Hydrogen Sulfide Is a Mediator of Cerebral Ischemic Damage

<jats:p> <jats:bold> <jats:italic>Background and Purpose—</jats:italic> </jats:bold> We observed recently that elevated plasma cysteine levels are associated with poor clinical outcome in acute stroke patients. In a rat stroke model, cysteine administration increased the infarct volume apparently via its conversion to hydrogen sulfide (H <jats:sub>2</jats:sub> S). We therefore investigated the effects of H <jats:sub>2</jats:sub> S and the inhibition of its formation on stroke. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods—</jats:italic> </jats:bold> Cerebral ischemia was studied in a rat stroke model created by permanent occlusion of the middle cerebral artery (MCAO). The resultant infarct volume was measured 24 hours after occlusion. </jats:p> <jats:p> <jats:bold> <jats:italic>Results—</jats:italic> </jats:bold> Administration of sodium hydrosulfide (NaHS, an H <jats:sub>2</jats:sub> S donor) significantly increased the infarct volume after MCAO. The NaHS-induced increase in infarct volume was abolished by the administration of dizolcilpine maleate (an <jats:italic>N</jats:italic> -methyl- <jats:sc>d</jats:sc> -aspartate receptor channel blocker). MCAO caused an increase in H <jats:sub>2</jats:sub> S level in the lesioned cortex as well as an increase in the H <jats:sub>2</jats:sub> S synthesizing activity. Administration of 4 different inhibitors of H <jats:sub>2</jats:sub> S synthesis reduced MCAO-induced infarct volume dose dependently. The potency of these inhibitors in effecting neuroprotection in vivo appeared to parallel their potency as inhibitors of H <jats:sub>2</jats:sub> S synthesis in vitro. It also appeared that most of the H <jats:sub>2</jats:sub> S synthesizing activity in the cortex results from the action of cystathionine β-synthase. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> The present results strongly suggest that H <jats:sub>2</jats:sub> S plays a part in cerebral ischemic damage after stroke. Inhibition of H <jats:sub>2</jats:sub> S synthesis should be investigated for its potential as a novel neuroprotective stroke therapy. </jats:p>