Robust beneficial effects of a non-competitive AMPA receptor antagonist in an ALS model mice
Creators: name: Akamatsu, Megumi
name: Takenari Yamashita
name: Teramoto, Sayaka
name: Kwak, Shin
Publisher: name: F1000Research
Year: 2016

description: The candidate drugs that have been developed to treat ALS are largely based on studies in SOD1 transgenic ALS animal models, but virtually all of these drugs have proven ineffective. Therefore, a novel strategy for drug development that exploits evaluation markers that are closely linked with ALS pathogenesis would be valuable. Both TAR DNA-binding protein 43 (TDP-43) pathology and RNA editing failure at the glutamine/arginine (Q/R) site of GluA2, α-amino-3- hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit, are characteristic etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of the majority of patients with ALS. Adenosine deaminase acting on RNA 2 (ADAR2) specifically catalyzes RNA editing at the Q/R site of GluA2, and conditional ADAR2 knockout mice (ADAR2flox/flox/ VAChT-Cre.Fast; AR2) exhibit a progressive ALS phenotype with TDP-43 mislocalization through a Ca<sup>2+</sup>-permeable AMPA receptor-mediated mechanism. Therefore, amelioration of the increased Ca<sup>2+</sup> influx through the use of AMPA receptor antagonists may be a potential ALS therapy. Objectives: Because amelioration of the exaggerated Ca<sup>2+</sup> influx through the abnormal AMPA receptors could be a therapeutic target for sporadic ALS, and AR2 mice will be useful to evaluate the efficacy of treatment, we assessed the efficacy of systemic AMPA receptor antagonists on the AR2 mice. Methods: Homozygous and heterozygous AR2 mice were used in this study. A non-competitive AMPA receptor antagonist perampanel (provided by Eisai Co., Ltd.) was administered daily to the mice via oral gavage for 14 days (either dose of 3.3, 6.6, 13.2 or 20 mg/kg to AR2<sup>+/-</sup> or AR2<sup>/</sup> mice; n = 5–8 in each group) or for 90 days (at a dosage of 13.2 mg/kg/day for the first four days and then at 20 mg/kg/day for the remaining 86 days to AR2<sup>/</sup> mice; n=8). The age-matched control mice received oral gavage of the same volume of a 0.5% methyl cellulose solution for the same period. Effects on motor dysfunction were assessed by rotarod scores and grip power, and on ALS pathology were assessed by the number of spinal anterior horn cells and TDP-43 immunohistochemistry at the end of drug administration. Results: Oral administration of perampanel to AR2 mice for 14 days effectively normalized TDP-43 pathology in motor neurons. All the mice completed the 90-day administration of perampanel and the progression of the ALS phenotype and the death of motor neurons were markedly ameliorated in the perampanel-treated AR2 mice. Moreover, the number of spinal motor neurons that exhibit nuclear localization of TDP-43 was markedly Platform Communication Mouse Models 49 increased in the perampanel-treated AR2<sup>/</sup> mice as compared to non-treated AR2<sup>/</sup> mice. Conclusion: Given that perampanel has already been approved as an anti-epileptic drug, perampanel is a potential candidate ALS drug worthy of a clinical trial.<br>