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Oxidative stress plays an important role in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The oxindole compound GIF-2165X-G1 is a hybrid molecule composed of the oxindole skeleton of the neuroprotective compound GIF-0726-r and the polyphenolic skeleton of the antioxidant curcumin. We previously reported that novel oxindole derivatives such as GIF-0726-r and GIF-2165X-G1 prevent endogenous oxidative stress-induced cell death in mouse hippocampal HT22 cells. In this study, we present a detailed investigation of the effect of GIF-2165X-G1 on endogenous oxidative stress in HT22 cells in comparison with GIF-0726-r and curcumin. GIF-2165X-G1 exhibited more potent neuroprotective activity than GIF-0726-r or curcumin and had less cytotoxicity than that observed with curcumin. Both GIF-0726-r and GIF-2165X-G1 were found to have ferrous ion chelating activity similar to that exhibited by curcumin. GIF-2165 X-G1 and curcumin induced comparable antioxidant response element transcriptional activity. Although the induction of heme oxygenase-1, an antioxidant response element-regulated gene product, was much stronger in curcumintreated cells than in GIF-2165X-G1-treated cells, it turned out that the induction of heme oxygenase-1 is dispensable for neuroprotection. These results demonstrate that the introduction of the polyphenol skeleton of curcumin to the oxindole GIF-0726-r improves neuroprotective features. Furthermore, intrastriatal injection of GIF-2165X-G1 alleviated apomorphineinduced rotation and prevented dopaminergic neuronal loss in a 6-hydroxydopamine mouse model of Parkinson's diseases. Collectively, our novel findings indicate that the novel oxindole compound GIF-2165X-G1 serves to delay the progression of Parkinson's disease by suppressing oxidative stress.

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