Upregulation of CBS/H2S system contributes to asymmetric dimethylarginine-triggered protection against the neurotoxicity of glutamate to PC12 cells by inhibiting NOS/NO pathway

Abstract

Glutamate-induced neurotoxicity involves in overproduction of nitric oxide (NO) and oxidative stress. Our previous data demonstrated that asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, has a protective effect against glutamate-induced neurotoxicity. Hydrogen sulfide (H2S), the third endogenous gaseous mediator, has potential therapeutic value for oxidative stress-induced neural damage. Therefore, we hypothesized that ADMA provides protection against the neurotoxicity of glutamate by regulating endogenous H2S generation. In the present study, we found that ADMA prevented glutamate-triggered decrease in endogenous H2S generation in PC12 cells and reversed glutamate-induced suppression in the expression and activity of cystathionine-β-synthetase (CBS), the predominant enzymatic source of H2S in PC12 cells. Furthermore, AOAA, a potent inhibitor of CBS, significantly abolished the protective action of ADMA against glutamate-induced neurotoxicity to PC12 cells. We also showed that ADMA suppressed glutamate-elicited NOS excessive activation and NO overproduction in PC12 cells. These data indicate that the protection of ADMA against glutamate-induced neurotoxicity is by promoting endogenous H2S generation, resulting from suppression in NOS excessive activation and NO overproduction. These findings provide a novel mechanism underlying the protection of ADMA against glutamate-induced neurotoxicity.