去甲基氯胺酮快速抗抑郁作用机制的研究

Research progress on the mechanism of rapid antidepressant action of hydronorketamine

抑郁症是一种常见的精神疾病,以情绪低落、兴趣缺乏、快感缺失等为主要特征,并伴有认知行为障碍。目前,临床抗抑郁药物起效缓慢,治疗有效率较低。(2R,6R)-去甲基氯胺酮(HNK)作为快速抗抑郁药物氯胺酮的关键代谢产物,既可以发挥快速持久地抗抑郁效应,又没有氯胺酮致幻、成瘾等毒副作用,具有潜在的临床应用价值。研究发现,(2R,6R)-HNK的抗抑郁效应与谷氨酸受体的调节机制以及突触可塑性密切相关。此外,其下游信号通路的改变包括脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)表达上调,真核延长因子2(eukaryotic elongation factor 2,eEF2)的去磷酸化,以及哺乳动物雷帕霉素(mammalian target of rapamycin,mTOR)靶蛋白信号通路的激活均在该药物抗抑郁过程中发挥关键作用。深入了解这些分子靶点在(2R,6R)-HNK抗抑郁效果中的作用机制,对开发新型、快速、有效的抗抑郁药物具有重要意义。

Major depressive disorder is a mental illness characterized by depressed mood,lack of engagement in pleasurable activities,anhedonia,and cognitive-behavioral disorders.Currently,traditional pharmacological treatments for depression have a delayed therapeutic onset and low treatment effectiveness.(2R,6R)-HNK,as a key metabolite of ketamine,can not only exert rapid and lasting antidepressant effects but also has no side effects such as hallucination and addiction caused by ketamine,which has potential clinical application values.Studies have found that the antidepressant effect of(2R,6R)-HNK is closely related to the regulation mechanism of glutamate receptor and synaptic plasticity.Besides,the changes of downstream signaling pathways include the upregulation of brain-derived neurotrophic factor(BDNF)expression,dephosphorylation of eukaryotic elongation factor 2(eEF2),and activation of the mammalian target of rapamycin(mTOR)play a key role in the antidepressant process of the drug.Understanding the molecular mechanisms underpinning(2R,6R)-HNK's antidepressant effects will be invaluable for the identification of targets,which will drive the development of novel,effective,next-generation pharmacotherapies for the treatment of depression.