SEA0400

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Background

SEA0400 is a potent and selective inhibitor of Na+-Ca2+ exchanger (NCX) with IC50 values of 5 to 33 nM in cultured neurons, microglia and astrocytes [1].The Na+-Ca2+ exchanger is an anti-porter that pumps Ca2+ out of the cells and keeps the low concentration of Ca2+ inside cells through exchanging the Na+ and Ca2+. In the reperfusion injury, the reverse mode NCX is activated, inducing the paradoxical Ca2+ influx and subsequently causing the generation of free radicals, leucotriene and thromboxane. Many existed drugs target NCX treated for reperfusion injury are reported of lacking selectivity or cell- permeability while SEA0400 is reported to be the most selective and potent NCX inhibitor [1]. SEA0400 was screened out of a chemical library designed for inhibition of NCX in cultured astrocytes and isolated cardiac sarcolemmal vesicles. It showed potent inhibitory effects on Na+-dependent Ca2+ uptake in cultured microglia, astrocytes and neurons with IC50 values of 8.3, 5 and 33 nM, respectively. The activity of SEA0400 was more than 100-fold higher than that of KB-R7943. SEA0400 was also proved to be selective against NCX over other ion fluxes since it displayed no significant effect on SOCE even at the concentration up to 3 μM. Besides that, SEA0400 had no effect on a serious of similar ion channels or ion transporters such as Ca2+-ATPase, Na+, K+-ATPase and K+ channel. Moreover, SEA0400 was found to suppress the Ca2+ influx-induced apoptosis in astrocytes [1].In a rat model of cerebral ischemia, injection of SEA0400 at dose of 3 mg/kg resulted in decreased infarct volume in both striatum and cerebral cortex. In a rabbit model of Langendorff-perfused 1-month myocardial infarction, SEA0400 administration inhibited the pacing-induced ventricular premature beats and displayed proarrhythmic activity through enhancing spatially discordant alternans (SDA) and steepening Action potential duration (APD) restitution [1 and 2].

[1] Matsuda T, Arakawa N, Takuma K, et al. SEA0400, a novel and selective inhibitor of the Na+-Ca2+ exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models. Journal of Pharmacology and Experimental Therapeutics, 2001, 298(1): 249-256.
[2] CHOU C C, CHANG P O C, WEN M S, et al. Effects of SEA0400 on Arrhythmogenicity in a Langendorff-Perfused 1-Month Myocardial Infarction Rabbit Model Pacing and Clinical Electrophysiology, 2013, 36(5): 596-606.