title: Thiosulfate Mediates Cytoprotective Effects of Hydrogen Sulfide Against Neuronal Ischemia.
abstract: BACKGROUND
  Hydrogen sulfide (H2S) exhibits protective effects in various disease models including cerebral ischemia-reperfusion (I/R) injury. Nonetheless, mechanisms and identity of molecules responsible for neuroprotective effects of H2S remain incompletely defined. In the current study, we observed that thiosulfate, an oxidation product of H2S, mediates protective effects of an H2S donor compound sodium sulfide (Na2S) against neuronal I/R injury.
  
  
  RESULTS
  We observed that thiosulfate in cell culture medium is not only required but also sufficient to mediate cytoprotective effects of Na2S against oxygen glucose deprivation and reoxygenation of human neuroblastoma cell line (SH-SY5Y) and murine primary cortical neurons. Systemic administration of sodium thiosulfate (STS) improved survival and neurological function of mice subjected to global cerebral I/R injury. Beneficial effects of STS, as well as Na2S, were associated with marked increase of thiosulfate, but not H2S, in plasma and brain tissues. These results suggest that thiosulfate is a circulating "carrier" molecule of beneficial effects of H2S. Protective effects of thiosulfate were associated with inhibition of caspase-3 activity by persulfidation at Cys163 in caspase-3. We discovered that an SLC13 family protein, sodium sulfate cotransporter 2 (SLC13A4, NaS-2), facilitates transport of thiosulfate, but not sulfide, across the cell membrane, regulating intracellular concentrations and thus mediating cytoprotective effects of Na2S and STS.
  
  
  CONCLUSIONS
  The protective effects of H2S are mediated by thiosulfate that is transported across cell membrane by NaS-2 and exerts antiapoptotic effects via persulfidation of caspase-3. Given the established safety track record, thiosulfate may be therapeutic against ischemic brain injury.
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (E.M., M.Y., K.T., K.I., S.K., K.S., K.H., S.K., M.K., F.I.).
authors.forename: Eizo
authors.initials: E
authors.lastname: Marutani
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (E.M., M.Y., K.T., K.I., S.K., K.S., K.H., S.K., M.K., F.I.) Shriners Hospitals for Children, Boston, MA (M.Y., M.K.).
authors.forename: Marina
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan (T.I., T.A.).
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ida
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (E.M., M.Y., K.T., K.I., S.K., K.S., K.H., S.K., M.K., F.I.).
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tokuda
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (E.M., M.Y., K.T., K.I., S.K., K.S., K.H., S.K., M.K., F.I.).
authors.forename: Kohei
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (E.M., M.Y., K.T., K.I., S.K., K.S., K.H., S.K., M.K., F.I.).
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kai
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (E.M., M.Y., K.T., K.I., S.K., K.S., K.H., S.K., M.K., F.I.).
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shirozu
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (E.M., M.Y., K.T., K.I., S.K., K.S., K.H., S.K., M.K., F.I.).
authors.forename: Kei
authors.initials: K
authors.lastname: Hayashida
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (E.M., M.Y., K.T., K.I., S.K., K.S., K.H., S.K., M.K., F.I.).
authors.forename: Shizuko
authors.initials: S
authors.lastname: Kosugi
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan (K.H.).
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Hanaoka
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (E.M., M.Y., K.T., K.I., S.K., K.S., K.H., S.K., M.K., F.I.) Shriners Hospitals for Children, Boston, MA (M.Y., M.K.).
authors.forename: Masao
authors.initials: M
authors.lastname: Kaneki
authors.affiliation: Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan (T.I., T.A.).
authors.forename: Takaaki
authors.initials: T
authors.lastname: Akaike
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (E.M., M.Y., K.T., K.I., S.K., K.S., K.H., S.K., M.K., F.I.).
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D005865:Gestational Age; D005947:Glucose / Q000172:deficiency; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000076988:Sulfate Transporters; D013447:Sulfites / Q000378:metabolism / Q000494:pharmacology*; D027981:Symporters / Q000378:metabolism; D013885:Thiosulfates / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D027321:Anion Transport Proteins; D018696:Neuroprotective Agents; C400428:SLC13A4 protein, human; C576994:Slc13a4 protein, mouse; D000076988:Sulfate Transporters; D013447:Sulfites; D027981:Symporters; D013885:Thiosulfates; C569244:sodium hydrogen sulfite; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D005947:Glucose
keywords: apoptosis; cerebral ischemia; hydrogen sulfide; sulfidation; thiosulfate