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 1mM 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 1µM.
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.