Abstract WP253: Increased Hydrogen Sulfide As A New Mechanism For Hyperglycemic Worsening Of Stroke Outcome
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Introduction: Hyperglycemia at stroke onset worsens outcome and reduces the effectiveness of reperfusion therapies. Increased oxidative and mitochondrial injury likely contribute. To treat this mechanism, we synthesized (PEG)-ylated carbon nanoparticles (CNPs) from acid oxidation of activated charcoal (OAC) generating 3 nm discs, catalytic superoxide dismutase mimetics that protect mitochondrial complexes. Cellular uptake is rapid and delayed I.V. PEG-CNPs are highly protective in reversible MCAO in hyperglycemic rats. Hydrogen sulfide (H 2 S) is an essential gaseous transmitter with a narrow therapeutic index associated with many disorders e.g., diabetes. Its synthesis is influenced by radicals. Excess H 2 S is toxic to mitochondrial complex IV. H 2 S is endogenously oxidized to polysulfides (PS), potent antioxidants also needed for protein persulfidation. We hypothesized that OACs favorable redox potential will catalyze H 2 S oxidization to PS, acute hyperglycemia will increase H 2 S and PEG-OACs will blunt the increase. Methods: b.End3 brain endothelial and HEK293 cultured cells were employed. SSP4 fluorescence measured PS levels with increasing concentrations of PEG-OACs. AzMC fluorescence detected H 2 S levels in cells incubated in 100 mg/dL glucose media followed by glucose 500 mg/dL with or without PEG-OACs, first in normoxia followed by anoxia/normoxia. Results: PEG-OACs dose dependently increased cellular PS levels (Fig 1a). High glucose increased H 2 S levels especially during anoxia/normoxia (Fig 1b). PEG-OACs completely eliminated the glucose-induced increase in H 2 S (Fig 1c). Conclusions: Acute hyperglycemia increased H 2 S production especially under conditions mimicking ischemia/reperfusion, an effect eliminated by PEG-OACs. Because of mitochondrial toxicity, an H 2 S increase may contribute to worsened outcome in hyperglycemic stroke. These results suggest a new therapeutic target for this important cause of poor stroke outcome.
