Seiwakai Nishikawa Hospital, Hamada, Japan.
Psychiatry Clin Neurosci. 2015 Apr;69(4):179-91. doi: 10.1111/pcn.12262. Epub 2015 Feb 16.
Psychiatrists empirically recognize that excessive or chronic psychological stress can result in long-lasting impairments of brain functions that partly involve neuronal cell damage. Recent studies begin to elucidate the molecular pathways activated/inhibited by psychological stress. Activation of the hypothalamic-pituitary-adrenal 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 promote upregulation of molecular chaperones to protect macromolecules from degradation. The unfolded protein response, 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, unfolded protein response and cytokine signaling. The sigma-1 receptor also regulates morphogenesis of neuronal cells, such as neurite outgrowth, synaptogenesis, and myelination, which 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 sigma receptor research imply that not only cell surface monoamine effectors but also intracellular molecules, especially those at the ER, may provide novel therapeutic targets for future drug developments.
精神科医生从经验上认识到，过度或慢性心理压力会导致大脑功能的持久损伤，部分涉及神经元细胞损伤。最近的研究开始阐明心理压力激活/抑制的分子途径。心理压力下下丘脑-垂体-肾上腺轴的激活导致大脑中的炎症氧化应激，部分原因是细胞因子的升高。心理压力或神经病理学状况（例如，β-淀粉样蛋白的积累）触发“细胞应激反应”，促进分子伴侣的上调，以保护大分子免受降解。未折叠蛋白反应，内质网（ER）特异性细胞应激反应，最近与神经精神疾病的病理生理学和某些临床使用药物的药理学有关。σ-1 受体是一种 ER 蛋白，其配体被证明具有抗抑郁和神经保护作用。最近的研究发现，σ-1 受体是一种新型的配体操纵的 ER 伴侣，可调节生物能量学、自由基生成、氧化应激、未折叠蛋白反应和细胞因子信号转导。σ-1 受体还调节神经元细胞的形态发生，如突起生长、突触形成和髓鞘形成，这些过程可能受到细胞应激的干扰。因此，σ-1 受体可能有助于提供一种细胞防御系统，保护神经系统免受慢性心理压力的影响。σ 受体研究的结果表明，不仅细胞表面单胺效应物，而且细胞内分子，特别是内质网中的分子，可能为未来的药物开发提供新的治疗靶点。
