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(Stroke. 2006;37:889.)
© 2006 American Heart Association, Inc.

Original Contributions

Hydrogen Sulfide Is a Mediator of Cerebral Ischemic Damage

Kun Qu, BSc; Christopher P.L.H. Chen, BMBCh, FRCP; Barry Halliwell, DPhil, DSc; Philip K. Moore, PhD Peter T.-H. Wong, PhD

From the Departments of Pharmacology (K.Q., C.P.L.H.C., P.K.M., P.T.-H.W.) and Biochemistry (B.H.), Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore; and Department of Neurology (C.P.L.H.C.), National Neuroscience Institute, Singapore General Hospital Campus, Singapore General Hospital.

Correspondence to Dr Peter T.-H. Wong, Department of Pharmacology, National University of Singapore, 18 Medical Dr, Singapore 117597. E-mail phcwth{at}nus.edu.sg

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 (H₂S). We therefore investigated the effects of H₂S 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 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 ß-synthase.

Conclusions— 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.

Key Words: hydrogen sulfide • N-methyl-D-aspartate • receptor • stroke

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