Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity
Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity
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Sigma-1 受体的变构调节可引发快速抗抑郁活性。
DOI：
10.1111/cns.12502
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发表时间：
2016
影响因子：
5.5
通讯作者：
Zhen Xue-Chu
中科院分区：
文献类型：
--
作者：
Wang Yun;Guo Lin;Jiang Hua-Feng;Zheng Long-Tai;Zhang Ao;Zhen Xue-Chu
AimsSigma-1受体参与癫痫、抑郁症等多种神经精神疾病的病理生理过程。变构调节是受体功能调节的重要机制。在这项研究中，我们检查了最新发现的新型和选择性的sigma-1受体变构调节剂3-甲基-苯基-2，3，4，5-四氢-1H-苯并[d]氮杂卓-7-醇的抗抑郁活性方法和结果SOMCL-668的单次给药减少了小鼠强迫游泳试验（FST）和尾部悬挂试验中的不动时间，这些作用通过sigma-1受体拮抗剂BD 1047的预处理而被消除。在慢性不可预测的轻度应激（MISS）模型中，SOMCL-668的长期应用迅速改善了快感缺乏样行为（一周内），伴随着海马中脑源性神经营养因子（BDNF）的表达增强和糖原合成酶激酶3β（GSK 3 β）（Ser-9）的磷酸化。SOMCL-668还在体外以变构方式快速促进GSK 3 β（Ser-9）的磷酸化。在原代培养的神经元中，SOMCL-668增强sigma-1受体激动剂诱导的神经突起生长和BDNF的分泌。结论SOMCL-668是一种新型的sigma-1受体变构调节剂，具有强效、快速的抗抑郁作用。目前的数据提供了第一个证据，即sigma-1受体的变构调节可能代表了抗抑郁药物发现的新方法。
AimsSigma‐1 receptors are involved in the pathophysiological process of several neuropsychiatric diseases such as epilepsy, depression. Allosteric modulation represents an important mechanism for receptor functional regulation. In this study, we examined antidepressant activity of the latest identified novel and selective allosteric modulator of sigma‐1 receptor 3‐methyl‐phenyl‐2, 3, 4, 5‐tetrahydro‐1H‐benzo[d]azepin‐7‐ol (SOMCL‐668).Methods and ResultsA single administration of SOMCL‐668 decreased the immobility time in the forced swimming test (FST) and tailing suspended test in mice, which were abolished by pretreatment of sigma‐1 receptor antagonist BD1047. In the chronic unpredicted mild stress (CUMS) model, chronic application of SOMCL‐668 rapidly ameliorated anhedonia‐like behavior (within a week), accompanying with the enhanced expression of brain‐derived neurotrophic factor (BDNF) and phosphorylation of glycogen synthase kinase 3β(GSK3β) (Ser‐9) in the hippocampus. SOMCL‐668 also rapidly promoted the phosphorylation of GSK3β(Ser‐9) in an allosteric mannerin vitro. In the cultured primary neurons, SOMCL‐668 enhanced the sigma‐1 receptor agonist‐induced neurite outgrowth and the secretion of BDNF.ConclusionSOMCL‐668, a novel allosteric modulator of sigma‐1 receptors, elicits a potent and rapid acting antidepressant effect. The present data provide the first evidence that allosteric modulation of sigma‐1 receptors may represent a new approach for antidepressant drug discovery.