北京基础医学研究所Yun-feng Li和北京大学Yong Zhang共同合作，近期取得重要工作进展。他们研究发现Sigma-1受体激活通过增加BDNF水平介导氯胺酮在小鼠体内的持续抗抑郁作用。相关研究成果2023年12月14日在线发表于《中国药理学报》杂志上。

据介绍，Sigma-1受体（S1R）是内质网中一种独特的多任务伴侣蛋白。由于S1R激动剂表现出强大的抗抑郁样活性，S1R已成为抗抑郁治疗的新靶点。氯胺酮具有快速和持续的抗抑郁作用，也可能与S1R相互作用。

研究人员探讨了氯胺酮的抗抑郁作用是否与S1R的激活有关。在尾部悬吊试验（TST）中评估抑郁状态，并使用慢性皮质酮（CORT）程序诱导小鼠的绝望样行为。分别用光纤记录和免疫荧光染色法评估内侧前额叶皮层（mPFC）锥体神经元的活动和结构变化。研究人员发现S1R的药理学操作调节了氯胺酮诱导的行为效应。

此外，用S1R拮抗剂BD1047（3 mg·kg⁻¹·d⁻¹，腹腔注射，连续3天）显著削弱氯胺酮引起的mPFC锥体神经元的结构和功能恢复（10 mg·kg⁻¹，腹腔注射，一次）。氯胺酮间接触发S1R的激活，随后增加BDNF的水平。用S1R激动剂SA4503（1 mg·kg⁻¹·d⁻¹，腹腔注射，连续3天）增强了氯胺酮的持续抗抑郁作用，该作用通过敲低mPFC中的BDNF而消除。

总之，这些结果揭示了S1R在氯胺酮持续抗抑郁作用中的关键功能，并表明氯胺酮和S1R激动剂的组合可能对抑郁症患者更有益。

附：英文原文

Title: Sigma-1 receptor activation mediates the sustained antidepressant effect of ketamine in mice via increasing BDNF levels

Author: Ma, Hui, Li, Jin-feng, Qiao, Xin, Zhang, Yue, Hou, Xiao-juan, Chang, Hai-xia, Chen, Hong-lei, Zhang, Yong, Li, Yun-feng

Issue&Volume: 2023-12-14

Abstract: Sigma-1 receptor (S1R) is a unique multi-tasking chaperone protein in the endoplasmic reticulum. Since S1R agonists exhibit potent antidepressant-like activity, S1R has become a novel target for antidepression therapy. With a rapid and sustained antidepressant effect, ketamine may also interact with S1R. In this study, we investigated whether the antidepressant action of ketamine was related to S1R activation. Depression state was evaluated in the tail suspension test (TST) and a chronic corticosterone (CORT) procedure was used to induce despair-like behavior in mice. The neuronal activities and structural changes of pyramidal neurons in medial prefrontal cortex (mPFC) were assessed using fiber-optic recording and immunofluorescence staining, respectively. We showed that pharmacological manipulation of S1R modulated ketamine-induced behavioral effect. Furthermore, pretreatment with an S1R antagonist BD1047 (3mg·kg1·d1, i.p., for 3 consecutive days) significantly weakened the structural and functional restoration of pyramidal neuron in mPFC caused by ketamine (10mg·kg1, i.p., once). Ketamine indirectly triggered the activation of S1R and subsequently increased the level of BDNF. Pretreatment with an S1R agonist SA4503 (1mg·kg1·d1, i.p., for 3 consecutive days) enhanced the sustained antidepressant effect of ketamine, which was eliminated by knockdown of BDNF in mPFC. These results reveal a critical role of S1R in the sustained antidepressant effect of ketamine, and suggest that a combination of ketamine and S1R agonists may be more beneficial for depression patients.

DOI: 10.1038/s41401-023-01201-8

Source: https://www.nature.com/articles/s41401-023-01201-8