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Abstract
BackgroundFormaldehyde (FA) induces neurotoxicity by overproduction of intracellular reactive oxygen species (ROS). Increasing studies have shown that hydrogen sulfide (H2S), 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 H2S-generating enzyme in the central nervous system.ObjectiveWe 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 H2S synthesis in PC12 cells, and whether this disturbance is associated with overproduction of NO.Principal FindingsWe showed that exposure of PC12 cells to FA causes reduction of viability, inhibition of CBS expression, decrease of endogenous H2S production, and NO production. CBS silencing deteriorates FA-induced decreases in endogenous H2S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells; while ADMA, a specific inhibitor of NOS significantly attenuates FA-induced decreases in endogenous H2S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells.Conclusion/SignificanceOur data indicate that FA induces neurotoxicity by inhibiting the generation of H2S through excess of NO and suggest that strategies to manipulate endogenous H2S could open a suitable novel therapeutic avenue for FA-induced neurotoxicity.
Highlights
Formaldehyde (FA), a pungent, highly flammable and colorless gas, is a well-known indoor and outdoor pollutant
We simultaneously evaluated whether FA alters the production of H2S in PC12 cells
The present study shows that treatment of PC12 cells with FA leads to (i) cytotoxicity; (ii) inhibition of CBS expression and decrease in endogenous H2S production; and (iii) increase in the levels of neuronal NOS (nNOS) and inducible NOS (iNOS) and overproduction of nitric oxide (NO)
Summary
Formaldehyde (FA), a pungent, highly flammable and colorless gas, is a well-known indoor and outdoor pollutant. Everyone is exposed to FA from many sources, including exhaust gas, cigarette smoke, household products, and many other medical and industrial products. It has been shown that FA induces neurotoxic effects in the cultured cortical neurons and PC12 cells in vitro [4,5,6]. The neurotoxicity of FA has been confirmed by animal studies that exposure of rats to FA causes various morphological changes in the brain [7] and damages the prefrontal cortex including the hippocampus [8,9] and that Inhaled FA leads to learning and memory disorders in rats and mice [10,11,12]. Increasing studies have shown that hydrogen sulfide (H2S), 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 H2S-generating enzyme in the central nervous system
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