Fibroblast growth factor 9 upregulates heme oxygenase-1 and gamma-glutamylcysteine synthetase expression to protect neurons from 1-methyl-4-phenylpyridinium toxicity

Jui-Yen Huang, Jih-Ing Chuang
Free Radical Biology & Medicine 2010 September 15, 49 (6): 1099-108
Oxidative stress and lower levels of trophic factors involved in nigrostriatal dopaminergic neurodegeneration are a hallmark of Parkinson disease. Our previous studies found that fibroblast growth factor 9 (FGF9) prevented 1-methyl-4-phenylpyridinium (MPP(+))-induced nigral dopaminergic neuron death and was involved in the neuroprotection of the antioxidant melatonin. However, the protective mechanisms mediated by FGF9 remain unclear. Herein, we explored whether FGF9 regulated the cellular antioxidant defense protecting dopaminergic neurons against MPP(+) intoxication. We found that FGF9 treatment alone induced a decrease in hydrogen peroxide (H(2)O(2)) level, an increase in glutathione content, and an upregulation of gamma-glutamylcysteine synthetase (gamma-GCS) and heme oxygenase 1 (HO-1) expression in primary cortical neurons but not in astrocytes. Simultaneous treatment with FGF9 and MPP(+) prevented MPP(+)-induced neuron death and H(2)O(2) overproduction but did not affect the FGF9-increased gamma-GCS and HO-1 protein expression. Inhibition of gamma-GCS or HO-1 prevented the inhibitory effect of FGF9 on MPP(+)-induced H(2)O(2) production and death in mesencephalic dopaminergic and cortical neurons. However, in the absence of MPP(+), the FGF9-induced H(2)O(2) reduction was blocked by HO-1 inhibitors, but not by gamma-GCS inhibitors. These results indicate that FGF9 upregulates gamma-GCS and HO-1 expression to protect cortical and dopaminergic neurons from MPP(+)-induced oxidative insult.

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