The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice.
The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice.
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DOI：
10.1038/srep28649
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发表时间：
2016-06-28
影响因子：
4.6
通讯作者：
Kwak S
中科院分区：
文献类型：
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作者：
Akamatsu M;Yamashita T;Hirose N;Teramoto S;Kwak S
TDP-43 病理学和 AMPA 受体亚基 GluA2 的 RNA 编辑失败都是与病因学相关的分子异常，大多数肌萎缩侧索硬化症 (ALS) 患者的运动神经元中同时发生这种异常。 AR2 小鼠的运动神经元中作用于 RNA 2 的 RNA 编辑酶腺苷脱氨酶 (ADAR2) 被条件性敲除，通过 Ca2+ 渗透性 AMPA 受体介导的机制，在运动神经元中表现出进行性 ALS 表型和 TDP-43 病理学。因此，通过 AMPA 受体拮抗剂改善 Ca2+ 流入增加可能是一种潜在的 ALS 治疗方法。在这里，我们发现口服吡仑帕奈（一种选择性、非竞争性 AMPA 受体拮抗剂）可显着阻止 AR2 小鼠 ALS 表型的进展，并使 TDP-43 病理相关的运动神经元死亡正常化。鉴于吡仑帕奈是一种已批准的抗癫痫药物，吡仑帕奈是一种值得进行临床试验的潜在候选 ALS 药物。
Both TDP-43 pathology and failure of RNA editing of AMPA receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of the majority of patients with amyotrophic lateral sclerosis (ALS). AR2 mice, in which an RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) is conditionally knocked out in the motor neurons, exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons through a Ca2+-permeable AMPA receptor-mediated mechanism. Therefore, amelioration of the increased Ca2+ influx by AMPA receptor antagonists may be a potential ALS therapy. Here, we showed that orally administered perampanel, a selective, non-competitive AMPA receptor antagonist significantly prevented the progression of the ALS phenotype and normalized the TDP-43 pathology-associated death of motor neurons in the AR2 mice. Given that perampanel is an approved anti-epileptic drug, perampanel is a potential candidate ALS drug worthy of a clinical trial.