Targeting the sigma-1 receptor chaperone in the treatment of perinatal brain injury

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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9 The Sigma-1 Receptor Agonist PRE-084 Attenuates Inflammation-Sensitized Nmdar-Mediated Excitotoxic Brain Injury in Newborn Mice

Archives of Disease in Childhood ◽

10.1136/archdischild-2012-302724.0009 ◽

2012 ◽

Vol 97 (Suppl 2) ◽

pp. A3-A3

Author(s):

A. Posod ◽

K. Neumayer ◽

V. Neubauer ◽

M. Keller ◽

K. Wegleiter ◽

...

Keyword(s):

Brain Injury ◽

Receptor Agonist ◽

Newborn Mice ◽

Sigma 1 Receptor ◽

Sigma 1

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

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.685201 ◽

2021 ◽

Vol 15 ◽

Author(s):

Mingming Shi ◽

Fanglian Chen ◽

Zhijuan Chen ◽

Weidong Yang ◽

Shuyuan Yue ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Endoplasmic Reticulum ◽

Brain Injury ◽

Neurological Disorders ◽

Inflammatory Responses ◽

Current Knowledge ◽

Glutamate Excitotoxicity ◽

Sigma 1 Receptor ◽

Beneficial Effects ◽

Sigma 1

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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