Isothiocyanates as H2S-Releasing Agents and Their Cardioprotective Effects
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The endogenous gasotransmitter hydrogen sulfide (H2S) is an important regulator of the cardiovascular system, particularly of myocardial function. Moreover, H2S exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury and is considered an important mediator of “ischemic preconditioning”. In this work, a small library of isothiocyanates was evaluated for the H2S releasing properties; the compound named ISOTHIA25 has been selected to further investigate its protective activity both in vitro and in vivo experimental procedures of ischemia/reperfusion injury.
All the isothiocyanates were able to release H2S in a cell-free environment. The computational analysis lead to the selection of the compound named ISOTHIA25, which was able to release about 60 µM of H2S when incubated at the concentration of 1 mM in the presence of L-Cysteine and which showed good solubility and a promising ADME profile. Furthermore, ISOTHIA25 was able to enter into the H9c2 cells and release H2S in a concentration dependent manner. The protective effect was first evaluated using H9c2: the incubation of ISOTHIA25 before the treatment with H2O2, lead to a significant recovery in cell viability in a concentration dependent manner, with an almost complete recovery of the viability when incubated at the concentration of 1 µM.
The H2S-donor ISOTHIA25 has been then tested in different experimental models of myocardial I/R: in Langendorff-perfused rat hearts subjected to I/R, ISOTHIA25 significantly improved the post-ischemic damage, limiting the tissue injury in a concentration dependent manner. Accordingly, also the LDH biomarker was reduced. This effect was antagonized by 5-hydroxydecanoic acid (a blocker of mitoKATP channels). Finally, in an in vivo model of acute myocardial infarction in rats, ISOTHIA25 significantly decreased I/R-induced tissue injury.
Isothiocyanate-based H2S-releasing drugs like ISOTHIA25, can actually be considered a suitable pharmacological option in anti-ischemic therapy.
Isothia-25 exhibits H2S‐releasing properties both in a cell-free and in a cell-based assay, and due to this property, has cardioprotective effects in vitro and in vivo.
Keywords: Isothiocyanates, Cardioprotective Effects, Anti-ischemic therapy
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