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Drug Screening Identifies Sigma-1-Receptor as a Target for the Therapy of VWM Leukodystrophy.

Vanishing white matter (VWM) disease is an autosomal genetic leukodystrophy caused by mutations in subunits of eukaryotic translation initiation factor 2B (eIF2B). The clinical symptoms exhibit progressive loss of white matter in both hemispheres of the brain, accompanied by motor functions deterioration, neurological deficits, and early death. To date there is no treatment for VWM disease. The aim of this work was to expedite rational development of a therapeutic opportunity. Our approach was to design a computer-aided strategy for an efficient and reliable screening of drug-like molecules; a

Potential Molecular Mechanisms on the Role of the Sigma-1 Receptor in the Action of Cocaine and Methamphetamine.

The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum membrane protein that involves a wide range of physiological functions. The Sig-1R has been shown to bind psychostimulants including cocaine and methamphetamine (METH) and thus has been implicated in the actions of those psychostimulants. For example, it has been demonstrated that the Sig-1R antagonists mitigate certain behavioral and cellular effects of psychostimulants including hyperactivity and neurotoxicity. Thus, the Sig-1R has become a potential therapeutic target of medication development against drug abuse that differs from tra…

A variant of the sigma receptor type-1 gene is a protective factor for Alzheimer disease.

OBJECTIVE: Some preclinical evidence suggests that the sigma receptor type 1, which plays several roles in learning and memory, may also be involved in the pathogenesis of Alzheimer disease (AD). The authors provide here genetic evidence that the sigma receptor type 1 (SIGMAR1) gene is involved in susceptibility to AD. METHODS: Two polymorphisms of the SIGMAR1 gene, G-241T/C-240T and Q2P, were analyzed in a Japanese sample of 239 patients with AD and 227 comparisons subjects. These two polymorphisms were in complete linkage disequilibrium with each other, resulting in only two haplotypes, GC-

Sigma-1 receptor targeting inhibits connexin 43 based intercellular communication in chronic neuropathic pain.

BACKGROUND AND OBJECTIVE: Neuropathic pain is a chronic condition characterized by aberrant signaling within the somatosensory system, affecting millions of people worldwide with limited treatment options. Herein, we aim at investigating the potential of a sigma-1 receptor (σ1R) antagonist in managing neuropathic pain. METHODS: A Chronic Constriction Injury (CCI) model was used to induce neuropathic pain. The potential of (+)-MR200 was evaluated following daily subcutaneous injections of the compound. Its mechanism of action was confirmed by administration of a well-known σ1R agonist, PRE084.…

Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor.

The novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The escalating number of SARS-CoV-2-infected individuals has conferred the viral spread with the status of global pandemic. However, there are no prophylactic or therapeutic drugs available on the market to treat COVID-19, although several drugs have been approved. Recently, two articles using the comparative viral-human protein-protein interaction map revealed that the sigma-1 receptor in the endoplasmic reticulum plays an important role in SARS-CoV-2 replication in cells. …

Sigma 1 Receptor Antagonists Inhibit Manic-Like Behaviors in Two Congenital Strains of Mice.

BACKGROUND: Several currently available animal models reproduce select behavioral facets of human mania as well as the abnormal glutamatergic neurotransmission and dysregulation of glycogen synthase kinase 3β that accompanies this disease. METHODS: In this study, we addressed the therapeutic potential of ligands of sigma receptor type 1 (σ1R) in 2 putative models of mania: the "manic" Black Swiss outbred mice from Taconic farms (BStac) and mice with the 129 genetic background and histidine triad nucleotide-binding protein 1 (HINT1) deletion (HINT1-/- mice) that exhibit bipolar-like behaviors.

Iloperidone treatment mitigates the Juvenile Huntington's Disease phenotype possibly via Sigma-1 Receptor Modulation.

Juvenile Huntington's disease (jHD) is a severe genetic disorder with combined neurodegenerative and neurodevelopmental features, characterized by early onset and markedly reduced life expectancy. Despite extensive efforts, drug development has been largely unsuccessful and no effective therapy capable of mitigating the pathological phenotype is currently available. Here, we investigated the potential of the FDA-approved drug iloperidone to ameliorate disease-related phenotypes in cortical neurons differentiated from patient-derived induced pluripotent stem cells. Given previous reports indica

Design, synthesis, and characterization of F-18 sigma-1 receptor radiotracers for Alzheimer disease.

Sigma-1 receptor (σ1R) has been implicated in the pathogenesis of Alzheimer disease (AD). Positron emission tomography (PET) imaging of σ1R presents a novel strategy for the diagnosis and prognosis of AD. We previously reported a group of promising σ1R radiotracers. Continuing our efforts, we utilized an alternative labeling approach of our lead radiotracer (-)-[18F]TZ3108 to (-)-[18F]15, and facilitated the synthesis of three new radiotracers: (-)-[18F]13, (-)-[18F]14, and (-)-[18F]21. We performed systematic characterizations of these radiotracers including in vitro potency and selectivity, …

New strategy for treating visceral pain: Enhancing opioid antinociception by Sigma-1 receptor inhibition.

Visceral pain remains a major clinical challenge, often resistant to conventional analgesics. Sigma-1 receptor (σ1R) antagonists enhance opioid antinociception in somatic and neuropathic pain, yet their role in visceral nociception remains unclear. Here we investigated whether σ1R blockade potentiates the antinociceptive effects of µ-opioid agonists in a well-established model of capsaicin-induced visceral pain in mice. To this end, female wild-type (WT) and σ1R-knockout (σ1R-KO) mice received intracolonic capsaicin (0.1%). Visceral pain-related behaviors and referred mechanical hyperalgesia w…

The sigma-1 receptor agonist fluvoxamine alleviates endotoxin-induced acute lung injury in mice.

INTRODUCTION: Acute lung inflammation has recently gained increasing attention due to the high acute respiratory distress syndrome complications with subsequent fibrosis during the COVID-19 pandemic. Our group identified that the antifibrotic effect of the antidepressant fluvoxamine (FLU) in various organs is meditated via sigma-1 receptor (S1R) agonism. Since the actions of FLU on the inflammatory components have not been elucidated, this study investigated its effects in a mouse model of interstitial pneumonitis. METHODS: Pneumonitis was induced in wild-type (WT) and S1R knockout (S1r -/- )…

Sigma-1 Receptor Ligand Blarcamesine (ANAVEX 2-73) for Alzheimer's Disease: A Systematic Review.

BACKGROUND AND OBJECTIVES: Alzheimer's disease (AD) remains a major cause of dementia, and currently available therapies provide only modest clinical benefit or are limited by intravenous administration and treatment-related adverse effects. Blarcamesine (ANAVEX 2-73) is an orally administered sigma-1 receptor (S1R) agonist that has demonstrated neuroprotective effects in preclinical studies and has progressed through Phase I, Phase II and Phase IIb/III clinical trials. This systematic review evaluated the current clinical evidence for the efficacy and safety of blarcamesine in early-stage and…

Обнаружение агонистов-рецепторов на основе новела Бензамида на основе сигмы-1 с повышенной избирательностью и безопасностью.

Такие нарушения центральной нервной системы (ЦНС), как нейродегенеративные заболевания, множественный склероз или даже ишемия мозга, представляют собой серьезные терапевтические проблемы с ограниченным количеством эффективных методов лечения. Сигма-1-рецептор (S1R) — уникальный молекулярный сопровождающий, обогащенный мембранами, связанными с митохондрией, — стал перспективной целью в связи с его ролью в нейрозащите и нейронном воспалении. Опираясь на наш ранее идентифицированный S1R Ligand (состав 1), мы разработали и синтезировали шесть новых производных бензамидов посредством фармакодулиров

Совпадение в аннотации оригинала
Central nervous system (CNS) disorders such as neurodegenerative diseases, multiple sclerosis, or even brain ischemia represent major therapeutic challenges with limited effective treatments. The sigma-1 receptor (S1R), a unique ligand-operated molecular chaperone enriched at mitochondria-associated membranes, has emerged as a promising drug target due to it…

Sigma-1 Receptor Inhibition Reduces Mechanical Allodynia and Modulate Neuroinflammation in Chronic Neuropathic Pain.

Neuropathic pain is one of the most debilitating forms of chronic pain, resulting from an injury or disease of the somatosensory nervous system, which induces abnormal painful sensations including allodynia and hyperalgesia. Available treatments are limited by severe side-effects and reduced efficacy in the chronic phase of the disease. Sigma-1 receptor (σ1R) has been identified as a chaperone protein, which modulate opioid receptors activities and the functioning of several ion channels, exerting a role in pain transmission. As such, it represents a druggable target to treat neuropathic pain.…

The Sigma-1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models.

Pridopidine is a selective Sigma-1 receptor (S1R) agonist in clinical development for Huntington disease (HD) and amyotrophic lateral sclerosis. S1R is a chaperone protein localized in mitochondria-associated endoplasmic reticulum (ER) membranes, a signaling platform that regulates Ca2+ signaling, reactive oxygen species (ROS) and mitochondrial fission. Here, we investigate the protective effects of pridopidine on various mitochondrial functions in human and mouse HD models. Pridopidine effects on mitochondrial dynamics were assessed in primary neurons from YAC128 HD mice expressing the mutant…

Sigma 1 receptor regulates ERK activation and promotes survival of optic nerve head astrocytes.

The sigma 1 receptor (S1R) is a unique transmembrane protein that has been shown to regulate neuronal differentiation and cellular survival. It is expressed within several cell types throughout the nervous system and visceral organs, including neurons and glia within the eye. S1R ligands are therapeutic targets for diseases ranging from neurodegenerative conditions to neoplastic disorders. However, effects of S1R activation and inhibition within glia cells are not well characterized. Within the eye, the astrocytes at the optic nerve head are crucial to the health and survival of the neurons th

Sigma-1 Receptor Regulates Mitochondrial Function in Glucose- and Oxygen-Deprived Retinal Ganglion Cells.

PURPOSE: Understanding the role of mitochondria in retinal ganglion cells (RGCs) is relevant to human disease as studies have shown mitochondrial abnormalities in primary open-angle glaucoma patients. This study seeks to determine the effects of the sigma-1 receptor (σ-1r) and its agonists on mitochondrial function in oxygen- and glucose- deprived (OGD) purified neonatal RGCs. METHODS: Retinal ganglion cells were isolated from rat pups and subjected to OGD in varying conditions in the presence or absence of σ-1r agonist and antagonist and following addition of an AAV2-σ-1r vector that was use…

Decreased brain sigma-1 receptor contributes to the relationship between heart failure and depression.

AIMS: Depression often coexists with cardiovascular disease, such as hypertension and heart failure, in which sympathetic hyperactivation is critically involved. Reduction in the brain sigma-1 receptor (S1R) functions in depression pathogenesis via neuronal activity modulation. We hypothesized that reduced brain S1R exacerbates heart failure, especially with pressure overload via sympathetic hyperactivation and worsening depression. METHODS AND RESULTS: Male Institute of Cancer Research mice were treated with aortic banding and, 4 weeks thereafter, fed a high-salt diet for an additional 4 wee…

Sigma-1 receptor antagonism as a potential mechanism of sertraline-associated Alice in Wonderland syndrome.

Recent pharmacovigilance data identified sertraline as the only SSRI associated with Alice in Wonderland syndrome (AIWS) in adults. This commentary proposes sigma-1 receptor antagonism, together with dopamine transporter inhibition, as plausible mechanisms linking sertraline to transient perceptual distortion and cortical network instability. Integrating molecular, neurophysiological, and neuroanatomical evidence, this perspective highlights the need for mechanistic and pharmacogenomic studies to clarify causality and improve the safety of serotonergic pharmacotherapy.

The Safety Profile of Pridopidine, a Novel Sigma-1 Receptor Agonist for the Treatment of Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a rare, fatal, chronic progressive neurodegenerative disorder with a significant unmet medical need for effective treatments. Pridopidine is a novel, first-in-class, highly selective and potent sigma-1 receptor (S1R) agonist in development for HD. Pridopidine has been extensively studied in adult HD across the full spectrum of disease severity and age ranges, and its safety profile has been characterized in approximately 1600 participants across multiple studies and a broad range of doses. The specific objective of this study was to gain an in-depth und…

Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids.

In addition to modulating serotonin transport, selective serotonin reuptake inhibitors (SSRIs) have multiple other mechanisms that may contribute to clinical effects, and some of these latter actions prompt repurposing of SSRIs for non-psychiatric indications. In a recent study of the SSRIs fluvoxamine, fluoxetine and sertraline we found that, unlike the other two SSRIs, sertraline acutely inhibited LTP at a low micromolar concentration through inverse agonism of sigma 1 receptors (S1Rs). In the present studies, we pursued mechanisms contributing to sertraline modulation of LTP in rat hippocam