A novel hydrogen sulfide-releasing N-methyl-D-aspartate receptor antagonist prevents ischemic neuronal death

Eizo Marutani, Shizuko Kosugi, Kentaro Tokuda, Ashok Khatri, Rebecca Nguyen, Dmitriy N. Atochin, Kotaro Kida, Klaus Van Leyen, Ken Arai, Fumito Ichinose

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Physiological levels of H2S exert neuroprotective effects, whereas high concentrations of H2S may cause neurotoxicity in part via activation ofNMDAR.To characterize the neuroprotective effects of combination of exogenous H2S and NMDAR antagonism, we synthesized a novel H2S-releasing NMDAR antagonist N-((1r,3R,5S,7r)-3,5- dimethyladamantan-1-yl)-4-(3-thioxo-3H-1,2-dithiol-4-yl)-benzamide (S-memantine) and examined its effects in vitro and in vivo. S-memantine was synthesized by chemically combining a slow releasing H2S donor 4-(3-thioxo-3H-1,2- dithiol-4-yl)-benzoic acid (ACS48) with a NMDAR antagonist memantine. S-memantine increased intracellular sulfide levels in human neuroblastoma cells (SH-SY5Y) 10-fold as high as that was achieved by ACS48. Incubation with S-memantine after reoxygenation following oxygen and glucose deprivation (OGD) protected SH-SY5Y cells and murine primary cortical neurons more markedly than did ACS48 or memantine. Glutamate-induced intracellular calcium accumulation in primary cortical neurons were aggravated by sodium sulfide (Na2S) or ACS48, but suppressed by memantine and S-memantine. S-memantine prevented glutamate-induced glutathione depletion in SH-SY5Y cells more markedly than did Na2S or ACS48. Administration of S-memantine after global cerebral ischemia and reperfusion more robustly decreased cerebral infarct volume and improved survival and neurological function of mice than did ACS48 or memantine. These results suggest that an H2S-releasing NMDAR antagonist derivative S-memantine prevents ischemic neuronal death, providing a novel therapeutic strategy for ischemic brain injury.

Original languageEnglish
Pages (from-to)32124-32135
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number38
DOIs
Publication statusPublished - 2012 Sep 14

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Marutani, E., Kosugi, S., Tokuda, K., Khatri, A., Nguyen, R., Atochin, D. N., Kida, K., Van Leyen, K., Arai, K., & Ichinose, F. (2012). A novel hydrogen sulfide-releasing N-methyl-D-aspartate receptor antagonist prevents ischemic neuronal death. Journal of Biological Chemistry, 287(38), 32124-32135. https://doi.org/10.1074/jbc.M112.374124