Efficient three-drug cocktail for disease induced by mutant superoxide dismutase
Efficient three-drug cocktail for disease induced by mutant superoxide dismutase
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DOI：
10.1002/ana.10500
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发表时间：
2003-04-01
影响因子：
11.2
通讯作者：
Julien, JP
中科院分区：
文献类型：
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作者：
Kriz, J;Gowing, G;Julien, JP
目前尚无有效的药物治疗肌萎缩侧索硬化症(ALES)。由于证据表明多条途径可能有助于ALS的发病机制，我们在ALS(SOD1(G37R)小鼠模型)上测试了一种由三种药物组成的联合方法，该方法针对神经元死亡复杂途径中的不同靶点：米诺环素，一种抑制小胶质细胞激活的抗菌剂，利鲁唑，一种谷氨酸拮抗剂，以及尼莫地平，一种电压门控钙通道阻滞剂。从症状前期晚期(8~9个月)开始饮食，三药联用效果显著。延缓疾病的发生，减缓肌肉力量的丧失，使SOD1(G37R)小鼠的平均寿命延长6周。SOD1(G37R)小鼠脊髓胶质增生和神经变性标志物的免疫检测信号减弱，证实了该治疗的保护作用。这些结果表明，三联用药可能是治疗ALS的一种有效策略。
There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (AILS). Because evidence suggests that multiple pathways may contribute to ALS pathogenesis, we tested in a mouse model of ALS (SOD1(G37R) mice) a combination approach consisting of three drugs for distinct targets in the complex pathway to neuronal death: minocycline, an antimicrobial agent that inhibits microglial activation, riluzole, a glutamate antagonist, and nimodipine, a voltage-gated calcium channel blocker. The efficacy of this three-drug cocktail was remarkable when administered in the diet from late presymptomatic stage (8-9 months). It delayed the onset of disease, slowed the loss of muscle strength, and increased the average longevity of SOD1(G37R) mice by 6 weeks. The protective effect of the treatment was corroborated by the reduced immunodetection signals for markers of gliosis and neurodegeneration in the spinal cord of SOD1(G37R) mice. These results indicate that such three-drug combination may represent an effective strategy for ALS treatment.