Dantrolene (F368), a muscle relaxant, non-competitively inhibits human erythrocyte glutathione reductase. Ki and IC50 values are 111.6 μM and 52.3 μM, respectively. Dantrolene is a ryanodine receptor antagonist and Ca2+ signaling stabilizer. Dantrolene can be used for the research of muscle spasticity, malignant hyperthermia, Huntington's disease and other neuroleptic malignant syndrome[1][2][3][4][5].
Dantrolene interferes with calcium release from the sarcoplasmic reticulum and thus to inhibit excitation--contraction coupling[1]. Dantrolene acts directly on the RYR1 to reduce the extent of channel activation by calmodulin (CaM) and thereby decreases the Ca2+ sensitivity of channel activation[2].Dantrolene inhibits abnormal Ca2+ release from the sarcoplasmic reticulum[3]. Dantrolene depresses excitation-contraction coupling in muscle fibers by inhibiting calcium release from the sarcoplasmic reticulum[3].Dantrolene also shows calcium channel blocker effect in the smooth muscle membrane as well as antioxidative and cytoprotective properties[3]. Dantrolene affects the membrane calcium channel of smooth muscle cells and inhibits calcium influx[3].Dantrolene is a skeletal muscle-specific muscle relaxant that works on the cardiac muscle. Dantrolene (0.3 μM) binds to domain 601-620 of RyR2 and corrects defective inter-domain interaction within RyR2 in failing hearts. This in turn inhibits spontaneous Ca2++ leak/Ca2+ sparks, and improves cardiomyocyte function in failing hearts[4].
Dantrolene is neuroprotective in Huntington's disease transgenic mouse model[5].Feeding dantrolene (5 mg/kg) twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays[5].
[1]. W J Meyler, et al. The effect of dantrolene sodium on rat skeletal muscle in relation to the plasma concentration. Eur J Pharmacol. 1979 Feb 1;53(4):335-42.
[2]. F Zhao, et al. Dantrolene inhibition of ryanodine receptor Ca2+ release channels. Molecular mechanism and isoform selectivity. J Biol Chem. 2001 Apr 27;276(17):13810-6.
[3]. Murat SentÜrk, et al. Dantrolene inhibits human erythrocyte glutathione reductase. Biol Pharm Bull. 2008 Nov;31(11):2036-9.
[4]. Shigeki Kobayashi, et al. Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor. J Am Coll Cardiol. 2009 May 26;53(21):1993-2005.
[5]. Xi Chen, et al. Dantrolene is neuroprotective in Huntington's disease transgenic mouse model. Mol Neurodegener. 2011 Nov 25;6:81.