DETA/NONOate, a nitric oxide donor, produces antidepressant effects by promoting hippocampal neurogenesis
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Increasing evidence suggests that depression may be associated with a lack of hippocampal neurogenesis. Our recent study shows that endogenous nitric oxide (NO) contributes to chronic mild stress (CMS)-induced depression by suppressing hippocampal neurogenesis.
The aim of this study was to investigate the effects of exogenous NO in CMS-induced depression in young adult mice.
In normal mice, administration of a pure NO donor (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA/NONOate; 0.4 mg/kg, i.p., for 7 days) produced an antidepressant-like effect and significantly increased hippocampal neurogenesis. The mice exposed to CMS exhibited behavioral changes typical of depression and impaired neurogenesis in the hippocampus. Treatment with DETA/NONOate (0.4 mg/kg, i.p., for 7 days) reversed CMS-induced behavioral despair and hippocampal neurogenesis impairment. We treated mice with a telomerase inhibitor 3′-azido-deoxythymidine (AZT; 100 mg/kg, i.p., for 14 days) to disrupt neurogenesis. From day 4 to day 11 of AZT treatment, mice were injected with DETA/NONOate (0.4 mg/kg, i.p., for 7 days). Disrupting hippocampal neurogenesis blocked the antidepressant effect of DETA/NONOate.
Our findings suggest that exogenous NO benefits chronic stress-induced depression by stimulating hippocampal neurogenesis and may represent a novel approach for the treatment of depressive disorders.
KeywordsDepression Nitric oxide Stress Neurogenesis Hippocampus Antidepressant Mice Behavior Dentate gyrus BrdU
This work was supported by grants (to Dong-Ya Zhu) from the National Natural Science Foundation of China (30371640 and 30572174) and from the Natural Science Foundation of Jiangsu Province (BK 2007728).
Conflict of interest
The authors declare that no conflict of interest exists.
- Czeh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M, Bartolomucci A, Fuchs E (2001) Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA 98:12796–12801PubMedCrossRefGoogle Scholar
- Fu W, Lu C, Mattson MP (2002) Telomerase mediates the cell survival-promoting actions of brain-derived neurotrophic factor and secreted amyloid precursor protein in developing hippocampal neurons. J Neuorsci 22:10710–10719Google Scholar
- Luo CX, Zhu XJ, Zhou QG, Wang B, Wang W, Cai HH, Sun YJ, Hu M, Jiang J, Hua Y, Han X, Zhu DY (2007) Reduced neuronal nitric oxide synthase is involved in ischemia-induced hippocampal neurogenesis by up-regulating inducible nitric oxide synthase expression. J Neurochem 103:1872–1882PubMedCrossRefGoogle Scholar
- Zhu XJ, Hua Y, Jiang J, Zhou QG, Luo CX, Han X, Lu YM, Zhu DY (2006) Neuronal nitric oxide synthase-derived nitric oxide inhibits neurogenesis in the adult dentate gyrus by down-regulating cyclic AMP response element binding protein phosphorylation. Neuroscience 141:827–835PubMedCrossRefGoogle Scholar