Hydrogen Sulfide Is a Mediator of Cerebral Ischemic Damage

Abstract

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 (H2S). We therefore investigated the effects of H2S and the inhibition of its formation on stroke. 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. Administration of sodium hydrosulfide (NaHS, an H2S donor) significantly increased the infarct volume after MCAO. The NaHS-induced increase in infarct volume was abolished by the administration of dizolcilpine maleate (an N-methyl-d-aspartate receptor channel blocker). MCAO caused an increase in H2S level in the lesioned cortex as well as an increase in the H2S synthesizing activity. Administration of 4 different inhibitors of H2S 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 H2S synthesis in vitro. It also appeared that most of the H2S synthesizing activity in the cortex results from the action of cystathionine beta-synthase. The present results strongly suggest that H2S plays a part in cerebral ischemic damage after stroke. Inhibition of H2S synthesis should be investigated for its potential as a novel neuroprotective stroke therapy.