Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China.
Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China.
Sci Rep. 2023 Oct 3;13(1):16611. doi: 10.1038/s41598-023-43684-9.
Esketamine provides an immediate and noticeable antidepressant effect, although the underlying molecular processes are yet unclear. Irisin induced by aerobic exercise has been implicated in the alleviation of depressive symptoms, whether irisin expression responds to the administration of esketamine remains unknown. In this study, we found that irisin was reduced in the hippocampus and peripheral blood of chronic unpredictable mild stress (CUMS) mice, whereas the irisin level was rescued by esketamine treatment. The reduction of PGC-1α expression (transcriptional regulator of irisin gene expression) in the CUMS mice was rescued by esketamine treatment, PGC-1α knockdown significantly reduced the irisin level induced by esketamine. Additionally, FNDC5/irisin-knockout mice developed more severe depressant-like behaviors than wild-type mice under CUMS stimulation, with an attenuated the antidepressant effect of esketamine. Further research indicated that irisin-mediated modulation of esketamine on depressive-like behaviors in CUMS mice involved the ERK1/2 pathway. Overall, the PGC-1α/irisin/ERK1/2 signaling activation may be a new mechanism underlying the antidepressant activity of esketamine, denoting that irisin may be a promising therapeutic target for the treatment of depression.
氯胺酮能立即产生显著的抗抑郁效果，但其潜在的分子机制尚不清楚。有氧运动诱导的鸢尾素与抑郁症状的缓解有关，而氯胺酮的给药是否会引起鸢尾素的表达变化尚不清楚。在本研究中，我们发现慢性不可预测轻度应激（CUMS）小鼠的海马体和外周血中的鸢尾素减少，而氯胺酮治疗可挽救鸢尾素水平。CUMS 小鼠中 PGC-1α 表达（鸢尾素基因表达的转录调节因子）减少可被氯胺酮治疗挽救，PGC-1α 敲低显著降低了氯胺酮诱导的鸢尾素水平。此外，FNDC5/鸢尾素敲除小鼠在 CUMS 刺激下比野生型小鼠表现出更严重的抑郁样行为，氯胺酮的抗抑郁作用减弱。进一步的研究表明，鸢尾素介导的氯胺酮对 CUMS 小鼠抑郁样行为的调节涉及 ERK1/2 通路。总的来说，PGC-1α/鸢尾素/ERK1/2 信号通路的激活可能是氯胺酮抗抑郁作用的新机制，提示鸢尾素可能是治疗抑郁症的有前途的治疗靶点。
