Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication

Abstract

Endoplasmic reticulum (ER) protein sigma-1 receptor represents unique chaperone activity in the central nervous system, and it exerts a potent influence on a number of neurotransmitter systems. Several lines of evidence suggest that activation of sigma-1 receptor plays a role in the pathophysiology of neuropsychiatric diseases, as well as in the mechanisms of some therapeutic drugs and neurosteroids. Preclinical studies showed that some selective serotonin reuptake inhibitors (SSRIs; fluvoxamine, fluoxetine, excitalopram), donepezil, and ifenprodil act as sigma-1 receptor agonists. Furthermore, sigma-1 receptor agonists could improve the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP)-induced cognitive deficits in mice. A study using positron emission tomography have demonstrated that an oral administration of fluvoxamine or donepezil could bind to sigma-1 receptor in the healthy human brain, suggesting that sigma-1 receptor might be involved in the therapeutic mechanisms of these drugs. Moreover, case reports suggest that sigma-1 receptor agonists, including fluvoxamine, and ifenprodil, may be effective in the treatment of cognitive impairment in schizophrenia, delirium in elderly people, and flashbacks in post-traumatic stress disorder. In this review article, the author would like to discuss the clinical implication of sigma-1 receptor agonists, including endogenous neurosteroids, in the neuropsychiatric diseases.

The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis

“…Indeed, IP 3 production following stimulation of G protein-coupled receptors (GPCRs) enhances mitochondrial calcium transport and ATP production in neurons and cardiomyocytes (19,20). Furthermore, the physiological relevance of Sig-1R in neuropsychotherapeutic drug actions is well documented in the current issue (21,22). The pathophysiological relevance of Sig-1R in neurodegenerative disorders and ALS is also extensively discussed in the present issue (23,24).…”

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

“…This dissociated sigma-1 receptor is free to stimulate chaperone activity, resulting in neuroprotection. This represents a slight modification from Hayashi et al (2011, 2015. the GluN2B subunit of the NMDA receptor in the hippocampus during juvenile and adult stages (Li et al, 2014).…”

Systolic blood pressure as a potential target of sigma‐1 receptor agonist therapy

“…1,2 Several studies demonstrate that sigma-1 receptor stimulation promotes neuroprotection, neuroplasticity, cardioprotection, and renoprotection. [3][4][5] Accordingly, the sigma-1 receptor is a major target of ongoing pharmaceutical research.…”