Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-24644-1
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Funding
- Japan Society for the Promotion of Sciences KAKENHI [19K07306, 19H03198, 20H04511, 20K11368, 19K07105, 19K06955, 19H03404]
- USA National Institute of Arthritis, Musculoskeletal and Skin Diseases [R01AR068897]
- Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from the Japan Agency for Medical Research and Development (AMED) [JP20am0101098, 1858, JP20am0101085, JP20am0101123, 1424, JP20am0101080]
- Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) [19ek0109202]
- Vehicle Racing Commemorative Foundation [6114, 6237]
- Research Center for Biomedical Engineering
- Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP [29-4, 2-5, 30-9, 2-6]
- Grants-in-Aid for Scientific Research [19K06955, 19K07105, 19K07306, 19H03404, 19H03198, 20K11368, 20H04511] Funding Source: KAKEN
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The study shows that an oxolinic acid-derivative RyR1 inhibitor can effectively prevent and treat various malignant hyperthermia (MH) and heat stroke mouse models.
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.
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