期刊
BRAIN RESEARCH
卷 1632, 期 -, 页码 19-26出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2015.12.017
关键词
Spinal cord injury; Prolyl hydroxylase inhibitor; HIF1 alpha; Apoptosis
资金
- National Natural Science Foundation of China [81401871, 81401162]
- Zhejiang Provincial Natural Science Foundation of China [LY14H170002]
- Zhejiang Medical Science Foundation (Zhejiang Provincial Project for Medical and Health Science and Technology) [2013KYA127, 2013KYB177]
- Wenzhou Science and Technology Bereau Foundation [S20100048, Y20100357]
Previous studies have shown that inhibition of prolyl hydroxylase(PHD) stabilizes Hypoxia-inducible factor 1, alpha subunit(HIF-1 alpha), increases tolerance to hypoxia, and improves the prognosis of many diseases. However, the role of PHD inhibitor (PHDI) in the recovery of spinal cord injury remains controversial. In this study, we investigated the protective role of a novel PHDI FG-4592 both in vivo and in vitro. FG-4592 treatment stabilized HIF1 alpha expression both in PC12 cells and in spinal cord. FG-4592 treatment significantly inhibited tert-Butyl hydroperoxide(TBHP)-induced apoptosis and increases the survival of neuronal PC-12 cells. FG-4592 administration also improved recovery and increased the survival of neurons in spinal cord lesions in the mice model. Combination therapy including the specific HIF-1 alpha blocker YC-1 down-regulated the HIF-1 alpha expression and partially abolished the protective effect of FG-4592. Taken together, our results revealed that the role of FG-4592 in SCI recovery is related to the stabilization of HIF-1 alpha and inhibition of apoptosis. Overall, our study suggests that PHDIs may be feasible candidates for therapeutic intervention after SCI and central nervous system disorders in humans. (C) 2015 Elsevier B.V. All rights reserved.
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