Citation

Hayashi T. Psychiatry Clin. Neurosci. 2014; 69(4): 179-191.

Affiliation

Seiwakai Nishikawa Hospital, 293-2 Minato-machi, Hamada, Shimane 697-0052. Japan.

Copyright

(Copyright © 2014, John Wiley and Sons)

DOI

10.1111/pcn.12262

PMID

25495202

Abstract

Psychiatrists empirically recognize that excessive or chronic psychological stress can result in long-lasting impairments of brain functions that partly involve neuronal cell damages. Recent studies begin to elucidate the molecular pathways activated/inhibited by psychological stress. Activation of the HPA axis under psychological stress causes inflammatory oxidative stresses in the brain, in part due to elevation of cytokines. Psychological stress or neuropathological conditions (e.g., accumulation of β-amyloids) trigger 'cellular stress responses,' which promotes up-regulation of molecular chaperones to protect macromolecules from degradation. The unfolded protein response (UPR), the endoplasmic reticulum (ER)-specific cellular stress response, has been recently implicated in the pathophysiology of neuropsychiatric disorders and the pharmacology of certain clinically used drugs. The sigma-1 receptor is an ER protein whose ligands are shown to exert antidepressant-like and neuroprotective actions. Recent studies found that the sigma-1 receptor is a novel ligand-operated ER chaperone that regulates bioenergetics, free radical generation, oxidative stress, UPR and cytokine signaling. The sigma-1 receptor also regulates morphogenesis of neuronal cells, such as neurite outgrowth, synaptogenesis, and myelination that can be perturbed by cellular stress. The sigma-1 receptor may thus contribute to a cellular defense system that protects nervous systems against chronic psychological stress.

FINDINGS from the sigma receptor research provide an implication that not only the cell surface monoamine effectors but also intracellular molecules, especially those at the ER, may provide novel therapeutic targets of future drug developments.

Language: en