Abstract
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.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, characterized by the progressive loss of both upper and lower motor neurons
The mice were akinetic for several hours following the administration, but the duration of the sedative phase became increasingly shorter with time, and all of the mice tolerated the 14-day administration of perampanel at dosages below 20 mg/kg/day
In the AR2H mice, perampanel significantly increased the total number of anterior horn cells (AHCs) at dosages greater than 13.2 mg/kg/day (Fig. 1a) and of TAR DNA-binding protein 43 (TDP-43)-positive AHCs at dosages greater than 6.6 mg/ kg/day, and these increases occurred in a dose-dependent manner (Fig. 1b)
Summary
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, characterized by the progressive loss of both upper and lower motor neurons. Conditional ADAR2 knockout mice (ADAR2flox/flox/VAChT-Cre.Fast; AR2) exhibit a progressive ALS phenotype[19,20] resulting from the death of motor neurons due to ADAR2-downregulation, and notably exhibit mislocalization of TDP-43 from the nucleus to the cytoplasm in the ADAR2-lacking motor neurons[21]. These lines of evidence indicate that a Ca2+-permeable AMPA receptor-mediated mechanism similar to the mechanism that takes place in AR2 mice likely occurs in the motor neurons of ALS patients[22]. The exaggerated Ca2+ influx through the abnormal AMPA receptors could be a therapeutic target for sporadic ALS, and the normalization of TDP-43 mislocalization in AR2 mice could serve as a reliable marker to evaluate the efficacy of newly developed treatments[22]
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