nerve damage and, subsequently, neuropathic pain.

Wu et al. (2024) demonstrated that PPARα can alter the composition of the microbiota in chronic constriction injury (CCI) model mice. Compared to the CCI group, the abundance of Adlercreutzia increased following administration of the PPARα agonist GW7647, while the abundances of Rikenella and Alistipes were significantly reduced. Adlercreutzia possesses anti-inflammatory properties both in vivo and in vitro , mildly inhibiting the pro-inflammatory NF-κB pathway and reducing IL-6 expression (Oñate et al., 2023). Additionally, N-palmitoyl-D-glucose produced by Rhizobium leguminosae exerts anti-inflammatory effects by preventing TLR4/NLRP3/iNOS pathway activation through a PPARα-mediated mechanism (Das et al., 2016; Palenca et al., 2022).

Recently, metabolic dysfunction, including impaired glucose metabolism and insulin resistance, has been identified as a major factor in the initiation of peripheral inflammation (Cai and Liu, 2012). In a transgenic mouse model of AD fed a high-fat diet, neuroinflammation and Aβ pathology in the brain were more severe than in mice fed a normal diet (Cole et al., 2010; Kim et al., 2016). Additionally, a high-fat diet can induce changes in PPAR expression in the midbrain dopaminergic pathway, leading to PD-like symptoms (Kao et al., 2020). This diet reduces dopaminergic neurons in the substantia nigra and leads to a decrease in dendritic spine density in both the substantia nigra and the striatum (Kao et al., 2020). Furthermore, there is increasing epidemiological evidence supporting the existence of numerous pathophysiological similarities between diabetes and AD (Barbagallo and Dominguez, 2014; Burillo et al., 2021). Studies have shown that up to 80% of AD patients may have significant diabetes or impaired glucose tolerance (Janson et al., 2004; Vieira et al., 2018). Exposure of β cells to hyperglycemia rapidly reduces PPARα gene expression, which is necessary for sugar phosphorylation (Roduit et al., 2000). Further studies have shown that the energy sensor AMPK can activate PPARα expression, which is related to hyperglycemic conditions (Joly et al., 2009; de Souza et al., 2017). These findings provide important clues for a deeper understanding of the interaction between metabolic dysfunction and neurodegenerative diseases and offer new perspectives for future treatment strategies.

Notably, a lipidomics analysis study found that oleoylethanolamide (OEA) was downregulated in the plasma and cerebrospinal fluid of AD patients compared with non-demented controls, and OEA was identified as the strongest predictor of AD among both plasma and cerebrospinal fluid metabolites (Borkowski et al., 2021). PPARα agonists, such as fibrates, have been found to exert neuroprotective effects by modulating the levels of the tryptophan metabolite kynurenic acid (KYNA) (Wójtowicz et al., 2020). Initially, KYNA was considered only a byproduct of tryptophan degradation; however, with a deeper understanding of its molecular structure, KYNA was confirmed to be an antagonist of the N-methyl-D-aspartate receptor, which is involved in excitatory neurotransmission in the CNS, and it has neuroprotective effects (Gulaj et al., 2010). Specifically, data from Zakrocka et al. (2018) showed that the PPARα agonist gemfibrozil could reduce KYNA synthesis in the rat cerebral cortex in vitro , suggesting that PPARα activation may regulate neural excitability and protect neurons by affecting KYNA levels (Deora et al., 2017; Zakrocka et al., 2018).

Furthermore, studies have shown that gut microbiota composition and activity can significantly influence the host’s metabolic and immune responses, including the regulation of PPAR activity (Oh et al., 2019; Grabacka et al., 2022). Short-chain fatty acids are among the most abundant metabolites produced by the gut microbiota through the anaerobic fermentation of dietary fiber and function as PPAR agonists (Oh et al., 2019). Research indicates that short-chain fatty acids can cross the blood–brain barrier and regulate microglial activation, leading to subsequent polarization to a pro-inflammatory phenotype in the hippocampus and spinal cord, which plays a key role in the pathogenesis of neuropathic pain (Zhou et al., 2021; Fock and Parnova, 2023). Additionally, acetate significantly attenuated cognitive impairment in APP/PS1 mice and reduced CD11b levels (Liu et al., 2020). Acetate inhibited NF-κB p65, ERK, and JNK phosphorylation in Aβ-stimulated BV2 microglia and reduced COX-2 and IL-1β levels (Liu et al., 2020). Furthermore, butyrate limits the formation of TGF-β1 and IL-6, upregulates anti-inflammatory cytokines, and exerts anti-inflammatory effects by stimulating Treg cell activity and improving host immunity (Asarat et al., 2016). Therefore, PPARα agonists not only act through direct metabolic regulation but may also affect the host nervous system and behavior through the gut–brain axis, providing a new perspective for the treatment of neuroinflammatory diseases.

Application of Peroxisome Proliferator-Activated Receptor Alpha Agonists in Neurodegenerative Diseases

Peroxisome proliferator-activated receptor alpha natural agonists

Over the past decade, scientists have conducted in-depth research on the biological and physiological functions of PPARα agonists and have made significant progress. PPARα agonists can be divided into two major categories: natural (endogenous) and synthetic (exogenous) ( Table 1 ). The most potent endogenous agonists of PPARα are fatty acids and related compounds, including palmitic acid, fatty amides such as palmitoylethanolamide (PEA) and OEA, and leukotriene B4 (Devchand and Wahli, 1998; Wahli and Michalik, 2012; Rigano et al., 2017; Kamata et al., 2020). These endogenous agonists exert their biological effects by binding to PPARα. In particular, both PEA and clofibrate can activate TRPV1 channels through PPARα activation, leading to the desensitization of these channels, which may be an important mechanism for their anti-inflammatory and analgesic effects (Verme et al., 2005; Ambrosino et al., 2013, 2014; Alsalem et al., 2019). Additionally, PEA is involved in promoting microglial polarization to the M2 type, attenuating the activation of neuroinflammation and intervening in pain-induced neural tissue changes with repeated treatments (Zhou et al., 2022). For example, in the CCI mouse model, PEA can significantly increase the myelin sheath, axon diameter, and fiber number (Di Cesare Mannelli et al., 2013). OEA, as an endocannabinoid analog, can improve levodopa-induced dyskinesia and reduce the overexpression of FosB and histone 3 phosphoacetylation induced by levodopa in the diseased striatum (González-Aparicio and Moratalla, 2014).

Table 1 Natural and synthetic compounds identified as PPARα agonists PPARα agonist Function Targeted disease System Reference
Natural agonists
    Oleoylethanolamide Improves movement disorders; reduces FosB and histone 3 phosphoacetylation. Parkinson’s disease
In vivo
González-Aparicio and Moratalla, 2014     Palmitoylethanolamide Promotes microglia polarization to M2 phenotype; alleviates pathological changes in damaged nerves. Neuropathic pain
In vivo
Di Cesare Mannelli et al., 2013; Zhou et al., 2022 Activates the PI3K/Akt signaling pathway; promotes the recovery of motor function. Neuropathic pain
In vivo
Zhang et al., 2021     Hexadecanamide Upregulates BDNF and stimulates synaptic function. AD
In vivo
Patel et al., 2020     Dehydroabietic acid Inhibits the production of pro-inflammatory mediators such as MCP-1, TNF-α, and NO in macrophages and adipocytes. ND
In vitro
Kang et al., 2008     Resveratrol Reduces cerebral ischemia. Stroke
In vivo
Inoue et al., 2003     Cinnamic acid Induces lysosomal biogenesis; attenuates amyloid plaque pathology. AD
In vitro
Chandra et al., 2019 Protects striatal fibers and restores motor function. Parkinson’s disease
In vivo
Prorok et al., 2019     Short-chain fatty acids Modulates microglial activation in the hippocampus and spinal cord. Neuropathic pain
In vivo
Zhou et al., 2021; Fock and Parnova, 2023
Synthetic agonists
    Fenofibrate Reduces neuroinflammation in mouse DRG. Chemotherapy-induced hyperalgesia
In vivo
Caillaud et al., 2021; Aliyah et al., 2023 Negatively regulates NF-κB and AP-1 pathways. Radiation-induced brain injury
In vivo
Ramanan et al., 2008, 2009 Promotes myelination in zebrafish by activating SREBFs. ND
In vivo
Ashikawa et al., 2016 Reduces spinal cord neuronal cell loss and spinal cord gliosis. Amyotrophic lateral sclerosis
In vivo
Lee et al., 2021 Increases the expression of M1 macrophages in males and M2 macrophages in females. Stroke
In vivo
Dotson et al., 2016     WY 14.643 Protects neurons by modulating mitochondrial fusion and fission. AD
In vitro
Zolezzi et al., 2013 Increases SIRT1 expression. Neuropathic pain
In vivo
Wen et al., 2020     Clofibrate Reduces TRPV1-dependent integration and transmission of pain signals. ND
In vitro
Ambrosino et al., 2014     Pemafibrate Inhibits NF-kB phosphorylation and microglial activation. ND
In vitro
Ogawa et al., 2020     GW7647 Improves disruption of iron homeostasis and alleviates lipid peroxidation. AD
In vivo
Qu et al., 2022 Changes the richness of the gut microbiota. Neuropathic pain
In vivo
Wu et al., 2024     Aspirin Upregulates BDNF and CREB to increase hippocampal plasticity ND
In vivo
Patel et al., 2018     Gemfibrozil Upregulates ADAM10 and induce lysosomal biogenesis; lowers the amyloid plaque burden in the hippocampus and cortex. AD
In vivo
Corbett et al., 2015; Ghosh et al., 2015; Chandra and Pahan, 2019 Reduces kynurenic acid synthesis in the cerebral cortex. AD
In vitro
Deora et al., 2017; Zakrocka et al., 2018 Transforms astrocytes from type A1 to type A2, and promotes the internalization of Aβ. AD
In vitro
Ghosh et al., 2015 Stimulates GDNF expression in astrocytes. Parkinson’s disease
In vitro
Gottschalk et al., 2021 Upregulates GATA3 expression and inhibits T-bet expression; promotes the differentiation of T cells from Th1 to Th2. Multiple sclerosis
In vivo
Dasgupta et al., 2007 Increases anti-inflammatory factors such as SOCS3 and IL-1Ra; reduces neuronal apoptosis. Late infantile neuronal ceroid lipofuscinosis
In vivo
Ghosh et al., 2017     Simvastatin Increases BDNF in the hippocampus and cortex; improves memory and learning ability. AD
In vivo
Sanford and Curran, 2008 This table summarizes the mechanisms of action of common natural and synthetic PPARα agonists in different neurological diseases. AD: Alzheimer’s disease; ADAM10: a disintegrin and metalloproteinase 10; AP-1: activator protein-1; Aβ: amyolid-beta; BDNF: brain-derived neurotrophic factor; CREB: cAMP response element binding protein; DRG: dorsal root ganglion; GATA3: GATA binding protein 3; GDNF: glial cell-derived neurotrophic factor; IL-1Ra: interleukin-1 receptor antagonist; MCP-1: monocyte chemoattractant protein-1; ND: not defined; NF-κB: nuclear factor κB; NO: nitric oxide; PI3K/Akt: phosphoinositide 3-kinase/protein kinase B; PPARα: peroxisome proliferator-activated receptor alpha; SIRT1: sirtuin 1; SOCS3: suppressor of cytokine signaling 3; SREBFs: sterol regulatory element-binding protein; Th1: T helper 1; Th2: T helper 2; TNF-α: tumour necrosis factor-α; TRPV1: transient receptor potential vanilloid 1.

Natural and synthetic compounds identified as PPARα agonists

This table summarizes the mechanisms of action of common natural and synthetic PPARα agonists in different neurological diseases. AD: Alzheimer’s disease; ADAM10: a disintegrin and metalloproteinase 10; AP-1: activator protein-1; Aβ: amyolid-beta; BDNF: brain-derived neurotrophic factor; CREB: cAMP response element binding protein; DRG: dorsal root ganglion; GATA3: GATA binding protein 3; GDNF: glial cell-derived neurotrophic factor; IL-1Ra: interleukin-1 receptor antagonist; MCP-1: monocyte chemoattractant protein-1; ND: not defined; NF-κB: nuclear factor κB; NO: nitric oxide; PI3K/Akt: phosphoinositide 3-kinase/protein kinase B; PPARα: peroxisome proliferator-activated receptor alpha; SIRT1: sirtuin 1; SOCS3: suppressor of cytokine signaling 3; SREBFs: sterol regulatory element-binding protein; Th1: T helper 1; Th2: T helper 2; TNF-α: tumour necrosis factor-α; TRPV1: transient receptor potential vanilloid 1.

In addition to the endogenous agonists mentioned above, many natural compounds have also been found to exhibit PPARα agonist activity. For example, dehydroabietic acid is a class of phytochemicals that can act as dual activators of PPARα and PPARγ, significantly inhibiting the production of pro-inflammatory mediators such as MCP-1, TNF-α, and NO in macrophages and adipocytes (Kang et al., 2008). Resveratrol, a polyphenol found in grapes, can reduce cerebral infarct volume after a stroke through PPARα activation (Inoue et al., 2003). Cinnamic acid induces lysosomal biogenesis through PPARα and acts as a PPARα-dependent attenuator of amyloid plaque pathology in the 5XFAD mouse model (Chandra et al., 2019).

However, natural agonists of PPARα are often non-specific, meaning that they may simultaneously activate other PPAR family subtypes, such as PPARβ/δ and PPARγ, which can lead to unintended biological effects. For example, PPARγ activation is associated with improved insulin sensitivity, but in some cases, it may also result in side effects such as weight gain, osteoporosis, and heart failure (Wang et al., 2016). The low potency, insufficient bioavailability, and lack of stability of natural agonists limit their use in clinical treatment. In contrast, synthetic agonists are emerging as potential candidates for the treatment of related diseases due to their higher potency and specificity, as well as better stability and bioavailability. Clinical research on these synthetic agonists is also advancing, providing new possibilities for future treatments.

Peroxisome proliferator-activated receptor alpha synthetic agonists

When exploring the potency of synthetic PPARα agonists, we found that there may be differences in potency between human and mouse receptors. A compound called urea-substituted thioisobutyric acid (GW9578) is a highly selective PPARα agonist, with a selectivity of 300-fold for mouse receptors and 20-fold for human receptors (Brown et al., 1999). Brown et al. (1999) reported that GW9578 exhibited potent lipid-lowering activity in a mouse model fed cholesterol or bile acid. However, there are relatively few reports on its therapeutic effects in neurological diseases. Another synthetic PPARα agonist, GW7647, acutely inhibited the functional activity of acid-sensing ion channels in rat dorsal root ganglion neurons, which are key sensors of extracellular protons. Pre-application of the PPARα agonist GW7647 for 2 minutes resulted in a concentration-dependent reduction in the amplitude of proton-gated currents mediated by acid-sensing ion channels (Wu et al., 2017). Qu et al. (2022) demonstrated that GW7647 could improve iron homeostasis disruption in the brains of AD model mice and reduce neuronal inflammation and lipid peroxidation. Fenofibrate, another synthetic PPARα agonist, not only intervenes in and reduces the duration of diabetes but also inhibits the expression of vascular endothelial growth factor and vascular endothelial growth factor receptor in human retinal pigment epithelial cells under hypoxic conditions (Keech et al., 2005; Zhao et al., 2015). The pretreatment of BV-2 mouse microglia with fenofibrate suppressed radiation-induced pro-inflammatory responses by negatively regulating the NF-κB and AP-1 pathways and reduced the number of activated microglia in the granular zone of the dentate gyrus after whole-brain irradiation (Ramanan et al., 2008, 2009). Although pemafibrate can also inhibit NF-κB phosphorylation and microglial activation, its inhibitory effect on microglial IL-6 expression can be reversed by knocking down PPARα, indicating that this effect of pemafibrate is dependent on PPARα (Ogawa et al., 2020). Similar to the biological effects of cinnamic acid mentioned above, gemfibrozil can both upregulate the alpha-secretase a disintegrin and metalloproteinase 10 and stimulate cellular clearance by inducing lysosomal biogenesis, thereby attenuating amyloid deposition in the hippocampus and cortex of 5XFAD mice in a PPARα-dependent manner (Corbett et al., 2015; Ghosh et al., 2015; Chandra and Pahan, 2019). In a rat model of CCI, another PPARα agonist has been shown to increase the expression of SIRT1, a deacetylase involved in cell survival, metabolic regulation, and response to stress. WY-14643 inhibits the activity of NF-κB, a key pro-inflammatory signaling pathway, by increasing SIRT1 expression (Wen et al., 2020). WY-14643 can also protect neurons by modulating mitochondrial fusion and fission, significantly improving cognitive abilities and reducing neuronal damage in AD mouse models (Zolezzi et al., 2013).

Currently, research on PPARα agonists primarily focuses on hyperlipidemia and cardiovascular disease; however, these agonists also exhibit significant potential in the treatment of neurological disorders. For individuals with neurological diseases who also have dyslipidemia and cardiovascular risk, regulating PPARα activity may be beneficial. In the coming years, PPARα and its agonists are expected to remain key subjects of both basic science and clinical research.

Problems and limitations in the application of peroxisome proliferator-activated receptor alpha agonists

Currently, there are numerous studies investigating the protective effects of natural PPARα agonists on various diseases; however, reports on their potential toxicity are limited. Future research should focus on the long-term effects of natural PPARα agonists in humans and their potential adverse reactions in vivo . Despite their benefits, natural agonists do have some limitations in practical applications. OEA is an endogenous molecule that exhibits no nephrotoxicity or hepatotoxicity (Sabahi et al., 2022). It can inhibit food intake in rats by activating PPARα on local intestinal sensory fibers. From a pharmacological perspective, the conversion of OEA into oleate and ethanolamine—two non-toxic natural dietary compounds—is highly desirable (Nielsen et al., 2004). So far, no side effects have been reported for OEA. PEA is a non-endogenous cannabinoid lipid mediator, first isolated from soy lecithin, egg yolk, and peanut meal (Beggiato et al., 2019). It is currently used in treating neuroinflammatory and neurodegenerative diseases and is known for its high safety and tolerability (Petrosino and Di Marzo, 2017). However, PEA has limitations regarding solubility and bioavailability due to its poor water solubility, large particle size in its natural state, and potential short-lived effects (Beggiato et al., 2019). Its ability to penetrate the blood–brain barrier is low, with brain bioavailability estimated at only 0.95% of an oral dose (Gabrielsson et al., 2016). Micronized or ultra-micronized forms of PEA may improve its bioavailability in animals. The commercial use of resveratrol as a therapeutic agent currently faces several challenges. Its low bioavailability and rapid metabolism are considered the most significant limiting factors (Walle et al., 2004). After the oral administration of 25 mg of resveratrol, only trace amounts (< 5.0 ng/mL) of unmetabolized resveratrol can be detected in the plasma. Furthermore, resveratrol exhibits low water solubility and is stable in water only at room temperature and under acidic conditions (Zupančič et al., 2015). While short-term doses (1.0 g) of resveratrol appear to have no side effects, daily doses of 2.5 g or more may lead to adverse effects such as nausea, vomiting, diarrhea, and liver dysfunction in patients with NAFLD (Brown et al., 2010). Additionally, high doses of resveratrol can inhibit the systemic phenotype of cytochrome P450 enzymes (Calabrese et al., 2010).

Synthetic PPARα agonists, known as fibrates, have been effective in reducing the residual risk of atherogenic dyslipidemia and hypertriglyceridemia in patients. Generally considered safe with few side effects, the incidence of adverse events is still notable, with 2%–15% of the treated population experiencing adverse reactions during fibrate therapy (Blane, 1987). The most significant side effects associated with fibrates in clinical practice involve liver and muscle damage. Additionally, many side effects are typically mild and reversible, such as gastrointestinal disorders and skin reactions (Sgro and Escousse, 1991). Fenofibrate, while offering cardiovascular protection for diabetic patients, can also result in rare side effects, including pancreatitis, increased serum creatinine levels, and renal damage (Emami et al., 2020). In contrast, gemfibrozil appears to cause less renal damage than other fibrates (Broeders et al., 2000). However, its known adverse reactions primarily include gastrointestinal issues, such as cholelithiasis, elevated transaminases, and dyspepsia. Other possible adverse reactions include dizziness, vertigo, myopathy, rhabdomyolysis, angioedema, urticaria, and rash (Ahmed et al., 2021).

Due to the structural similarities between PPARα and other subtypes of the PPAR family (PPARδ and PPARγ), some compounds exhibit dual or multiple agonist effects. It is important to avoid unnecessary side effects caused by this overlap. Recently, a new tissue-specific transport mechanism utilizing peptide carriers has garnered attention. This approach enables the targeting of ligands to specific tissues or cells, thereby reducing adverse effects on other organs. This concept is inspired by the beneficial effects of estrogen on pancreatic β-cell function and insulin secretion (Tiano et al., 2011). However, excessive estrogen can lead to carcinogenic effects in the female uterus, which complicates its use in regulating blood glucose metabolism.

Finan et al. (2012) chemically coupled estrogen with glucagon-like peptide-1. Their study found that glucagon-like peptide-1-estrogen conjugates effectively target pancreatic tissue to exert anti-diabetic effects. Consequently, developing new peptide carriers to couple with PPARα agonists represents a promising direction for future research. However, ensuring that the chemical linker of such conjugates remains stable in plasma but unstable in cells—enabling effective nuclear receptor signaling—presents a new challenge. Additionally, delivering drugs across the blood–brain barrier to the nervous system remains a significant hurdle. In addition to advancing PPARα agonists, developing new PPARα antagonists could also help mitigate side effects. Furthermore, patient responses to PPARα agonists can vary due to differences in genetic background, lifestyle, disease etiology, and other factors. Therefore, future research should integrate genetic testing, metabolomics, and other technologies to explore the relationship between individual patient differences and the efficacy of PPARα agonists. This approach aims to facilitate precision medicine, enabling the development of personalized treatment plans to enhance treatment success rates and improve patient quality of life ( Figure 5 ).

Preclinical experiments involving PPARα agonists consist of in vitro cell studies and in vivo animal experiments designed to explore various mechanisms, including the molecular pathways of PPARα in neurodegenerative diseases, as well as to evaluate drug toxicity.

In phase I clinical trials, the safety and tolerability of the drugs, along with their pharmacokinetic and pharmacodynamic properties in humans, are assessed. PPARα: Peroxisome proliferator-activated receptor alpha.

Limitations

This review has certain limitations. This article focuses on the mechanisms of PPARα in the onset and progression of nervous system diseases. However, other subtypes of the PPAR family, such as PPARβ and PPARγ, are also present in the nervous system, and this review does not address the molecular mechanisms of these subtypes in neurodegenerative diseases. Additionally, the mechanisms underlying the onset and progression of neurodegenerative diseases are complex. While this review discusses common mechanisms, such as neuroinflammation, oxidative stress, and synaptic plasticity, it does not provide a detailed examination of other pathological mechanisms and signaling pathways.

Conclusions and Perspectives

This review summarizes the therapeutic effects and molecular mechanisms of PPARα in various neurological diseases, suggesting its potential as a promising target for the treatment of neuroinflammatory and neurodegenerative disorders. However, significant challenges remain. For instance, the well-studied PPARα agonist fenofibrate achieves plasma concentrations that have beneficial effects on target organs but may also lead to side effects due to the activation of other tissue types. Therefore, clinical researchers should consider the systemic effects of PPARα agonists on adipose tissue, the heart, and the liver (Lin et al., 2022). Future research may uncover new agonists or drug combinations that can serve not only as standalone treatments but also in conjunction with other conditions to achieve more substantial therapeutic effects. Patients with comorbid diabetes and neurodegenerative diseases may particularly benefit from fibrates.

This review will elaborate on the molecular mechanisms of PPARα involved in neurological diseases across three key aspects: neuroinflammation and oxidative stress, prominent plasticity, and the role of intestinal microbiota and its metabolites. However, there is a growing interest in PPARα’s neuroregenerative properties. Ouk et al. (2014) demonstrated that the administration of fenofibrate during the acute phase of cerebral ischemia positively affects nerve regeneration in ischemic brain regions, supports functional recovery, prevents post-ischemic amyloid deposition, and alleviates ischemia-induced learning disabilities. Nevertheless, the specific mechanisms underlying PPARα-mediated nerve regeneration remain unclear. In contrast, PPARγ has been shown to promote nerve regeneration following peripheral nerve injury (Lezana et al., 2016). PPARγ is present in the Schwann cells of myelinated fibers, endothelial cells of rat peripheral nerves, and axons of the sciatic nerve (Cao et al., 2012; Lezana et al., 2016). Following injury, Schwann cells undergo reprogramming into a repair state to facilitate regeneration; inhibiting PPARγ prevents this transition (Meyer Zu Reckendorf et al., 2020). Additionally, the administration of rosiglitazone in rat primary cortical neurons has been found to increase PPARγ expression and induce neurite growth (Lezana et al., 2016). Subsequent studies have revealed that PPARγ activation can inhibit the Rho/ROCK pathway, thus promoting nerve regeneration (Wakino et al., 2004). Rho GTPases, particularly RhoA, play a crucial role in neuronal function, survival, and axonal growth by coordinating the dynamics of growth cones (Pearn et al., 2018). A primary consequence of Rho activation is the reorganization of the actin cytoskeleton (Schollenberger et al., 2010). The activation of Rho-associated kinase (ROCK) leads to cytoskeletal stiffness and growth cone collapse (Kubo et al., 2008). When the cytoskeleton becomes rigid, it activates downstream effectors that inhibit axon elongation and mediate growth cone collapse, thereby obstructing nerve regeneration (Tang, 2003; Kubo et al., 2008).

Studies have shown that intestinal microbiota and its metabolism are dysregulated in patients with neurodegenerative diseases (Ferreiro et al., 2023; Salim et al., 2023). Transcriptomic analysis reveals that the PPARα gene is highly expressed in both the small intestine and colon (Bünger et al., 2007; Luo et al., 2019). Intestinal microbiota and its metabolites can significantly influence PPARα signaling, while, conversely, PPARα activation can alter the abundance of intestinal microbiota and lead to changes in metabolite profiles (Grabacka et al., 2022). This review summarizes the regulation of PPARα in neurological diseases from the perspective of gut microbiota and its metabolites, suggesting that the communication between gut microbiota and the nervous system may be facilitated by the gut–brain axis. However, the causal mechanisms by which intestinal microbiota contribute to neurodegenerative diseases remain inadequately studied, and there are significant challenges and limitations to their future clinical translation. This review suggests that PPARα plays a crucial role in regulating both body metabolism and neuroinflammation, opening new perspectives on potential treatments for neurodegenerative diseases.