Inhalative as well as Intravenous Administration of HS Provides Neuroprotection after Ischemia and Reperfusion Injury in the Rats' Retina.

BACKGROUND

Neuronal ischemia-reperfusion injury (IRI), such as it can occur in glaucoma or strokes, is associated with neuronal cell death and irreversible loss of function of the affected tissue. Hydrogen sulfide (HS) is considered a potentially neuroprotective substance, but the most effective route of application and the underlying mechanism remain to be determined.

METHODS

Ischemia-reperfusion injury was induced in rats by a temporary increase in intraocular pressure (1 h). HS was then applied by inhalation (80 ppm at 0, 1.5, and 3 h after reperfusion) or by intravenous administration of the slow-releasing HS donor GYY 4137. After 24 h, the retinas were harvested for Western blotting, qPCR, and immunohistochemical staining. Retinal ganglion cell survival was evaluated 7 days after ischemia.

RESULTS

Both inhalative and intravenously delivered HS reduced retinal ganglion cell death with a better result from inhalative application. HS inhalation for 1.5 h, as well as GYY 4137 treatment, increased p38 phosphorylation. Both forms of application enhanced the extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and inhalation showed a significant increase at all three time points. HS treatment also reduced apoptotic and inflammatory markers, such as caspase-3, intracellular adhesion molecule 1 (ICAM-1), vascular endothelial growth factor (VEGF), and inducible nitric oxide synthase (iNOS). The protective effect of HS was partly abolished by the ERK1/2 inhibitor PD98059. Inhalative HS also reduced the heat shock response including heme oxygenase (HO-1) and heat shock protein 70 (HSP-70) and the expression of radical scavengers such as superoxide dismutases (SOD1, SOD2) and catalase.

CONCLUSION

Hydrogen sulfide acts, at least in part, via the mitogen-activated protein kinase (MAPK) ERK1/2 to reduce apoptosis and inflammation. Both inhalative HS and intravenous GYY 4137 administrations can improve neuronal cell survival.