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Noncompetitive AMPA-receptor antagonist perampanel rescues TDP-43 mislocalization in mechanistic ALS model mice

  • P1-314
  • 蔡 慧玲 / Hui Lin Chai:1,2 郭 伸 / Shin Kwak:1,2,3 山下 雄也 / Takenari Yamashita:1,2 
  • 1:東京大院医疾患生命工学 / Div of Clin Biotech Ctr for Dis Biol and Integr Med, Grad Sch of Med, Univ of Tokyo, Tokyo, Japan 2:東京大院医神経内科 / Dept Neurol, Grad Sch of Med, Univ of Tokyo, Tokyo, Japan 3:国際医療福祉大学 / Clin Res Cent Med, Intl Univ Health Welfare, Chiba, Japan 

Inefficient glutamine/arginine (Q/R) site-editing of GluA2, a subunit of AMPA receptors, is a disease-specific molecular dysfunction found in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients. RNA editing at the GluA2 Q/R site is specifically catalyzed by adenosine deaminase acting on RNA 2 (ADAR2), and AMPA receptors containing unedited GluA2 are abnormally Ca2+-permeable. Motor neurons devoid of ADAR2 activity exhibit mislocalization of TAR DNA-binding protein of 43kDa (TDP-43), the pathological hallmark of ALS, and undergo slow death through Ca2+-permeable AMPA receptor-mediated mechanism in conditional ADAR2 knockout (AR2) mice. Therefore, amelioration of Ca2+ influx through the AMPA receptors by AMPA receptor antagonists would be a therapeutic strategy for ALS.
Perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile; E2007], is a non-competitive AMPA receptor antagonist approved the use for the treatment of epilepsy. Perambanel is superior to the prototypical AMPA antagonists in the oral administration, higher water-solubility, longer half-life and blood-brain barrier (BBB) penetrance,
We administered perampanel orally to 17 weeks heterozygous AR2 (AR2H) mice for 2 weeks and evaluated the potential therapeutic effect by observing the changes in the immunohistochemical localization of TDP-43 in the spinal motor neurons. All the mice tolerated perampanel at doses below 13.2 mg/kg/day, although they exhibited transient sedation. When the mouse spinal cords were examined for the immunohistochemically, perampanel significantly reduced the number of motor neurons exhibiting abnormal cytoplasmic localization of TDP-43. Because mislocalization of TDP-43 results from abnormal calpain activation due to exaggerated Ca2+ influx through the Ca2+-permeable AMPA receptors, these results indicate that perampanel can effectively ameliorate Ca2+ influx to a non-toxic level in the motor neurons of AR2 mice and suggest that perampanel may potentially be a drug for sporadic ALS.

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