甲基苯丙胺致神经炎性反应的机制研究

Drug abuse represents a serious health issue worldwide. Methamphetamine is one of the major substances were used. Although the role of dopamine system as a major target of methamphetamine cannot be overlooked, the abuse of methamphetamine has been related to neurotoxicity in human long-term abusers as evidenced that there is significant decrease of dopamine cells in the anterior midbrain in methamphetamine users. Both activated microglia/macrophages and infiltration of macrophages were significantly increased among methamphetamine users. These findings suggest that microglial activation and macrophage infiltration in the brain may be a critical element in methamphetamine-induced neuroinflammation with subsequent neurotoxicity. Despite the recognized impact of the abuse of methamphetamine on the brain reward system, mechanisms underlying the ability of methamphetamine to enhance the neuroinflammation comprising microglial activation and monocyte transmigration into the brain remain elusive. Microglia are resident macrophages of the central macrophages of the CNS, not only serve as productive hosts, but also elicit a plethora of cytokines, chemokines and neurotoxic factors in response to stimulation. Among the known chemokines involved in this process, MCP-1 is known to correlate positively with methamphetamine. This effect is mediated through the cognate receptor for methamphetamine, the sigma receptor 1 (sigma-R1). MCP-1 exerts robust chemostactic properties and, in this capacity, may recruit peripheral monocyte transmigration into CNS, thereby serving as focal sites for attracting monocyte migration to the brain. This in turn, facilitates enhanced transformation of monocyte into macrophages, propagation of release of neurotoxic factors by the microglia/macrophages resulting in exacerbation of the inflammatory cascade within the CNS. The detailed mechanisms underlying microglial activation and monocyte migration in response to methamphetamine however, remain unknown. We therefore hypothesized that methamphetamine-mediated enhancement of neuroinflammatin in the CNS was involved in activation of microglia via sigma receptor leading to induction of MCP-1 and monocyte migration. This　proposal is both novel and innovative in that the efficacy of sigma receptor and neutralizing MCP-1 in abrogating monocyte transmigration can be of value for methamphetamine-mediated neuroinflammation.

甲基苯丙胺滥用既是全球普遍存在的公共卫生问题，也是危害严重的社会问题，但其神经炎性反应和致神经损伤等的机制迄今未明。多巴胺能神经通路是早期认识甲基苯丙胺成瘾神经毒性的学说，但难以解释甲基苯丙胺引起的以小胶质细胞活化和巨噬细胞浸润为特征的神经炎性损伤。申请者前期的研究表明甲基苯丙胺激活小胶质细胞，诱导趋化因子MCP-1的产生。本项目拟在前期研究的基础上，提出甲基苯丙胺引起神经炎性反应的新假说：甲基苯丙胺作用于小胶质细胞上Sigma-受体,诱导小胶质细胞表达并释放MCP-1，弥散至血脑屏障的MCP-1可募集外周单核细胞迁移至中枢神经系统，进而分化成脑内巨噬细胞，导致神经炎性的级联放大反应，最终导致神经元炎性损伤，由此加重药物成瘾的发生发展。如果本假说得到证实，将为现有有关药物成瘾发生和治疗提供新的理论依据，对临床治疗策略的选择和治疗药物靶标的遴选具有重要的指导意义。

药物成瘾已成为严重危害人类健康的疾病之一，给家庭和社会带来沉重的经济负担和巨额的财政支出。成瘾性药物（甲基苯丙胺）可引起严重的精神障碍和神经毒性反应，由于甲基苯丙胺引起中枢毒性的机制仍未阐明，目前缺乏有效的治疗手段。因此，从新的视角深入研究甲基苯丙胺致神经系统损伤的机制，发展甲基苯丙胺滥用的早期发现和早期诊断技术，采取控制甲基苯丙胺致神经系统损伤的有针对性的干预措施，是降低甲基苯丙胺致神经系统损伤的发生率，提高成瘾者生存质量的关键。本项目紧密追踪国际上甲基苯丙胺滥用产生神经系统损伤作用这一研究热点，探寻甲基苯丙胺引起神经系统损伤过程中的关键靶标分子。结合成瘾性药物滥用和表观遗传学研究，应用高通量技术分析甲基苯丙胺致神经系统损伤的细胞分子机制，从新的视角深入研究甲基苯丙胺致神经系统损伤发生发展的机制，选择关键靶标分子作为甲基苯丙胺致神经系统损伤的生物标志，发展甲基苯丙胺致神经系统损伤的早期发现和早期诊断技术，采取控制成瘾性药物滥用致神经系统损伤有针对性的干预措施，提高患者生存质量，减少社会医疗的成本。目前本课题已经发现非编码编码RNA miR-143/PUMA，circHIPK2 /miR-124 /sigma-1受体circRNA HECTD1/miR142/TIPARP，CircDLGAP4/ miR-143/ PUMA在甲基苯丙胺致神经毒性发生发展中的重要作用。在该项目的资助下已发表论文16篇，包括Molecular Psychiatry，Pharmacology & therapeutics，Autophagy，Journal Of Neuroscience，Scientific Reports，J Neuroinflammation，J Neuroimmune Pharmacology 等杂志。根据目前所筛选的治疗靶标，已经开发研制具有自主知识产权的药物，正在进行实验治疗学研究。