Sigma-1受体激动剂用于治疗神经精神疾病的认知障碍..docVIP

Sigma-1受体激动剂用于治疗神经精神疾病的认知障碍 Tomihisa Niitsu1, Masaomi Iyo2,3 and Kenji Hashimoto3,* 摘要：神经精神疾病(如精神分裂症和精神病性抑郁症) 患者的核心特征是认知障碍。目前用于治疗认知障碍的药物有显著的局限性，所以人们仍在积极地寻找更有效的治疗药物。在大脑中，内质网sigma-1受体蛋白是大脑内唯一的结合位点，对多个神经递质系统产生强效作用。越来越多的证据表明，在神经精神性疾病的病理生理学方面和一些治疗药物【如选择性5-羟色胺再摄取抑制剂（SSRIs）、多奈哌齐和神经甾体】的作用机理中，sigma-1受体都发挥着作用。在SSRIs中，氟伏沙明是强效的sigma-1受体激动剂，与sigma-1受体的亲和力最高。sigma-1受体激动剂大大增强神经生长因子（NGF）诱导的PC12细胞轴突生长，选择性sigma-1受体拮抗剂NE-100可拮抗这一作用。此外，亚慢性给予sigma-1受体激动剂（例如氟伏沙明、SA4503（库他美新）和多奈哌齐）可显著改善苯环己哌啶（PCP）诱导的认知障碍（与精神分裂症动物模型有关）。通过联合给予NE-100，可拮抗这一作用。采用特定的sigma-1受体配体[11C] SA4503，进行正电子发射断层扫描（PET）研究，结果表明，氟伏沙明和多奈哌齐可与健康人脑中的sigma-1受体结合。在临床研究中，某些sigma-1受体激动剂，包括氟伏沙明、多奈哌齐和神经甾体，可改善神经精神疾病中的认知障碍和临床症状。在本文中，我们将回顾最近关于sigma-1受体激动剂作为潜在的治疗精神分裂症和精神病性抑郁症认知障碍药物的研究成果。关键词：sigma-1受体、认知、精神分裂症、精神病性抑郁症、谵妄 Sigma-1 Receptor Agonists as Therapeutic Drugs for Cognitive Impairment in Neuropsychiatric Diseases Tomihisa Niitsu1, Masaomi Iyo2,3 Kenji Hashimoto3,* 1Research Center for Child Mental Development, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan; 2Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan; 3Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan Abstract: Cognitive impairment is a core feature of patients with neuropsychiatric diseases such as schizophrenia and psychotic depression.The drugs currently used to treat cognitive impairment have significant limitations, ensuring that the search for more effective therapies remains active. Endoplasmic reticulum protein sigma-1 receptors are unique binding sites in the brain that exert a potent effect on multiple neurotransmitter systems. Accumulating evidence suggests that sigma-1 receptors play a role in both the pathophysiology of neuropsychiatric diseases, and the mechanistic action of some therapeutic drugs, such as the selective serotonin reuptake inhibitors(SSRIs), donepezil and neurosteroids. Among SSRIs