Abstract
Oxidative stress is a great challenge to neurons following cerebral ischemia. PGC-1α has been shown to act as a potent modulator of oxidative metabolism. In this study, the effects of ZLN005, a small molecule that activate PGC-1α, against oxygen–glucose deprivation (OGD)- or ischemia-induced neuronal injury in vitro and in vivo were investigated. Transient middle cerebral artery occlusion (tMCAO) was performed in rats and ZLN005 was administered intravenously at 2 h, 4 h, or 6 h after ischemia onset. Infarct volume and neurological deficit score were detected to evaluate the neuroprotective effects of ZLN005. Well-differentiated PC12 cells, which were subjected to OGD for 2 h followed by reoxygenation for 22 h, were used as an in vitro ischemic model. Changes in expression of PGC-1α, its related genes, and antioxidant genes were determined by real-time quantitative PCR. The results showed that ZLN005 reduced cerebral infarct volume and improved the neurological deficit in rat with tMCAO, and significantly protected OGD-induced neuronal injury in PC12 cells. Furthermore, ZLN005 enhanced expression of PGC-1α in PC12 cells and in the ipsilateral hemisphere of rats with tMCAO. Additionally, ZLN005 increased antioxidant genes, including SOD1 and HO-1, and significantly prevented the ischemia-induced decrease in SOD activity. Taking together, the PGC-1α activator ZLN005 exhibits neuroprotective effects under ischemic conditions and molecular mechanisms possibly involve activation of PGC-1α signaling pathway and cellular antioxidant systems.
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Acknowledgements
This study was supported by the National Natural Science Foundation of China (21402241), the Natural Science Foundation of Jiangsu Province (BK20160032), the Six Talent Peaks Project of Jiangsu Province (T.P.), and the Program for Jiangsu Province “Shuang Chuang” Team.
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All authors listed contributed immensely to this study. YX and JAK performed the experiments and wrote the paper. WR, YW, SZ, and XS performed the animal experiments and analyzed the data. TP, JL, and LZ, as experts in molecular pharmacology, provided technical supports and designed the research.
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Xu, Y., Kabba, J.A., Ruan, W. et al. The PGC-1α Activator ZLN005 Ameliorates Ischemia-Induced Neuronal Injury In Vitro and In Vivo. Cell Mol Neurobiol 38, 929–939 (2018). https://doi.org/10.1007/s10571-017-0567-0
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DOI: https://doi.org/10.1007/s10571-017-0567-0