Hydrogen Sulfide Is a Mediator of Cerebral Ischemic Damage

Abstract

Background and Purpose-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 2 S). We therefore investigated the effects of H 2 S and the inhibition of its formation on stroke. Methods-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. Results-Administration of sodium hydrosulfide (NaHS, an H 2 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 N-methyl-D-aspartate receptor channel blocker). MCAO caused an increase in H 2 S level in the lesioned cortex as well as an increase in the H 2 S synthesizing activity. Administration of 4 different inhibitors of H 2 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 2 S synthesis in vitro. It also appeared that most of the H 2 S synthesizing activity in the cortex results from the action of cystathionine ␤-synthase. Conclusions-The present results strongly suggest that H 2 S plays a part in cerebral ischemic damage after stroke.Inhibition of H 2 S synthesis should be investigated for its potential as a novel neuroprotective stroke therapy.

Enhanced Plasma H2S Levels Associated With Fasting Blood Glucose In Type-2 Diabetes Mellitus

“…Plasma H 2 S levels in the patients as well as control subjects in our study are comparable with earlier studies which is within the range of 10 to100 micromol/l in human subjects. 5 Elevated hydrogen sulfide levels in plasma were also reported in patients with proliferative diabetic retinopathy 20 as well as patients with cardiovascular disease 21 cerebral ischaemic damage 22 and septic shock 23 M. Yusuf et al has earlier reported that the streptozotocin-induced diabetes in rat is associated with enhanced tissue hydrogen sulfide biosynthesis. 17 The activities of H 2 S producing enzymes and the tissue H 2 S contents are known to increase under diabetic conditions.…”

H2S Biogenesis by Human Cystathionine γ-Lyase Leads to the Novel Sulfur Metabolites Lanthionine and Homolanthionine and Is Responsive to the Grade of Hyperhomocysteinemia

“…In an in vivo model for myocardial ischemia-reperfusion, a U-shaped H 2 S dose dependence curve was observed, with the cardioprotective effect of H 2 S decreasing at higher concentrations (7). In a rat model of stroke, administration of high NaHS levels increased infarct volume (42), and H 2 S was found to be proinflammatory in a mouse endotoxic shock model (8). Mutations in CBS are the most common cause of severe hyperhomocysteinemia in comparison with defects elsewhere in the pathway (e.g.…”

A Novel Hydrogen Sulfide-releasing N-Methyl-d-Aspartate Receptor Antagonist Prevents Ischemic Neuronal Death

“…For example, Moore et al reported that pre-treatment with Na 2 S at 90 mol/kg administered 10 min before middle cerebral artery occlusion (MCAO) did not affect, whereas at 180 mol/kg aggravated, cerebral injury of rats (8). Ren et al reported that NaHS at 25 mol/kg administered 30 min prior to ischemia, but not at 90 or 180 mol/kg, attenuated neuronal injury induced by global cerebral ischemia (18).…”

“…Some investigators have suggested that H 2 S-induced neurotoxicity may be mediated via enhancement of N-methyl-D-aspartate receptor (NMDAR) 2 activity (7-9), because toxicity of H 2 S was abolished by NMDAR antagonist in vitro and in vivo (8,9). Based on these observations, we hypothesized that a hybrid NMDAR antagonist that is capable of slowly releasing H 2 S in circulation is more effective in protecting neurons than H 2 S donor compounds alone.…”