Festoff Barry W, Suo Zhiming, Citron Bruce A
Department of Veterans Affairs Medical Center, Heartland Veterans Integrated Service Network, Kansas City, Missouri 64128, USA.
CNS Drugs. 2003;17(10):699-717. doi: 10.2165/00023210-200317100-00002.
Biomedical researchers interested in amyotrophic lateral sclerosis (ALS) must invoke newly developing technologies if we are to discover pharmaceutical treatments that will help a significant population of patients with the disease. The focus of ALS research over the last 10 years has been on reactive oxygen species (ROS) and glutamate excitotoxicity, resulting in several clinical trials and the launch of the only drug currently available for the treatment of ALS, riluzole. Unfortunately, the therapeutic benefits have been minimal, at best, and the prognosis for patients with ALS has not improved beyond very modest retardation of the disease course. By emphasising ROS and glutamate excitotoxicity, current ALS research has only partially been able to attenuate the rate of motor decline and neuronal loss associated with this illness. Clues to additional therapeutic potentialities will come from an increased understanding of the mode of cell death (apoptotic or other) and the pathways leading to neuronal demise. If death is apoptotic, inhibiting caspases may be useful. The regulatory modifications for cell death at the molecular level remain to be determined and exploited to prevent neuronal loss, although novel pathways have been recently elucidated that impact on protein aggregation and processing. Oxidative stress, seen in both familial and sporadic forms of ALS, may be only one post-translational mechanism likely to affect specific proteins essential for the health and stability of motor neurons. Protein cross-linking by transglutaminase paralleling that may lead to defects in proteasome function may also be a significant mechanism. The latest capabilities to screen protein changes in specific cells represent the kinds of advances needed to combat ALS in the third millennium.
如果我们想要发现能帮助大量肌萎缩侧索硬化症（ALS）患者的药物治疗方法，对ALS感兴趣的生物医学研究人员就必须采用新出现的技术。过去10年里，ALS研究的重点一直是活性氧（ROS）和谷氨酸兴奋性毒性，这导致了多项临床试验，并推出了目前唯一可用于治疗ALS的药物利鲁唑。不幸的是，其治疗效果充其量也很有限，ALS患者的预后并没有得到明显改善，疾病进程只是稍有延缓。目前的ALS研究通过强调ROS和谷氨酸兴奋性毒性，仅部分地减缓了与该疾病相关的运动功能衰退和神经元丧失的速度。更多治疗潜力的线索将来自于对细胞死亡模式（凋亡或其他）以及导致神经元死亡的途径的进一步了解。如果细胞死亡是凋亡性的，抑制半胱天冬酶可能会有帮助。尽管最近已经阐明了影响蛋白质聚集和加工的新途径，但细胞死亡在分子水平上的调节修饰仍有待确定和利用，以防止神经元丧失。在家族性和散发性ALS中都可见的氧化应激，可能只是一种翻译后机制，可能会影响运动神经元健康和稳定所必需的特定蛋白质。与转谷氨酰胺酶相关的蛋白质交联可能导致蛋白酶体功能缺陷，这也可能是一个重要机制。在特定细胞中筛选蛋白质变化的最新技术能力代表了在第三个千年对抗ALS所需的那种进步。
