神经退行性疾病病变机理及药物作用新靶点

Mechanisms and Therapeutic Targets of Neurodegenerative Diseases

神经退行性疾病是医学研究领域中的一大难题。近年来，该类疾病遗传因素及病变机理的研究取得了很大进展。研究表明这类疾病的发生与某些基因突变后产生的蛋白有关，这些蛋白可进而直接或间接地引起一系列反应，影响神经系统中某些特定的神经细胞，最终导致这些细胞死亡。氧化应激、线粒体机能障碍、兴奋性毒性、免疫炎症及细胞凋亡等机理在神经细胞死亡过程中起重要作用。这些研究结果为我们寻找神经退行性疾病的防治药物提供了分析的途径和作用靶点。抑制神经细胞退行性改变的启动因子，阻断神经细胞退行性改变的信号传导及／ 或激活内源性神经保护机制均有可能防止神经细胞退行性改变。尽管目前主要依靠细胞培养技术和动物模型来寻找神经保护药物，但通过这些研究很有可能找到治疗神经退行性疾病的新型药物。

Neurodegenerative disorders are among the most puzzling and devastating illnesses in medicine.Over the past few years,significant advances have been made in clarifying the genetic features of these diseases and in understanding pathogenic mechanisms.The emerging view is that these diseases result because the presence of the mutant proteins directly or indirectly triggers pathogenic cascades that eventually effect the physiology of subsets of neural cells.Ultimately,some of the affected nerve cells die.The pathogenic cascades may include oxidative stress,mitochondrial dysfunction,excitotoxicity,inflammatory mechanisms and apoptosis.These studies have led to a large number of putative therapeutic targets and approaches.At least three general approaches for determining agents with therapeutic potential seem reasonable:prevention of initiating factors;blocking downstream events in the neurodegenerative cascade;and activating endogenous neuroprotective mechanisms.Although current methods for these approaches have relied heavily on cell culture techniques and onanimal models,we believe that it is realistic to expect that these approaches will provide new clinical treatments based on effective protection against the neurodegenerative cascade.