Upregulation of CBS/H2S system contributes to asymmetric dimethylarginine-triggered protection against the neurotoxicity of glutamate to PC12 cells by inhibiting NOS/NO pathway.
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.
Department of Neurology, Third Clinical Hospital, China Three Gorges University, 60 Qiaohu 1st Road, 443002 Yichang, PR China; Department of Neurology, Gezhouba Central Hospital, 443002 Yichang, PR China. Electronic address: ycwangxy@163.com.
Xiang-Yu
XY
Wang
Department of Physiology, college of medical sciences, China Three Gorges University, 443002 Yichang, PR China.
Hong-Wei
HW
Yang
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003541:Cystathionine beta-Synthase / Q000378:metabolism*; D018698:Glutamic Acid / Q000633:toxicity*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D000066829:Neuroprotection / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects*
D018696:Neuroprotective Agents; D009498:Neurotoxins; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D018698:Glutamic Acid; C018524:N,N-dimethylarginine; D026423:S-Nitroso-N-Acetylpenicillamine; D001120:Arginine; D019001:Nitric Oxide Synthase; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide
Cystathionine-β-synthetase; Glutamate; Hydrogen sulfide; Neurotoxicity; Nitric oxide; Nitric oxide synthase