提高脑脊液镁浓度对MPTP小鼠保护作用的研究

The therapy of oral dopamine or treatment of deep brain stimulation can be effective remission of clinical symptoms of Parkinson's disease, but it can not prevent gradual missing of dopamine neurons. We hypothesize that elevation of magnesium concentration may be effective for Parkinson's disease, which based on the past studies: epidemiology research and clinical study indicated that magnesium deficiency is one of the pathogenetic factors of Parkinson's disease, animal experiments also demonstrated that magnesium deficiency can lead to Parkinson's disease. Magnesium affects multiple pathophysiological processes such as inflammation, mitochondrial disorders, calcium homeostasis and oxidative stress, which may mediate loss of dopamine neurons. Our research group had proved that magnesium exerts both preventive and ameliorating effects in dopamine neurons in vitro MPP+ Parkinson's disease model. In addition, we also reported that serum magnesium can not enter the cerebrospinal fluid in mice. Here we try to evaluation of dopamine neuronal loss and associated neurological symptoms after elevating magnesium concentration of the cerebrospinal fluid in MPTP mice, and determine the compatible magnesium concentrations for treatment, and further discuss the potential mechanism. This is the first study that investigation the protective effect by supplement magnesium in vivo Parkinson's disease model.

补充多巴胺或脑深部刺激等疗法可在数年内有效的缓解帕金森病的各种临床症状，但不能改变多巴胺神经元进行性缺失。本研究的目的是证明补充镁对帕金森模型的多巴胺神经元死亡起保护作用。流行病学的调查和临床研究提示镁缺乏是帕金森病的发病因素之一，动物实验也证明了镁摄取不足可导致帕金森病。研究表明镁缺乏导致的炎症，线粒体功能障碍、钙稳态失衡及氧化应激等细胞代谢障碍是多巴胺神经元死亡的生物学基础。申请人所属实验室已经在体外实验中证明了适量提高细胞外液镁浓度可以预防帕金森病模型的多巴胺神经元死亡。申请人的前期试验证明了镁离子不能自由通过血脑屏障，因此本项目用提高脑脊液镁浓度的方法来验证镁对MPTP小鼠模型的保护作用：评价多巴胺神经元缺失及相关神经症状；测量小鼠脑脊液确定镁的最佳治疗浓度；探讨补充镁后改善多巴胺神经元缺失的作用机制。本研究是国内外首次利用镁对体内帕金森病模型进行帕金森病根治性疗法的开发。

补充多巴胺或脑深部刺激等疗法可在数年内有效的缓解帕金森病的各种临床症状，但不能改变多巴胺神经元进行性缺失。流行病学的调查和临床研究提示镁缺乏是帕金森病的发病因素之一，动物实验也证明了镁摄取不足可导致帕金森病。研究表明镁缺乏导致的炎症，线粒体功能障碍、钙稳态失衡及氧化应激等细胞代谢障碍是多巴胺神经元死亡的生物学基础。由于前期研究表明镁离子不能自由通过血脑屏障，本项目用提高脑脊液镁浓度的方法来验证镁对MPTP小鼠模型的保护作用。研究结果显示提高脑脊液镁浓度可以减弱MPTP毒性，提高小鼠氨酸羟化酶（TH）阳性细胞即黑质多巴胺神经元存活率，最高可达56.33%。旷场实验和旋转棒实验证明给药组小鼠的运动和协调功能障碍出现了明显的改善。同时发现补充镁后MPTP小鼠黑质的iNOS、GFAP、Iba 1阳性细胞的活化被抑制，提示补充MgSO4后改善多巴胺神经元缺失可能是通过抑制胶质细胞的活化以及多巴胺神经元的氧化应激来实现的。本项目首次证明了在活体内提高脑脊液镁离子浓度可以改善帕金森病模型的多巴胺神经元缺失及相关神经症状，为确定镁可以成为根治帕金森病药物打下了前期基础。发表论著3篇（SCI论文一篇），待发表论文2篇。培养硕士研究生4名。