Lithium delays progression of amyotrophic lateral sclerosis
Lithium delays progression of amyotrophic lateral sclerosis
复制标题
DOI：
10.1073/pnas.0708022105
复制
发表时间：
2008-02-12
影响因子：
11.1
通讯作者：
Paparelli, Antonio
中科院分区：
文献类型：
--
作者：
Fornai, Francesco;Longone, Patrizia;Paparelli, Antonio
ALS是一种毁灭性的神经退行性疾病，没有有效的治疗方法。在目前的研究中，我们发现，每日剂量的锂，导致血浆水平范围从0.4至0.8 mEq/L，延缓受ALS影响的人类患者的疾病进展。在15个月的随访期间，接受锂治疗的患者无一死亡，与年龄、病程和性别匹配的利鲁唑治疗相同时间的对照患者相比，疾病进展明显减弱。在对遗传性ALS动物模型G93A小鼠的平行研究中，我们发现锂具有显著的神经保护作用，可延迟疾病发作和持续时间，并延长寿命。这些作用伴随着自噬的激活和运动神经元中线粒体数量的增加以及抑制反应性星形胶质细胞增生。同样，锂减少了以线粒体空泡化为特征的缓慢坏死，并增加了在盐水处理的G93A小鼠中受到严重影响的第VII层中计数的神经元数量。在G93A小鼠中给予锂后，即使与盐水处理的WT相比，这些神经元的数量也较高。所有这些机制都可能有助于锂的作用，这些结果为治疗受ALS影响的人类患者提供了有希望的前景。
ALS is a devastating neurodegenerative disorder with no effective treatment. In the present study, we found that daily doses of lithium, leading to plasma levels ranging from 0.4 to 0.8 mEq/liter, delay disease progression in human patients affected by ALS. None of the patients treated with lithium died during the 15 months of the follow-up, and disease progression was markedly attenuated when compared with age-, disease duration-, and sex-matched control patients treated with riluzole for the same amount of time. In a parallel study on a genetic ALS animal model, the G93A mouse, we found a marked neuroprotection by lithium, which delayed disease onset and duration and augmented the life span. These effects were concomitant with activation of autophagy and an increase in the number of the mitochondria in motor neurons and suppressed reactive astrogliosis. Again, lithium reduced the slow necrosis characterized by mitochondrial vacuolization and increased the number of neurons counted in lamina VII that were severely affected in saline-treated G93A mice. After lithium administration in G93A mice, the number of these neurons was higher even when compared with saline-treated WT. All these mechanisms may contribute to the effects of lithium, and these results offer a promising perspective for the treatment of human patients affected by ALS.