A novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke
| Autor: | Kazuto Nunomura, Shinsaku Nakagawa, Christine P. Diggle, Xiaochen Liu, Masato Konishi, Bangzhong Lin, Jose R. Lopez, Takashi Sakurai, Keigo Ikeda, Paul D. Allen, Nagomi Kurebayashi, Toshiko Yamazawa, Jose A. Adams, Takuya Kobayashi, Arkady Uryash, Ichizo Nishino, Takayoshi Inoue, Satoru Noguchi, Hiroyuki Kagechika, Hiroto Iinuma, Yui Ikemi, Yukiko U. Inoue, Noriaki Manaka, Takashi Murayama, Shuichi Mori, Sho Kakizawa |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Science General Physics and Astronomy Pharmacology Sudden death Article General Biochemistry Genetics and Molecular Biology Dantrolene Mice 03 medical and health sciences 0302 clinical medicine In vivo medicine Animals Drug discovery and development Pharmacokinetics Muscle Skeletal RYR1 Multidisciplinary Isoflurane Chemistry Ryanodine receptor Calcium signalling Malignant hyperthermia Skeletal muscle Ryanodine Receptor Calcium Release Channel General Chemistry Neuromuscular disease Calcium Channel Blockers medicine.disease musculoskeletal system 030104 developmental biology medicine.anatomical_structure Mutation Calcium Halothane Malignant Hyperthermia tissues 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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