National Institute on Drug Abuse, National Institutes of Health-Cellular Stress Signaling Unit, Integrative Neuroscience Branch, Baltimore, MD 21224, USA.
Expert Opin Ther Targets. 2011 May;15(5):557-77. doi: 10.1517/14728222.2011.560837. Epub 2011 Mar 5.
Current drugs for the treatment of psychiatric or neurodegenerative disorders have limitations. Psychotherapeutic drugs such as typical and atypical antipsychotics, tricyclic antidepressants and selective monoamine reuptake inhibitors, aim to normalize the hyper- or hypo-neurotransmission of monoaminergic systems. Despite their contribution to the outcomes of psychiatric patients, these agents often exert severe side effects and require chronic treatments to promote amelioration of symptoms. Drugs available for the treatment of neurodegenerative disorders are severely limited.
Recent evidence that has shed light on sigma-1 receptor ligands, which may serve as a new class of antidepressants or neuroprotective agents. Sigma-1 receptors are novel ligand-operated molecular chaperones regulating signal transduction, ER stress, cellular redox, cellular survival and synaptogenesis. Selective sigma-1 receptor ligands exert rapid antidepressant-like, anxiolytic, antinociceptive and robust neuroprotective actions in preclinical studies. Recent studies that suggest that reactive oxygen species might play a role as signal integrators downstream of Sig-1Rs are also covered.
The advances in sigma receptor research in the last decade have begun to elucidate the intracellular signal cascades upstream and downstream of sigma-1 receptors. The novel ligand-operated properties of the sigma-1 receptor chaperone may enable interventions by which stress-related cellular systems can be pharmacologically controlled.
目前用于治疗精神或神经退行性疾病的药物存在局限性。精神治疗药物，如典型和非典型抗精神病药、三环类抗抑郁药和选择性单胺再摄取抑制剂，旨在使单胺能系统的过度或不足神经传递正常化。尽管这些药物对精神科患者的治疗结果有贡献，但它们往往会产生严重的副作用，需要长期治疗才能改善症状。可用于治疗神经退行性疾病的药物非常有限。
最近的证据表明，sigma-1 受体配体可能成为一类新的抗抑郁药或神经保护剂。sigma-1 受体是新型配体操纵的分子伴侣，调节信号转导、内质网应激、细胞氧化还原、细胞存活和突触发生。选择性 sigma-1 受体配体在临床前研究中具有快速的抗抑郁样、抗焦虑、抗伤害和强大的神经保护作用。最近的研究表明，活性氧可能作为 Sig-1Rs 下游的信号整合因子发挥作用，这也涵盖在其中。
过去十年中 sigma 受体研究的进展开始阐明 sigma-1 受体上游和下游的细胞内信号级联。sigma-1 受体伴侣的新型配体操作特性可能使应激相关细胞系统能够通过药理学进行控制。
