Jackson Mandy, Lladó Jerònia, Rothstein Jeffrey D
Department of Preclinical Veterinary Sciences, The University of Edinburgh, Scotland, UK.
Expert Opin Investig Drugs. 2002 Oct;11(10):1343-64. doi: 10.1517/13543784.11.10.1343.
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterised by the selective death of motor neurones. The mechanisms and processes responsible for the selective loss of motor neurones are still unknown, however several hypotheses have been put forward, including oxidative damage and/or toxicity from intracellular aggregates due to mutant superoxide dismutase-1 activity, axonal strangulation from cytoskeletal abnormalities, loss of trophic factor support and glutamate-mediated excitotoxicity. These theories are based on a better understanding of the genetics of amyotrophic lateral sclerosis and on biochemical and pathological analysis of post-mortem tissue. They have led to the development of appropriate animal and cell culture models, allowing the sequence of events in motor neuronal degeneration to be unravelled and potential therapeutic agents to be screened. Unfortunately, the majority of therapeutics found to be efficacious in the animal and cell culture models have failed in human trials. Riluzole is still the only proven therapy in humans, shown to extend survival of amyotrophic lateral sclerosis patients by approximately 3 months, but it has no effect on muscle strength. Other potential therapeutic approaches are being identified, including inhibition of caspase-mediated cell death, maintenance of mitochondrial integrity and energy production, regulation of glutamate homeostasis, reduction of inflammation and control of neurofilament synthesis. Hopefully, in the near future some new agents will be found that can alter the course of this devastating and fatal disease.
肌萎缩侧索硬化症是一种进行性神经退行性疾病，其特征是运动神经元选择性死亡。导致运动神经元选择性丧失的机制和过程仍然未知，不过已经提出了几种假说，包括由于突变的超氧化物歧化酶-1活性导致的氧化损伤和/或细胞内聚集体的毒性、细胞骨架异常导致的轴突绞窄、神经营养因子支持的丧失以及谷氨酸介导的兴奋性毒性。这些理论基于对肌萎缩侧索硬化症遗传学的更好理解以及对死后组织的生化和病理分析。它们促使了合适的动物和细胞培养模型的开发，从而能够揭示运动神经元变性的事件序列并筛选潜在的治疗药物。不幸的是，在动物和细胞培养模型中被发现有效的大多数治疗方法在人体试验中都失败了。利鲁唑仍然是唯一被证实对人类有效的疗法，它能使肌萎缩侧索硬化症患者的生存期延长约3个月，但对肌肉力量没有影响。正在确定其他潜在的治疗方法，包括抑制半胱天冬酶介导的细胞死亡、维持线粒体完整性和能量产生、调节谷氨酸稳态、减轻炎症以及控制神经丝合成。有望在不久的将来找到一些能够改变这种毁灭性致命疾病进程的新药物。
