title: Cystathionine β-synthase inhibition is a potential therapeutic approach to treatment of ischemic injury.
abstract: Hydrogen sulfide (H2S) has been reported to exacerbate stroke outcome in experimental models. Cystathionine β-synthase (CBS) has been implicated as the predominant H2S-producing enzyme in central nervous system. When SH-SY5Y cells were transfected to overexpress CBS, these cells were able to synthesize H2S when exposed to high levels of enzyme substrates but not substrate concentrations that may reflect normal physiological conditions. At the same time, these cells demonstrated exacerbated cell death when subjected to oxygen and glucose deprivation (OGD) together with high substrate concentrations, indicating that H2S production has a detrimental effect on cell survival. This effect could be abolished by CBS inhibition. The same effect was observed with primary astrocytes exposed to OGD and high substrates or sodium hydrosulfide. In addition, CBS was upregulated and activated by truncation in primary astrocytes subjected to OGD. When rats were subjected to permanent middle cerebral artery occlusion, CBS activation was also observed. These results imply that in acute ischemic conditions, CBS is upregulated and activated by truncation causing an increased production of H2S, which exacerbate the ischemic injuries. Therefore, CBS inhibition may be a viable approach to stroke treatment.
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore.
authors: Su Jing
authors: SJ
authors: Chan
authors: Duke-NUS Graduate Medical School, Singapore.
authors: Chou
authors: C
authors: Chai
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore.
authors: Tze Wei
authors: TW
authors: Lim
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore.
authors: Mie
authors: M
authors: Yamamoto
authors: Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors: Eng H
authors: EH
authors: Lo
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore.
authors: Mitchell Kim Peng
authors: MK
authors: Lai
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore peter_wong@nuhs.edu.sg.
authors: Peter Tsun Hon
authors: PT
authors: Wong
mesh_terms: D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003541:Cystathionine beta-Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D000625:Aminooxyacetic Acid; D003541:Cystathionine beta-Synthase; D005947:Glucose; D006862:Hydrogen Sulfide
keywords: cystathioine β-synthase; cysteine; homocysteine; hydrogen sulfide; oxygen glucose deprivation; stroke