A novel saline-soluble, rapidly-metabolized RyR1 inhibitor rescues volatile anesthesia-induced death and environmental heat stroke in a mouse model relevant to malignant hyperthermia

Yamazawa, T.; Kobayashi, T.; Kurebayashi, N.; Konishi, M.; Noguchi, S.; Inoue, T.; Inoue, Y. U.; Nishino, I.; Mori, S.; Iinuma, H.; Manaka, N.; Kagechika, H.; Uryas, A.; Adams, J.; Lopez, J. R.; Liu, X.; Allen, P. D.; Kakizawa, S.; Ikeda, K.; Lin, B.; Nunomura, K.; Nakagawa, S.; Sakurai, T.; Murayama, T.

doi:10.1101/2020.07.02.185520

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bioRxiv · 10.1101/2020.07.02.185520

A novel saline-soluble, rapidly-metabolized RyR1 inhibitor rescues volatile anesthesia-induced death and environmental heat stroke in a mouse model relevant to malignant hyperthermia

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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.

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Yamazawa, T., Kobayashi, T., Kurebayashi, N., Konishi, M., Noguchi, S., Inoue, T., Inoue, Y. U., Nishino, I., Mori, S., Iinuma, H., Manaka, N., Kagechika, H., Uryas, A., Adams, J., Lopez, J. R., Liu, X., Allen, P. D., Kakizawa, S., Ikeda, K., Lin, B., Nunomura, K., Nakagawa, S., Sakurai, T., Murayama, T.. 2020-07-02. A novel saline-soluble, rapidly-metabolized RyR1 inhibitor rescues volatile anesthesia-induced death and environmental heat stroke in a mouse model relevant to malignant hyperthermia. https://doi.org/10.1101/2020.07.02.185520

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