氯胺酮的抗抑郁作用已受到国内外学者重视，但精神副作用限制其用于抑郁症治疗。我们前期研究发现：R-氯胺酮同样具有快速持久的抗抑郁作用，且无明显精神副作用，其机制与上调脑内腹侧被盖区-伏核环路中脑源性神经营养因子（BDNF）有关，但何种途径引起BDNF的上调尚不清楚。我们预实验结果提示：脑及骨骼肌中过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC1α）和Ⅲ型纤连蛋白结构域5（FNDC5）在抑郁症发病及R-氯胺酮抗抑郁中具有重要作用。据此，本课题组提出以下科学假说：PGC1α-FNDC5-BDNF信号通路参与了R-氯胺酮的抗抑郁作用。因此，我们拟通过抑郁动物模型及神经和骨骼肌细胞共培养研究R-氯胺酮抗抑郁作用与脑和骨骼肌组织PGC1α-FNDC5-BDNF信号通路的关系以及脑与骨骼肌的交互作用如何影响抑郁症发生发展。明确这些机制为今后开发新型抗抑郁药物及防治抑郁症均具有重要参考价值。

Ketamine’s antidepressant effects have attracted considerable worldwide research attentions, but its psychotomimetic side-effects limit its clinical use as a strategy for depression treatment. Our previous studies showed that R-ketamine also has rapid and lasting antidepressant effects, but without significant psychotomimetic side-effects. Furthermore, the antidepressant action of R-ketamine is closely related to the facilitating effects of brain-derived neurotrophic factor (BDNF) in the ventral tegmental area-nucleus accumbens circuit, but the mechanisms underlying the increased BDNF levels remain obscure. Our previous findings demonstrated that peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) and fibronectin type III domain-containing protein 5 (FNDC5) in brain and skeletal muscle are involved in the pathogenesis of depression and the therapeutic mechanisms of R-ketamine. Based on these findings, we propose the following hypothesis: the PGC1α–FNDC5–BDNF signaling pathway is involved in the mechanisms underlying the antidepressant effects of R-ketamine. We therefore apply depression animal models and co-cultivation of neurons and skeletal muscle cells to elucidate the relationship between the antidepressant effects of R-ketamine and PGC1α–FNDC5–BDNF signaling pathway in brain and skeletal muscle, and to explain the interaction between brain and skeletal muscle and its crosstalk in the pathogenesis of depression. Our findings could provide a novel investigative avenue for the development of antidepressant agents, and would have significant clinical values for the prevention and treatment of depression.