sigma-1受体生物学研究进展及对其与神经精神系统疾病关系的最新认识  

Recent advances in biology of sigma-1 receptor and new findings of its relations with neuropsychiatric diseases

作　　者：曹丹旎 吴宁 李锦 CAO Dan-ni;WU Ning;LI Jin(Institute of Pharmacology and Toxicology,Academy of Military Medical Sciences,Beijing 100850,China)

机构地区：[1]军事科学院军事医学研究院毒物药物研究所,北京100850

出　　处：《中国药理学与毒理学杂志》2022年第12期881-902,共22页Chinese Journal of Pharmacology and Toxicology

基　　金：国家自然科学基金(81874310)。

摘　　要：随着神经精神疾病发病率不断攀升,尽快阐明其发病机制、发现新的药物靶标及研发理想的治疗药物逐渐成为急需解决的重大科学问题。近年来,对sigma-1受体(SA1R)的研究,特别是其在神经精神疾病相关领域的研究取得了一系列重要进展。SA1R是一类既不同于经典受体、也不同于经典分子伴侣蛋白的特殊生物活性分子,通过受体和分子伴侣双重机制对线粒体能量代谢、蛋白质和脂质代谢、细胞内物质转运和细胞兴奋性等细胞生理功能及氧化应激、氮化应激、内质网应激、神经炎症、细胞自噬和细胞凋亡等病理生理过程发挥重要的调控作用。以SA1R为靶点,可能能够治疗抑郁症、神经退行性疾病和药物成瘾等多种神经精神疾病。上调SA1R功能具有显著抗抑郁活性,与其上调神经营养因子表达和抑制神经炎症相关,如SA1R激动剂SA4503正处于抑郁症治疗的临床Ⅲ期试验中。SA1R激动剂抗神经退行性疾病的作用与其神经保护作用、促进神经元存活和恢复突触可塑性相关。SA1R参与药物成瘾病理生理过程,一方面SA1R调节多巴胺和5-羟色胺能神经系统,另一方面成瘾性物质如甲基苯丙胺和可卡因直接作用于SA1R。然而,SA1R参与药物成瘾确切的分子机制尚不清楚。本文对近年来取得的有关SA1R生物学研究的最新进展及其与神经精神系统疾病关系的最新认识予以综述。With increasing incidence of neuropsychiatric disorders,it is urgent to clarify the pathogenesis of neuropsychiatric diseases,discover new targets and develop ideal therapeutic drugs.Recently,there has been a series of important progress in research on sigma-1 receptor(SA1R),especially in the field of psychiatric diseases.SA1R,as a unique bioactive substance that is distinct from classical receptors and chaperone proteins,exerts vital modulatory effects on both cellular functions including mitochondrial energy metabolism,protein and lipid metabolism,intracellular transport and excitability,and pathophysiological processes including oxidative stress,nitrosative stress,endoplasmic reticulum stress,neuroinflammation,autophagy and apoptosis through receptor and chaperone mechanisms.Targeting SA1R may potentially help treat depression,neurodegenerative diseases and drug addiction.Upregulation of SA1R function has significant antidepressant effects,which can be attributed to the upregulated expressions of neurotrophic factors and inhibition of neuroinflammation,SA1R agonist SA4503 is currently in phaseⅢclinical trials for the treatment of depression.In addition,SA1R agonists treat neurodegenerative diseases via neuroprotection,promotion of neuronal survival and restoration of synaptic plasticity.Moreover,SA1R participates in the pathophysiology of drug addiction via the regulatory effects of SA1R on dopamine and serotonin systems and direct actions of addictive substances,such as methamphetamine and cocaine,on SA1R.However,the exact molecular mechanism underlying drug addiction remains unclear.In this review,the recent progress in biological research on SA1R and the new findings of its association with neuropsychiatric diseases were summarized.

关 键 词：sigma-1受体 抑郁症 神经退行性疾病 药物成瘾 

分 类 号：R964[医药卫生—药理学]