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.
Highlights
Hydrogen sulfide (H2S) exerts neuroprotective effects, whereas H2S may cause neurotoxicity via N-methylD-aspartate receptor (NMDAR) activation
S-memantine Improved Viability of SH-SY5Y Cells and Murine Primary Cortical Neurons after Oxygen-Glucose Deprivation and Reoxygenation—We examined whether or not ACS48, memantine, and S-memantine improves viability of SH-SY5Y cells subjected to 15 h of oxygen and glucose deprivation (OGD) followed by 24 h of reoxygenation
The current study demonstrated that a newly-synthesized H2S-releasing NMDAR antagonist derivative S-memantine increases intracellular H2S levels and protects neurons from OGD more robustly than conventional H2S donor compounds Na2S and ACS48 without cyotoxicity
Summary
Hydrogen sulfide (H2S) exerts neuroprotective effects, whereas H2S may cause neurotoxicity via N-methylD-aspartate receptor (NMDAR) activation. 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. Some investigators have suggested that H2S-induced neurotoxicity may be mediated via enhancement of N-methyl-D-aspartate receptor (NMDAR) activity [7,8,9], because toxicity of H2S was abolished by NMDAR antagonist in vitro and in vivo [8, 9] Based on these observations, we hypothesized that a hybrid NMDAR antagonist that is capable of slowly releasing H2S in circulation is more effective in protecting neurons than H2S donor compounds alone. That S-memantine exhibits high therapeutic potential with low toxicity against ischemic neuronal death
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