Others The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice

Akamatsu, Megumi  ,  Yamashita, Takenari  ,  Hirose, Naoki  ,  Teramoto, Sayaka  ,  Kwak, Shin

62016-06-28 , Nature Publishing Group , Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo , Department of Neuropathology, Graduate School of Medicine, University of Tokyo , Clinical Research Center for Medicine, International University of Health and Welfare
ISSN:2045-2322 (online)
UTokyo Research掲載「筋萎縮性側索硬化症の治療法に向けて」 URI: http://www.u-tokyo.ac.jp/ja/utokyo-research/research-news/finding-a-treatment-for-als.html
UTokyo Research "Finding a treatment for ALS" URI: http://www.u-tokyo.ac.jp/en/utokyo-research/research-news/finding-a-treatment-for-als.html
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.


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