蛋白激酶K信号通路的抑制在苯丙胺中枢神经毒性中的作用及其机制

Amphetamine is one of the most commonly used drugs all over the world. It can damage the dopaminergic(DA) and serotonergic(5-HT) terminals in the central nervous system. Now, it is proposed that the excessive released DA could lead to the formation of oxidative stress and free radicals that induce nerve terminals damage. However, it is unreasonable to explain why the postsynaptic neurons which synapse DA terminals are intact. We found that Akt/GSK-3β/DRP-2 singal pathway was inhibited in the terminal damaged regions of mice after administration of amphetamine.So, we suggest that inhibition of Akt/GSK-3β/DRP-2 pathway may be closely related to damage of DA and 5-HT terminals. Therefore, based on our previous results from the animal model, our study plan to use antagonist, agonist, siRNA and gene overexpression methods to regulate the Akt,GSK-3β and DRP-2 in the cell culture model, and determine whether the terminal damage depends on Akt/GSK-3β/DRP-2 pathway. We hope to better understand that mechanisms of amphetamine neurotoxicity in the central nervous system by exploring the inhibition of Akt signaling pathway and enlighten a new clue for treatment of amphetamine neurotoxicity.

苯丙胺是全世界最滥用的毒品之一。在中枢它主要损伤多巴胺（DA）和5-羟色胺（5-HT）的神经末梢，目前认为损伤机理主要是神经末梢释放过量DA至突触间隙，产生自由基及活性氮而导致，但它无法解释与神经末梢相连的突触后神经元为何没有受损。我们前期实验发现使用苯丙胺后，动物DA和5-HT神经末梢损伤的部位Akt/GSK-3β/DRP-2信号通路都受到抑制，故假设该通路的抑制与神经末梢的损伤密切相关。为此，本项目在动物模型的基础上，通过细胞模型，用抑制剂或激动剂等方法干预Akt/GSK-3β/DRP-2通路上的分子，研究神经末梢的损伤是否依赖于此通路，进而探讨该通路抑制的机理，以阐明Akt通路在中枢损伤中的作用和机制，也为苯丙胺产生中枢毒性效应的治疗提供新的思路。

苯丙胺一类新型合成毒品，在中枢它主要损伤多巴胺（DA）和5-羟色胺（5-HT）的神经末梢，损伤的信号通路目前仍不清楚。我们实验发现给大鼠注射苯丙胺后，动物行为学表现异常明显，出现了刻板行为。DA和5-HT神经末梢损伤的部位Akt/GSK-3β信号通路都受到抑制。用苯丙胺作用PC12细胞，Akt/ GSK -3β信号通路也同样受到抑制。进而在PC12细胞模型上，用抑制剂抑制Akt/GSK-3β通路，可导致细胞突起的变短和细胞的损伤，而激活Akt/ GSK -3β信号通路则可保护细胞。进一步研究发现，苯丙胺可致Akt上游分子PP2A活性的增加，激活PP2A可抑制Akt/ GSK -3β信号通路，抑制PP2A则可保护细胞。并且发现PP2A上游的Ca2+内流增加。因此，实验表明苯丙胺损伤DA和5-HT的神经末梢与激活了PP2A，从而抑制Akt/ GSK -3β信号通路密切相关。本实验为苯丙胺产生中枢毒性机理揭示了一条新的信号通路。