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

Sci Rep. 2016 Jun 28;6:28649. doi: 10.1038/srep28649.

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 Ca(2+)-permeable AMPA receptor-mediated mechanism. Therefore, amelioration of the increased Ca(2+) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / genetics
  • Animals
  • Anticonvulsants / pharmacology
  • Calcium / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Progression
  • Female
  • Homozygote
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Neurons / metabolism
  • Phenotype
  • Pyridones / pharmacology*
  • RNA Editing*
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, AMPA / genetics
  • Spinal Cord / metabolism

Substances

  • Anticonvulsants
  • DNA-Binding Proteins
  • Pyridones
  • Receptors, AMPA
  • TDP-43 protein, mouse
  • perampanel
  • glutamate receptor ionotropic, AMPA 2
  • Calcium