Sigma-1 Receptor: A Potential Therapeutic Target for Traumatic Brain Injury

The sigma-1 receptor (Sig-1R) is a chaperone receptor that primarily resides at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and acts as a dynamic pluripotent modulator regulating cellular pathophysiological processes. Multiple pharmacological studies have confirmed the beneficial effects of Sig-1R activation on cellular calcium homeostasis, excitotoxicity modulation, reactive oxygen species (ROS) clearance, and the structural and functional stability of the ER, mitochondria, and MAM. The Sig-1R is expressed broadly in cells of the central nervous system (CNS) and has been reported to be involved in various neurological disorders. Traumatic brain injury (TBI)-induced secondary injury involves complex and interrelated pathophysiological processes such as cellular apoptosis, glutamate excitotoxicity, inflammatory responses, endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction. Thus, given the pluripotent modulation of the Sig-1R in diverse neurological disorders, we hypothesized that the Sig-1R may affect a series of pathophysiology after TBI. This review summarizes the current knowledge of the Sig-1R, its mechanistic role in various pathophysiological processes of multiple CNS diseases, and its potential therapeutic role in TBI.

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The sigma 1 receptor (S1R) is a potential therapeutic target for the treatment of Huntington's disease

10.31219/osf.io/mcefx ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Endoplasmic Reticulum ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Therapeutic Target ◽

Structural Integrity ◽

Neuronal Cell ◽

Glutamate Excitotoxicity ◽

Potential Therapeutic Target ◽

Sigma 1 Receptor ◽

Sigma 1

During the progression of Huntington's disease (HD), changes in Ca2+ signaling cause neuronal cells to lose a range of functional properties. GABAergic medium spiny neurons (MSNs) are able to prevent Ca2+ imbalance in the early stages of the illness through a number of compensatory strategies. However, as people become older, their neuroprotective potential diminishes due to a decrease in metabolic activity and the generation of Ca2+-buffering proteins. Continuing Ca2+ regulation problems exhaust the cells' compensatory abilities, resulting in a continuous surge in cytosolic Ca2+ and neuronal degeneration.The sigma 1 receptor (S1R) is a potential therapeutic target for the treatment of HD because it regulates a number of cytosolic Ca2+-dependent signaling cascades. S1R activation by selective agonists protects neurons from glutamate excitotoxicity, reduces store-operated Ca2+ entry (SOCE) hyperactivation, and maintains the structural integrity of mitochondria-associated endoplasmic reticulum membranes (MAMs), which is required for synchronizing mitochondrial and endoplasmic reticulum (ER) activity to maintain cell bioenergetics balance. Because of the stability of Ca2+ signaling in neurons, pridopidine, a highly selective S1R agonist, has been demonstrated to protect neurons in cellular and animal models of HD.The synaptoprotective effect of pridopidine is very important since it is found in both cortical and striatal neurons, indicating that pridopidine has a systemic influence on HD therapy. Because synaptic dysfunctions are one of the earliest markers of neuropathology at the cellular level, normalization of Ca2+ balance by pridopidine may prevent disease development at the molecular level at the earliest stages. In this regard, the most significant therapeutic advantage of pridopidine will almost certainly be in preventative treatment, even before the start of the first clinical indications, which will improve neuronal cell compensatory abilities and significantly reduce the progression of HD.

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Sigma-1 Receptor Modulates Neuroinflammation After Traumatic Brain Injury

Cellular and Molecular Neurobiology ◽

10.1007/s10571-015-0244-0 ◽

2015 ◽

Vol 36 (5) ◽

pp. 639-645 ◽

Cited By ~ 14

Author(s):

Hui Dong ◽

Yunfu Ma ◽

Zengxi Ren ◽

Bin Xu ◽

Yunhe Zhang ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Sigma 1 Receptor ◽

Sigma 1

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Reduced GFAP Expression in Bergmann Glial Cells in the Cerebellum of Sigma-1 Receptor Knockout Mice Determines the Neurobehavioral Outcomes after Traumatic Brain Injury

International Journal of Molecular Sciences ◽

10.3390/ijms222111611 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11611

Author(s):

Gundega Stelfa ◽

Edijs Vavers ◽

Baiba Svalbe ◽

Rinalds Serzants ◽

Anna Miteniece ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Glial Cells ◽

Motor Coordination ◽

Molecular Layer ◽

Neurological Deficits ◽

Sigma 1 Receptor ◽

Gfap Expression ◽

Bergmann Glial Cells ◽

Sigma 1

Neuroprotective effects of Sigma-1 receptor (S1R) ligands have been observed in multiple animal models of neurodegenerative diseases. Traumatic brain injury (TBI)-related neurodegeneration can induce long-lasting physical, cognitive, and behavioral disabilities. The aim of our study was to evaluate the role of S1R in the development of neurological deficits after TBI. Adult male wild-type CD-1 (WT) and S1R knockout (S1R-/-) mice were subjected to lateral fluid percussion injury, and behavioral and histological outcomes were assessed for up to 12 months postinjury. Neurological deficits and motor coordination impairment were less pronounced in S1R-/- mice with TBI than in WT mice with TBI 24 h after injury. TBI-induced short-term memory impairments were present in WT but not S1R-/- mice 7 months after injury. Compared to WT animals, S1R-/- mice exhibited better motor coordination and less pronounced despair behavior for up to 12 months postinjury. TBI induced astrocyte activation in the cortex of WT but not S1R-/- mice. S1R-/- mice presented a significantly reduced GFAP expression in Bergmann glial cells in the molecular layer of the cerebellum compared to WT mice. Our findings suggest that S1R deficiency reduces TBI-induced motor coordination impairments by reducing GFAP expression in Bergmann glial cells in the cerebellum.

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Drug Repurposing: Promises of Edaravone Target Drug in Traumatic Brain Injury

Current Medicinal Chemistry ◽

10.2174/0929867327666200812221022 ◽

2020 ◽

Vol 27 ◽

Author(s):

Zaynab Shakkour ◽

Hawraa Issa ◽

Helene Ismail ◽

Ohanes Ashekyan ◽

Karl John Habashy ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neurological Disorders ◽

Inflammatory Responses ◽

Apoptotic Cell ◽

Drug Repurposing ◽

Biochemical Properties ◽

Phase Iii ◽

Radical Scavenger ◽

Neuroprotective Effects

: Edaravone is a potent free-radical scavenger that has been in the market for more than 30 years. It was originally developed in Japan to treat strokes and has been used there since 2001. Aside from its anti-oxidative effects, edaravone demonstrated beneficial effects on pro-inflammatory responses, nitric oxide production, and apoptotic cell death. Interestingly, edaravone has shown neuroprotective effects in several animal models of diseases other than stroke. In particular, edaravone administration was found to be effective in halting amyotrophic lateral sclerosis (ALS) progression during the early stages. Accordingly, after its success in Phase III clinical studies, edaravone has been approved by the FDA as a treatment for ALS patients. Considering its promises in neurological disorders and its safety in patients, edaravone is a drug of interest that can be repurposed for traumatic brain injury (TBI) treatment. Drug repurposing is a novel approach in drug development that identifies drugs for purposes other than their original indication. This review presents the biochemical properties of edaravone along with its effects on several neurological disorders in the hope that it can be adopted for treating TBI patients.

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Sigma 1 Receptor, Cholesterol and Endoplasmic Reticulum Contact Sites

Contact ◽

10.1177/25152564211026505 ◽

2021 ◽

Vol 4 ◽

pp. 251525642110265

Author(s):

Vladimir Zhemkov ◽

Jen Liou ◽

Ilya Bezprozvanny

Keyword(s):

Endoplasmic Reticulum ◽

Protein Composition ◽

Sigma 1 Receptor ◽

Functional Roles ◽

Membrane Contact Sites ◽

Contact Sites ◽

Sigma 1 ◽

Membrane Contact ◽

Organelle Communication ◽

Cellular Organelles

Recent studies indicated potential importance of membrane contact sites (MCS) between the endoplasmic reticulum (ER) and other cellular organelles. These MCS have unique protein and lipid composition and serve as hubs for inter-organelle communication and signaling. Despite extensive investigation of MCS protein composition and functional roles, little is known about the process of MCS formation. In this perspective, we propose a hypothesis that MCS are formed not as a result of random interactions between membranes of ER and other organelles but on the basis of pre-existing cholesterol-enriched ER microdomains.

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Clinical Relevance of Cortical Spreading Depression in Neurological Disorders: Migraine, Malignant Stroke, Subarachnoid and Intracranial Hemorrhage, and Traumatic Brain Injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.191 ◽

2010 ◽

Vol 31 (1) ◽

pp. 17-35 ◽

Cited By ~ 422

Author(s):

Martin Lauritzen ◽

Jens Peter Dreier ◽

Martin Fabricius ◽

Jed A Hartings ◽

Rudolf Graf ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neurological Disorders ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Neuronal Damage ◽

Ion Homeostasis ◽

Large Body ◽

Treatment Strategies ◽

Pathophysiological Mechanism

Cortical spreading depression (CSD) and depolarization waves are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are widespread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This paper summarizes the evidence provided by novel invasive techniques, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders. The findings have implications for monitoring and treatment of patients with acute brain disorders in the intensive care unit. Drawing on the large body of experimental findings from animal studies of CSD obtained during decades we suggest treatment strategies, which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves.

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