Sigma receptors suppress multiple aspects of microglial activation

Abstract

During brain injury, microglia become activated and migrate to areas of degenerating neurons. These microglia release pro-inflammatory cytokines and reactive oxygen species causing additional neuronal death. Microglia express high levels of sigma receptors, however, the function of these receptors in microglia and how they may affect the activation of these cells remain poorly understood. Using primary rat microglial cultures, it was found that sigma receptor activation suppresses the ability of microglia to rearrange their actin cytoskeleton, migrate, and release cytokines in response to the activators adenosine triphosphate (ATP), monocyte chemoattractant protein 1 (MCP-1), and lipopolysaccharide (LPS). Next, the role of sigma receptors in the regulation of calcium signaling during microglial activation was explored. Calcium fluorometry experiments in vitro show that stimulation of sigma receptors suppressed both transient and sustained intracellular calcium elevations associated with the microglial response to these activators. Further experiments showed that sigma receptors suppress microglial activation by interfering with increases in intracellular calcium. In addition, sigma receptor activation also prevented membrane ruffling in a calcium-independent manner, indicating that sigma receptors regulate the function of microglia via multiple mechanisms.

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

“…Our results revealed a reduction of microglial immunoreactivity in the ventral spinal cord of PRE-084-treated SOD1 G93A mice compared to untreated SOD1 G93A mice. In vitro assays performed by Hall et al [13], in 2009, showed that the activation of sigma-1R suppresses adenosine triphosphate-induced Ca 2+ influx and attenuates microglial activation. Both findings point out that sigma-1R could directly modulate microglial activation in SOD1 G93A animals acting through a complementary non-neuronal pathway to ameliorate the MNs environment and promote their survival.…”

“…In the nervous system, sigma-1R mediates regulation of several processes, such as neuritogenesis, K + channels, and N-methyl-D-aspartate (NMDA) receptors activity, Ca 2+ homeostasis, and microglial activity. Furthermore, it is related to some central nervous system pathologies, including depression, schizophrenia, drug addiction, and Alzheimer disease [13][14][15][16]. Several studies have demonstrated potent therapeutic actions of sigma-1R agonists, reducing glutamate-mediated cell death [17,18] or modulating the inflammatory reaction after stroke in rats [19,20].…”

The cholinergic system, sigma-1 receptors and cognition

“…The efficacy of sigma-1 receptor agonists is known to be inversely correlated to brain progesterone levels. In rats treated with chronic intracerebroventricular infusion of ␤-amyloid(1-40) protein, or in ␤-amyloid (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) peptide-treated mice, a significant decrease of cerebral progesterone levels is accompanied by a corresponding increase of the antidepressant activity of sigma-1 receptor agonists [154,155]. In another study on murine aging, no differences in cerebral sigma-1 receptor density were observed between 2-and 24-month-old C57/BL6 mice, neither at the mRNA nor at the protein level [133].…”

“…Both pharmacological and pathological models of amnesia have been examined (see Table 1 for an overview). These include: (i) cholinergic deficits (either induced by muscarinic antagonists or by lesions of the forebrain or the nucleus basalis resulting in a selective loss of cholinergic neurons); (ii) pathology induced by direct administration of ␤-amyloid (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) peptide to the rodent CNS, an animal model of Alzheimer's disease; (iii) aging-induced losses of memory function, both in normal mice and SAM; (iv) neurodegeneration caused by exposure of animals to CO gas, or to trimethyltin; (v) prenatal stress (restraint, or exposure to cocaine), and (vi) glutamatergic, serotonergic, or calcium channel deficits induced by various drugs. The beneficial effects of sigma-1 receptor agonists on cognitive performance were detected in many different cognitive tests assessing short-term (working memory), long-term (reference memory), contextual or spatial memory processes.…”

Genesis of ER stress in Huntington’s Disease

“…Sigma-1R promotes cell survival upon ER stress [128]. Interestingly, Sigma-1R is also located predominantly at the MAMs [122].…”