大麻CB2受体及其激动剂AM1241在帕金森病运动并发症发病机制中的作用研究

Parkinson’s disease(PD) is a kind of neurodegenerative movement disorder,which is characterized primarily by a massive loss and degeneration of dopaminergic neurons in the substantia nigra compact(SNc) and a significant reduction of striatal dopamine. The main drug treatment of PD is replacement of dopamine with levodopa(L-dopa), but virtually almost all patients treated for extended periods developed disabling complications named as levodopa induced dyskenisia(LID), including motor fluctuation，dyskinesias and so on. Dopaminergic receptors and glutamatergic receptors are co-expressed on the membrane of striatal MSNs. The CB2 receptors and endocannabinoids(eCB).They play an important role in regulating the signal transductions between synapses. Empirical studies from foreign researchers have discovered that CB1 system has a regulating function for multiple neurotransmitters, such as glutamate, GABA and dopamine, to produce marked effects. CB2 receptor agonists can induce motor activity suppression of animals. Therefore, to research into propertiesof CB2 receptors is the basis for this thesis. And more, it is urgent to seek and discover some neotype drugs for PD treatments to make-up for the already used medicine. In this study, we investigated the pathogenesis of levodopa-induced motor complications in a rat model and the potential therapeutic effects of a CB2 receptor agonist.

帕金森病患者(PD)由于选择性中脑黑质致密部多巴胺能神经元变性缺失，导致下游的纹状体多巴胺含量显著性降低。目前帕金森病仍以左旋多巴治疗为主，而长期使用该药会出现左旋多巴诱导异动症等远期并发症，包括症状波动和运动障碍等。近年研究表明，多巴胺受体与大麻素CB2受体存在共表达，并且对突触之间的信号传递具有重要调节作用。PD 纹状体长期失去多巴胺能支配，以及后续的长期多巴胺替代治疗波动性刺激可引起大麻素系统功能的改变。同时神经退行性病变条件下CB2受体表达增加。CB2受体激动剂具有抑制持续及神经退行性病变等药理学特性，且长期给药不产生明显的精神和躯体依赖等副作用，显示出良好的临床应用前景。本研究拟采用左旋多巴长期治疗诱导运动并发症的PD 大鼠模型，试探讨异动症的发生机制，观察使用CB2 受体激动剂对异动症潜在的防治作用。

帕金森病主要的病理特点是黑质多巴胺能神经元的损失。在这项研究中,我们研究了大麻素受体2的(CB2R)受体激动剂AM1241在MPTP注射形成帕金森病的小鼠模型中的作用及其机制。我们的结果显示MPTP注射形成帕金森病小鼠大脑中CB2受体表达水平降低且行为学得分显著降低。经过AM1241治疗后, CB2受体表达水平增多且行为得分显著提高，同时伴随着多巴胺和5 -羟色胺表达的增加，并存在剂量依赖的相关性。此外,免疫印迹试验和免疫染色结果表明,AM1241显著激活黑质和海马区PI3K / Akt / MEK信号通路磷酸化，促进Parkin 和PINK1的表达增加。此外,黑质TH阳性细胞数量的增加表明AM1241 可以刺激帕金森病小鼠再生多巴胺能神经元。同时我们明确了CB2受体和多巴胺能神经元的共表达提示AM1241直接作用于 CB2受体可以成为有效的帕金森病治疗的靶点。总之,选择性CB2受体激动剂AM1241对帕金森病小鼠有明显的治疗效果,并导致多巴胺能神经元的再生后减轻神经毒性。AM1241的神经发生影响的潜在的机制可能是诱导PI3K / AKT信号通路磷酸化。