Xue Wenda, Wang Wei, Gong Tong, Zhang Hailou, Tao Weiwei, Xue Lihong, Sun Yan, Wang Fushun, Chen Gang
Center for Translational Systems Biology and Neuroscience, Key Laboratory of Integrative Medicine for Brain Diseases, Nanjing University of Chinese Medicine, Nanjing 210023, China.
School of Psychology, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Sci Rep. 2016 May 20;6:26331. doi: 10.1038/srep26331.
Yueju confers antidepressant effects in a rapid and long-lasting manner, similar to ketamine. CREB (cAMP-response element binding protein) signaling is implicated in depression pathology and antidepressant responses. However, the role of CREB and associated brain derived neurotrophic factor (BDNF) signaling in rapid and long-lasting antidepressant effects remains unclear. Here, we demonstrated that ICR and Kunming strain mice conferred antidepressant responses lasting for 1 and 5 days, respectively, following a single dose of Yueju. One day post Yueju in Kunming but not ICR strain mice, expression of total and phosphorylated CREB, as well as the CREB signaling activator, PKA (protein kinase A) was up-regulated in the hippocampus. Although BDNF gene expression increased at 3 hours in both strains, it remained up-regulated at 1 day only in Kunming mice. Ketamine showed similar strain-dependent behavioral effects. However, blockade of PKA/CREB signaling blunted the antidepressant effects and reversed the up-regulation of BDNF gene expression by Yueju, but not ketamine. Conversely, blockade of mammalian target of rapamycin signaling led to opposite effects. Taken altogether, prolonged transcriptional up-regulation of hippocampal BDNF may account for the stain-dependent enduring antidepressant responses to Yueju and ketamine, but it was mediated via PKA/CREB pathway only for Yueju.
越鞠丸以快速且持久的方式发挥抗抑郁作用，类似于氯胺酮。CREB（环磷腺苷反应元件结合蛋白）信号传导与抑郁症病理及抗抑郁反应有关。然而，CREB及相关的脑源性神经营养因子（BDNF）信号传导在快速且持久的抗抑郁作用中的作用仍不清楚。在此，我们证明，单剂量越鞠丸给药后，ICR小鼠和昆明种小鼠分别产生持续1天和5天的抗抑郁反应。在昆明种而非ICR小鼠中，越鞠丸给药1天后，海马体中总CREB和磷酸化CREB以及CREB信号激活剂蛋白激酶A（PKA）的表达上调。尽管两种品系小鼠在3小时时BDNF基因表达均增加，但仅在昆明种小鼠中1天时仍保持上调。氯胺酮表现出类似的品系依赖性行为效应。然而，阻断PKA/CREB信号传导会减弱抗抑郁作用，并逆转越鞠丸而非氯胺酮对BDNF基因表达的上调。相反，阻断雷帕霉素靶蛋白信号传导会产生相反的效果。综上所述，海马体BDNF的长期转录上调可能是对越鞠丸和氯胺酮产生品系依赖性持久抗抑郁反应的原因，但仅越鞠丸是通过PKA/CREB途径介导的。
