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 in | bioRxiv |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Cold Spring Harbor
Cold Spring Harbor Laboratory Press
06.02.2021
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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 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. |
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AbstractList | 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. |
Author | Ikeda, Keigo Diggle, Christine Ikemi, Yui Sakurai, Takashi Yamazawa, Toshiko Nishino, Ichizo Kagechika, Hiroyuki Inoue, Yukiko U Lopez, Jose R Uryas, Arkady Kakizawa, Sho Mori, Shuichi Noguchi, Satoru Liu, Xiaochen Inoue, Takayoshi Manaka, Noriaki Konishi, Masato Lin, Bangzhong Kobayashi, Takuya Murayama, Takashi Kurebayashi, Nagomi Allen, Paul D Iinuma, Hiroto Adams, Jose Nunomura, Kazuto Nakagawa, Shinsaku |
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Snippet | Abstract Mutations in the type 1 ryanodine receptor (RyR1), a Ca2+ release channel in skeletal muscle, hyperactivate the channel to cause malignant... |
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SubjectTerms | 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 |
Title | A novel RyR1 inhibitor prevents and rescues sudden death in a mouse model of malignant hyperthermia and heat stroke |
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