基于PI3K/Akt/mTOR自噬通路探讨针刺治疗帕金森病抑郁的研究

Clinical studies have shown that acupuncture has a good effect on the motor and depressive symptoms of Parkinson's disease (PD), however the mechanism is not clear. The pathological manifestations of PD are widely recognized as the decrease of nigrostriatal dopaminergic neurons and the presence of Lewy bodies in neurons, and the Lewy bodies are created by the abnormal accumulation of α-synuclein (α-syn). Meanwhile, the damaged synapses of pyramidal nerve cells and glial nerve cells can cause depressive symptoms. Studies have shown that autophagy can clean the accumulation of α-syn, and PI3K / Akt / mTOR pathway can regulate the expression of mTORC1, activation of the mTORC1 pathway can repair the damaged synapses. Our previous studies found that the dynamic expression of Beclin-1 and α-syn in the PD model, and it had a neural protective effect on 6-OHDA-induced rats by regulating autophagy. Those also proved that acupuncture played an antidepressant effect by protecting the damaged synapses of hippocampus and prefrontal cortex. Therefore, the focus of this study is autophagy. And the hypothesis of this study is “acupuncture will regulate autophagy by activating the PI3K / Akt / mTOR pathway”. The activator and inhibitor of autophagy will be applied to the study as control to study the mechanism of acupuncture on depression in Parkinson's disease (DPD). It is of great significance to study DPD with autophagy and damaged synapses together.

临床研究表明针刺治疗帕金森病（PD）的运动和抑郁症状具有很好疗效，而其机制尚未阐明。PD的病理改变为多巴胺能神经元丢失和路易小体(LB)形成，α-突触核蛋白（α-syn）的异常积聚形成LB，而锥体细胞和胶质细胞突触受损可引起抑郁症状。研究表明，自噬可清除异常积聚的α-syn，PI3K/Akt/mTOR自噬通路可激活mTORC1通路，修复受损的突触。我们研究已经证实在PD模型中自噬蛋白Beclin-1与α-syn呈正相关的动态表达，通过调节自噬可对多巴胺能神经元起到保护作用；并证实针刺可保护海马和前额叶神经细胞和胶质细胞的突触形态与功能，起到抗抑郁作用。因此，本研究从自噬的角度出发，围绕“针刺调节自噬，激活PI3K/Akt/mTOR信号通路”假说，应用通路的激活剂和抑制剂作为对照，探讨针刺治疗PD抑郁（DPD）的可能机制。将针刺治疗DPD与热门课题自噬和突触受损相联系，具有重要的科学意义。

针刺治疗帕金森病（PD）的运动和抑郁症状具有很好疗效，而其机制尚未阐明。本研究观察针刺对帕金森病抑郁（DPD）模型大鼠的行为学、单胺类神经递质、DA和5-HT合成、代谢的相关酶和α-syn的作用，探讨针刺治疗DPD的效应研究；应用自噬抑制剂和激活剂，观察针刺对DPD模型大鼠自噬的影响；应用PI3K抑制剂，观察针刺对DPD模型大鼠PI3K/Akt/mTOR自噬通路的影响。结果显示：针刺可改善DPD模型大鼠的运动症状和抑郁症状，增加DPD模型大鼠中脑内DA和5-HT的含量，对DPD模型大鼠中脑内DA合成酶及海马内5-HT合成、代谢酶的含量无影响，针刺下调DPD模型大鼠纹状体内ɑ-syn的含量，针刺抑制DPD模型大鼠海马和中脑内自噬的表达；针刺上调p-PI3K/p-AKT/p-mTOR的表达，抑制自噬的发生，促进突触蛋白表达。因此，针刺可能是通过激活PI3K/AKT/mTOR自噬信号通路抑制自噬的发生和修复损伤突触起到治疗帕金森病抑郁的作用。