氧化应激在免疫介导的脊髓运动神经元损伤过程中意义的探讨
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摘要
肌萎缩侧索硬化(amyotrophic lateral sclerosis, ALS )也称Lou Gehrig氏病,早在1869年由Charcot首先报道,是中枢神经系统的一种慢性进行性变性疾病,以脊髓、脑干和大脑选择性的运动神经元变性为特征,临床表现为缓慢起病、进行性发展的肌肉无力、萎缩。ALS是一种致死性疾病,患者多在首次出现症状后的3-5年内死于呼吸衰竭。根据其发病和遗传特点可分为家族型肌萎缩侧索硬化(Familial Amyotrophic Lateral Sclerosis,FALS)和散发型肌萎缩侧索硬化(Sporadic Amyotrophic Lateral Sclerosis,SALS),其中FALS不足10%,而SALS则占整体ALS的90%以上。FALS主要是由于编码Cu/Zn超氧化物歧化酶(SOD1)的基因突变引起,其突变位点在21号染色体长臂Cu/Zn SOD基因内,即21q22.1-22.2。SALS目前病因不清,其发病机制可能主要集中在以下几个方面:①谷氨酸的兴奋毒作用和钙离子超载;②自由基的毒性作用;③自身免疫机制;④线粒体功能异常;⑤神经丝的过度磷酸化;⑥神经营养因子缺乏等。
尽管对运动神经元变性的机制,有了一些了解。随着人口社会的老龄化,ALS仍是最严重的致死性疾病之一。美国FDA批准的唯一用于ALS临床的药物—riluzole也只能延缓病程的进展。目前仍无确实有效的治疗方法。由于尸体解剖资料为终末期改变,无法对该病的早期干预进行深入研究,这些都局限了ALS的深入研究。因此实验模型的建立至关重要。目前,ALS的实验模型主要集中在体外培养模型和转基因模型上。传统的运动神经元单细胞培养优点是干扰因素少,能直观、动态地观察神经元的形态和功能变化以及对药物的反应;其缺点是操作复杂,技术要求极高,且细胞存活时间太短,不适合研究像ALS这样的慢性进行性变性疾病,且纯运动神经元培养不能模拟体内复杂的生理环境,不能反应神经元与胶质细胞的相互作用,因此不是研究ALS的理想的实验模型。
脑片和脊髓片的器官型培养,可以长时间地存活,并可维持相对完整的形态,保持神经元与神经元之间以及神经元与胶质细胞间的突触联系,
Charcot first described amyotrophic lateral sclerosis (ALS) in 1869.This creeping disorder ,known colloquially as Lou Gehrig’s disease, is a chronic lethal neurodegenerative disease characterized by the progressive loss of motor neurons in the cortex,brainstem,and spinal cord.,leading to profound weakness and atrophy of muscles.Most patients die of respiratory failure within 3 to 5 years after symptoms onset.From its stigmata of episode and heredity,ALS can be divided into familial amyotrophic lateral sclerosis (FALS) and sporadic amyotrophic lateral sclerosis (SALS).FALS is less than 10% of the total ALS patients, while SALS is more than 90%. FALS is mainly caused by the mutation of copper/zinc superoxide dismutase (Cu/Zn SOD) gene, whose site is at 21q22.1～22.2. This suggests that FALS should be a kind of genetic disease. The etiology of SALS, which accounts for the majority of all ALS cases, remains to be resolved, and several pathogenic mechanisms may beinvolved:(1)excitotoxicity,(2)oxidativestress,(3)autoimmunity,(4)mitochon- dria dysfunction, (5) over phosphorylation of neurofilament , (6) deficiency of neurotrophic factors,et al.
Despite significant advances in our understanding of the pathogenesis of motor neuron degeneration,ALS remains one of the most catastrophic diseases of our aging population. Riluzole, the only drug launched for treatment ALS by FDA may only slow disease progression.Truly effective therapy is not currently available for the disease Autopsy materials offer only about end-stage changes.We can not investigate the early changes of ALS.So it is very necessary to established ALS models.
At present,the study is mainly focused on culture models in vitro and SOD1 transgenic mice models.Traditional motor neuron culture is another model. Its virtue is little interference. We can observe the form and function changes
尽管对运动神经元变性的机制,有了一些了解。随着人口社会的老龄化,ALS仍是最严重的致死性疾病之一。美国FDA批准的唯一用于ALS临床的药物—riluzole也只能延缓病程的进展。目前仍无确实有效的治疗方法。由于尸体解剖资料为终末期改变,无法对该病的早期干预进行深入研究,这些都局限了ALS的深入研究。因此实验模型的建立至关重要。目前,ALS的实验模型主要集中在体外培养模型和转基因模型上。传统的运动神经元单细胞培养优点是干扰因素少,能直观、动态地观察神经元的形态和功能变化以及对药物的反应;其缺点是操作复杂,技术要求极高,且细胞存活时间太短,不适合研究像ALS这样的慢性进行性变性疾病,且纯运动神经元培养不能模拟体内复杂的生理环境,不能反应神经元与胶质细胞的相互作用,因此不是研究ALS的理想的实验模型。
脑片和脊髓片的器官型培养,可以长时间地存活,并可维持相对完整的形态,保持神经元与神经元之间以及神经元与胶质细胞间的突触联系,
Charcot first described amyotrophic lateral sclerosis (ALS) in 1869.This creeping disorder ,known colloquially as Lou Gehrig’s disease, is a chronic lethal neurodegenerative disease characterized by the progressive loss of motor neurons in the cortex,brainstem,and spinal cord.,leading to profound weakness and atrophy of muscles.Most patients die of respiratory failure within 3 to 5 years after symptoms onset.From its stigmata of episode and heredity,ALS can be divided into familial amyotrophic lateral sclerosis (FALS) and sporadic amyotrophic lateral sclerosis (SALS).FALS is less than 10% of the total ALS patients, while SALS is more than 90%. FALS is mainly caused by the mutation of copper/zinc superoxide dismutase (Cu/Zn SOD) gene, whose site is at 21q22.1～22.2. This suggests that FALS should be a kind of genetic disease. The etiology of SALS, which accounts for the majority of all ALS cases, remains to be resolved, and several pathogenic mechanisms may beinvolved:(1)excitotoxicity,(2)oxidativestress,(3)autoimmunity,(4)mitochon- dria dysfunction, (5) over phosphorylation of neurofilament , (6) deficiency of neurotrophic factors,et al.
Despite significant advances in our understanding of the pathogenesis of motor neuron degeneration,ALS remains one of the most catastrophic diseases of our aging population. Riluzole, the only drug launched for treatment ALS by FDA may only slow disease progression.Truly effective therapy is not currently available for the disease Autopsy materials offer only about end-stage changes.We can not investigate the early changes of ALS.So it is very necessary to established ALS models.
At present,the study is mainly focused on culture models in vitro and SOD1 transgenic mice models.Traditional motor neuron culture is another model. Its virtue is little interference. We can observe the form and function changes
引文
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