Stabilization of HIF-1α by FG-4592 promotes functional recovery and neural protection in experimental spinal cord injury

• Published in: Brain research Vol. 1632; pp. 19 - 26
• Main Authors: Wu, Kai, Zhou, Kailiang, Wang, Yongli, Zhou, Yifei, Tian, Naifeng, Wu, Yaosen, Chen, Deheng, Zhang, Di, Wang, Xiangyang, Xu, Huazi, Zhang, Xiaolei
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2016
• Subjects: Animals; Apoptosis; Cell Survival - drug effects; Cell Survival - physiology; Dose-Response Relationship, Drug; Female; Glycine - analogs & derivatives; Glycine - pharmacology; Glycine - therapeutic use; HIF1α; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Isoquinolines - pharmacology; Isoquinolines - therapeutic use; Mice; Mice, Inbred C57BL; Neurology; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; PC12 Cells; Prolyl hydroxylase inhibitor; Rats; Recovery of Function - drug effects; Recovery of Function - physiology; Spinal Cord Injuries - drug therapy; Spinal Cord Injuries - metabolism; Spinal cord injury; Prolyl hydroxylase inhibitor; Spinal cord injury; HIF1α; Apoptosis
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2015.12.017

Abstract Previous studies have shown that inhibition of prolyl hydroxylase(PHD) stabilizes Hypoxia-inducible factor 1, alpha subunit(HIF-1α), 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 HIF1α 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-1α blocker YC-1 down-regulated the HIF-1α 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-1α 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.