1Research Center for Child Mental Development, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba, Japan.
Curr Pharm Des. 2012;18(7):875-83. doi: 10.2174/138161212799436476.
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, fluvoxamine, a potent sigma-1 receptor agonist, has the highest affinity at sigma-1 receptors. Sigma-1 receptor agonists greatly potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells, an effect that is antagonized by treatment with the selective sigma-1 receptor antagonist NE-100. Furthermore, phencyclidine (PCP)-induced cognitive impairment, associated with animal models of schizophrenia is significantly improved by sub-chronic administration of sigma-1 receptor agonists such as fluvoxamine, SA4503 (cutamesine) and donepezil. This effect is antagonized by co-administration of NE-100. A positron emission tomography (PET) study using the specific sigma-1 receptor ligand [11C]SA4503 demonstrates that fluvoxamine and donepezil bind to sigma-1 receptors in the healthy human brain. In clinical studies, some sigma-1 receptor agonists, including fluvoxamine, donepezil and neurosteroids, improve cognitive impairment and clinical symptoms in neuropsychiatric diseases. In this article, we review the recent findings on sigma-1 receptor agonists as potential therapeutic drugs for the treatment of cognitive impairment in schizophrenia and psychotic depression.
认知障碍是精神神经疾病（如精神分裂症和精神病性抑郁症）患者的核心特征。目前用于治疗认知障碍的药物存在显著局限性，这确保了对更有效的治疗方法的研究仍然活跃。内质网蛋白西格玛-1 受体是大脑中的独特结合位点，对多种神经递质系统产生强大影响。越来越多的证据表明，西格玛-1 受体在精神神经疾病的病理生理学和一些治疗药物的机制作用中发挥作用，如选择性 5-羟色胺再摄取抑制剂（SSRIs）、多奈哌齐和神经甾体。在 SSRIs 中，作为强效西格玛-1 受体激动剂的氟伏沙明，对西格玛-1 受体具有最高的亲和力。西格玛-1 受体激动剂极大地增强了 PC12 细胞中神经生长因子（NGF）诱导的神经突生长，这种作用可被选择性西格玛-1 受体拮抗剂 NE-100 治疗拮抗。此外，苯环利定（PCP）引起的认知障碍与精神分裂症的动物模型相关，通过亚慢性给予西格玛-1 受体激动剂，如氟伏沙明、SA4503（卡他米嗪）和多奈哌齐，可显著改善。这种作用可被 NE-100 共同给药拮抗。使用特定的西格玛-1 受体配体[11C]SA4503 的正电子发射断层扫描（PET）研究表明，氟伏沙明和多奈哌齐与健康人脑中的西格玛-1 受体结合。在临床研究中，一些西格玛-1 受体激动剂，包括氟伏沙明、多奈哌齐和神经甾体，可改善精神神经疾病中的认知障碍和临床症状。在本文中，我们综述了西格玛-1 受体激动剂作为治疗精神分裂症和精神病性抑郁症认知障碍的潜在治疗药物的最新发现。
