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

Mutations in the type 1 ryanodine receptor (RyR1), a Ca 2+ 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 solubilit...

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Published inNature communications Vol. 12; no. 1; p. 4293
Main Authors Yamazawa, Toshiko, Kobayashi, Takuya, Kurebayashi, Nagomi, Konishi, Masato, Noguchi, Satoru, Inoue, Takayoshi, Inoue, Yukiko U., Nishino, Ichizo, Mori, Shuichi, Iinuma, Hiroto, Manaka, Noriaki, Kagechika, Hiroyuki, Uryash, Arkady, Adams, Jose, Lopez, Jose R., Liu, Xiaochen, Diggle, Christine, Allen, Paul D., Kakizawa, Sho, Ikeda, Keigo, Lin, Bangzhong, Ikemi, Yui, Nunomura, Kazuto, Nakagawa, Shinsaku, Sakurai, Takashi, Murayama, Takashi
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 13.07.2021
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Summary:Mutations in the type 1 ryanodine receptor (RyR1), a Ca 2+ 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 Ca 2+ , inhibits halothane- and isoflurane-induced Ca 2+ 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. Mutations in ryanodine receptor 1 (RyR1), a Ca2+ release channel in skeletal muscle, cause malignant hyperthermia (MH) and are involved in heat stroke. Here, the authors show that an oxolinic acid-derivative RyR1 inhibitor effectively prevents and treats MH and heat stroke in various MH mouse models.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-24644-1