A novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke

Toshiko Yamazawa (), Takuya Kobayashi, Nagomi Kurebayashi, Masato Konishi, Satoru Noguchi, Takayoshi Inoue, Yukiko U. Inoue, Ichizo Nishino, Shuichi Mori, Hiroto Iinuma, Noriaki Manaka, Hiroyuki Kagechika, Arkady Uryash, Jose Adams, Jose R. Lopez, Xiaochen Liu, Christine Diggle, Paul D. Allen, Sho Kakizawa, Keigo Ikeda, Bangzhong Lin, Yui Ikemi, Kazuto Nunomura, Shinsaku Nakagawa, Takashi Sakurai and Takashi Murayama ()
Additional contact information
Toshiko Yamazawa: The Jikei University School of Medicine
Takuya Kobayashi: Juntendo University School of Medicine
Nagomi Kurebayashi: Juntendo University School of Medicine
Masato Konishi: Juntendo University School of Medicine
Satoru Noguchi: National Institute of Neuroscience, National Center of Neurology and Psychiatry
Takayoshi Inoue: National Institute of Neuroscience, National Center of Neurology and Psychiatry
Yukiko U. Inoue: National Institute of Neuroscience, National Center of Neurology and Psychiatry
Ichizo Nishino: National Institute of Neuroscience, National Center of Neurology and Psychiatry
Shuichi Mori: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University
Hiroto Iinuma: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University
Noriaki Manaka: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University
Hiroyuki Kagechika: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University
Arkady Uryash: Mount Sinai Medical Center
Jose Adams: Mount Sinai Medical Center
Jose R. Lopez: Mount Sinai Medical Center
Xiaochen Liu: Leeds Institute of Biomedical & Clinical Sciences, School of Medicine, University of Leeds, St James’s University Hospital
Christine Diggle: Leeds Institute of Biomedical & Clinical Sciences, School of Medicine, University of Leeds, St James’s University Hospital
Paul D. Allen: Leeds Institute of Biomedical & Clinical Sciences, School of Medicine, University of Leeds, St James’s University Hospital
Sho Kakizawa: Graduate School of Pharmaceutical Sciences, Kyoto University
Keigo Ikeda: Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Science, Osaka University
Bangzhong Lin: Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Science, Osaka University
Yui Ikemi: Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Science, Osaka University
Kazuto Nunomura: Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Science, Osaka University
Shinsaku Nakagawa: Center for Supporting Drug Discovery and Life Science Research, Graduate School of Pharmaceutical Science, Osaka University
Takashi Sakurai: Juntendo University School of Medicine
Takashi Murayama: Juntendo University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Mutations in the type 1 ryanodine receptor (RyR1), a Ca2+ release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that an oxolinic acid-derivative RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1, Cpd1), effectively prevents and treats MH and heat stroke in several mouse models relevant to MH. Cpd1 reduces resting intracellular Ca2+, inhibits halothane- and isoflurane-induced Ca2+ release, suppresses caffeine-induced contracture in skeletal muscle, reduces sarcolemmal cation influx, and prevents or reverses the fulminant MH crisis induced by isoflurane anesthesia and rescues animals from heat stroke caused by environmental heat stress. Notably, Cpd1 has great advantages of better water solubility and rapid clearance in vivo over dantrolene. Cpd1 has the potential to be a promising candidate for effective treatment of patients carrying RyR1 mutations.

Date: 2021
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DOI: 10.1038/s41467-021-24644-1

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