title: A novel hydrogen sulfide-releasing N-methyl-D-aspartate receptor antagonist prevents ischemic neuronal death.
abstract: Physiological levels of H(2)S exert neuroprotective effects, whereas high concentrations of H(2)S may cause neurotoxicity in part via activation of NMDAR. To characterize the neuroprotective effects of combination of exogenous H(2)S and NMDAR antagonism, we synthesized a novel H(2)S-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 H(2)S 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 (Na(2)S) or ACS48, but suppressed by memantine and S-memantine. S-memantine prevented glutamate-induced glutathione depletion in SH-SY5Y cells more markedly than did Na(2)S 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 H(2)S-releasing NMDAR antagonist derivative S-memantine prevents ischemic neuronal death, providing a novel therapeutic strategy for ischemic brain injury.
authors: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors: Eizo
authors: E
authors: Marutani
authors: Shizuko
authors: S
authors: Kosugi
authors: Kentaro
authors: K
authors: Tokuda
authors: Ashok
authors: A
authors: Khatri
authors: Rebecca
authors: R
authors: Nguyen
authors: Dmitriy N
authors: DN
authors: Atochin
authors: Kotaro
authors: K
authors: Kida
authors: Klaus
authors: K
authors: Van Leyen
authors: Ken
authors: K
authors: Arai
authors: Fumito
authors: F
authors: Ichinose
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000517:prevention & control*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015195:Drug Design; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D006862:Hydrogen Sulfide / Q000737:chemistry*; D007511:Ischemia; D008297:Male; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D009474:Neurons / Q000473:pathology*; D010100:Oxygen / Q000737:chemistry; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D005978:Glutathione; D005947:Glucose; D010100:Oxygen; D008559:Memantine; D006862:Hydrogen Sulfide