A novel RyR1 inhibitor prevents and rescues sudden death in a mouse model of malignant hyperthermia and heat stroke

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 s...

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Published inbioRxiv
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, Uryas, 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 Paper
LanguageEnglish
Japanese
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 06.02.2021
Subjects
Anesthesia
Animal models
Caffeine
Calcium (intracellular)
Calcium release channels
Carboxylic acids
Halothane
Heat
Heatstroke
Hyperthermia
Isoflurane
Malignant hyperthermia
Musculoskeletal system
Mutation
Ryanodine receptors
Skeletal muscle
Solubility
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Summary: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 a novel 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 reduced resting intracellular Ca2+, inhibited halothane- and isoflurane-induced Ca2+ release, suppressed caffeine-induced contracture in skeletal muscle, reduced sarcolemmal cation influx, and prevented or reversed the fulminant MH crisis induced by isoflurane anesthesia and rescued 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 new candidate for effective treatment of patients carrying RyR1 mutations. Competing Interest Statement The authors have declared no competing interest. Footnotes * All figures updated; authors added; Supplemental files updated.
DOI:10.1101/2020.07.02.185520