Cerebral hypoxia is one of the main causes of cerebral injury. This study was conducted to investigate the potential protective effect of H(2)S in in vitro hypoxic models by subjecting SH-SY5Y cells to either
oxygen-
glucose deprivation or Na(2)S(2)O(4) (an
oxygen scavenger) treatment. We found that treatment with
NaHS (an H(2)S donor, 10-100 microM) 15 min prior to
hypoxia increased cell viability in a concentration-dependent manner. Time-course study showed that
NaHS was able to exert its protective effect even when added 8 h before or less than 4 h after
hypoxia induction. Interestingly, endogenous H(2)S level was markedly reduced by
hypoxia induction. Over-expression of
cystathionine-beta-synthase prevented
hypoxia induced cell apoptosis. Blockade of
ATP-sensitive K(+) (K(
ATP)) channels with
glibenclamide and
HMR-1098,
protein kinase C (PKC) with its three specific inhibitors (
chelerythrine, bisindolylmaleide I and
calphostin C),
extracellular signal-regulated kinase 1/2 (ERK1/2) with
PD98059 and
heat shock protein 90 (Hsp90) with
geldanamycin and
radicicol significantly attenuated the protective effects of
NaHS. Western blots showed that
NaHS significantly stimulated ERK1/2 activation and Hsp90 expression. In conclusion, H(2)S exerts a protective effect against
cerebral hypoxia induced neuronal cell death via K(
ATP)/PKC/ERK1/2/Hsp90 pathway. Our findings emphasize the important neuroprotective role of H(2)S in the brain during
cerebral hypoxia.