Abstract 16322: Thiosulfate: A Carrier Molecule of the Protective Effects of Hydrogen Sulfide Against Neuronal Ischemia

Abstract

Hydrogen sulfide (H 2 S) is an endogenously produced gaseous signaling molecule that exhibits protective effects in various disease models including cardiac arrest and cardiopulmonary resuscitation. Nonetheless, mechanisms and identity of molecules responsible for the neuroprotective effects of exogenous sulfide donor compounds, such as sodium sulfide (Na 2 S), remain incompletely defined. In circulation, reaction with plasma proteins and or oxidation to sulfur oxides maintains free plasma H 2 S levels very low. Free H 2 S levels only transiently increase and quickly return to its baseline after systemic administration of sulfide donor compounds. Thiosulfate is an oxidation product of H 2 S that is relatively stable in blood and tissues. In the current study, we observed that thiosulfate mediates protective effects of Na 2 S against oxygen glucose deprivation and reoxygenation of human neuroblastoma cell line (SH-SY5Y) and murine primary cortical neurons. We also found that systemic administration of sodium thiosulfate (STS) improved survival and neurological function of mice subjected to global cerebral IR injury. Beneficial effects of STS, as well as Na 2 S, were associated with marked increase of thiosulfate, but not H 2 S, in plasma and brain tissues. These results suggest that thiosulfate is a circulating “carrier” molecule of beneficial effects of sulfide. Protective effects of thiosulfate are associated with modulation of Erk1/2, and JNK pathways and S-sulfhydration of cleaved caspase-3. Of note, we discovered that a SLC13 family protein, sodium sulfate co-transporter 2 (SLC13A4, NaS-2), facilitates the transport of sulfide or thiosulfate across the cell membrane, regulating intracellular concentrations and thus mediating cytoprotective effects of sulfide and thiosulfate. Given that STS is widely used as an antidote and has very low toxicity in humans, these observations suggest that STS represents a novel therapeutic agent for ischemic brain injury.