A novel mechanism of formaldehyde neurotoxicity: inhibition of hydrogen sulfide generation by promoting overproduction of nitric oxide.
BACKGROUND
Formaldehyde (FA) induces neurotoxicity by overproduction of intracellular reactive oxygen species (ROS). Increasing studies have shown that hydrogen sulfide (H(2)S), an endogenous gastransmitter, protects nerve cells against oxidative stress by its antioxidant effect. It has been shown that overproduction of nitric oxide (NO) inhibits the activity of cystathionine-beta-synthase (CBS), the predominant H(2)S-generating enzyme in the central nervous system.


OBJECTIVE
We hypothesize that FA-caused neurotoxicity involves the deficiency of this endogenous protective antioxidant gas, which results from excessive generation of NO. The aim of this study is to evaluate whether FA disturbs H(2)S synthesis in PC12 cells, and whether this disturbance is associated with overproduction of NO.


RESULTS
We showed that exposure of PC12 cells to FA causes reduction of viability, inhibition of CBS expression, decrease of endogenous H(2)S production, and NO production. CBS silencing deteriorates FA-induced decreases in endogenous H(2)S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells; while ADMA, a specific inhibitor of NOS significantly attenuates FA-induced decreases in endogenous H(2)S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells.


CONCLUSIONS
Our data indicate that FA induces neurotoxicity by inhibiting the generation of H(2)S through excess of NO and suggest that strategies to manipulate endogenous H(2)S could open a suitable novel therapeutic avenue for FA-induced neurotoxicity.
Department of Physiology, Medical College, University of South China, Hengyang, Hunan, PR China. txq01001@gmail.com
Xiao-Qing
XQ
Tang
Heng-Rong
HR
Fang
Cheng-Fang
CF
Zhou
Yuan-Yuan
YY
Zhuang
Ping
P
Zhang
Hong-Feng
HF
Gu
Bi
B
Hu
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D015153:Blotting, Western; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005557:Formaldehyde / Q000633:toxicity*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006862:Hydrogen Sulfide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats
D005557:Formaldehyde; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide