A Review of Hydrogen Sulfide (H2S) Donors: Chemistry and Potential Therapeutic Applications

4.2. Sulfide Salts

The most common class of H2S donors employed in biological studies are the sulfide salts, sodium hydrosulfide (NaSH) and sodium sulfide (Na2S). Although commonly referred to as donors, sulfide salts are simply solid analogs of the gas, providing direct, instantaneous access to the biologically relevant forms of sulfide (H2S and HS−). Use of sulfide salts has been integral in the establishment of H2S as a gasotransmitter, and these salts have been widely used to evaluate the therapeutic potential of exogenous H2S delivery.

One of the early studies on exogenous H2S delivery by Wang et al. employed aqueous NaSH solutions in evaluating rat aortic ring response in vitro.[37] NaSH delivery led to a 60% greater relaxation over controls, showing the vasorelaxant properties of H2S. In a separate study by Du et al., delivery of NaSH solution via intravenous injection to rats with oleic acid-induced acute lung injury (ALI) alleviated the degree of ALI by decreasing IL-6 and IL-8 levels while simultaneously increasing IL-10 levels in the plasma and lung tissue.[38] This study also verified the hypothesis that down-regulation of endogenous H2S levels in the cardiovascular system is involved in ALI pathogenesis.

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Sulfide salts as H2S donors have also exhibited efficacy in limiting cell damage from ROS in brain cells. Delivery of NaSH was tested as an antioxidant in an in vitro study where oxidative stress was induced in human nueroblastoma cells using hypochlorous acid (HOCl) to mimic HOCl overproduction from myeloperoxidase in the brain of patients with Alzheimer’s disease. Exogenous NaSH inhibited protein oxidation, lipid peroxidation, and overall cytotoxicity.[39] In a hepatic I/R injury model, delivery of Na2S (up to 1.0 mg/kg) prior to reperfusion inhibited lipid peroxidation and preserved a healthy balance of reduced glutathione (GSH), overall providing protection against I/R injuries.[40] Aqueous solutions of sulfide salts have also demonstrated efficacy in promoting ulcer healing,[41, 42] as well as quenching RNS.[43, 44]

While sulfide salts are a popular choice amongst biologists interested in elucidating endogenous roles and therapeutic prospects of H2S, there are drawbacks to these H2S donors both as chemical tools for studying H2S biology and as potential therapeutics. Sulfide salts hydrolyze immediately upon dissolution in water, instantaneously establishing the equilibrium between H2S, HS−, and S2- species. Once this equilibrium is established, volatilization of H2S occurs, lowering the overall concentration of sulfur species in solution. Additionally, air oxidation of HS− catalyzed by trace metals in water further reduces the actual concentration of H2S in solution.[6] These competing processes make it challenging to deliver a reproducible amount of H2S via sulfide salts. In addition, sulfide salts lack targeting capabilities and thus are only of utility in systemic delivery. Finally, studies on H2S biology using sulfide salts frequently require administration of high doses, causing H2S blood and tissue concentrations to surge to supraphysiological levels and then drop rapidly. This delivery method lies in stark contrast to the endogenous production of H2S, in which levels are tightly regulated. These shortcomings have led to the search for H2S donors that give researchers the ability to control the dose, duration, timing, and location of release.

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