title: Stabilization of HIF-1α by FG-4592 promotes functional recovery and neural protection in experimental spinal cord injury.
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.
authors.affiliation: Department of Orthopaedics, The Second affiliated hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key laboratory of orthopaedics, Wenzhou, Zhejiang Province, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Orthopaedics, The Second affiliated hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key laboratory of orthopaedics, Wenzhou, Zhejiang Province, China.
authors.forename: Kailiang
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Department of Orthopaedics, The Second affiliated hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key laboratory of orthopaedics, Wenzhou, Zhejiang Province, China.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, The Second affiliated hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key laboratory of orthopaedics, Wenzhou, Zhejiang Province, China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Orthopaedics, The Second affiliated hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key laboratory of orthopaedics, Wenzhou, Zhejiang Province, China.
authors.forename: Naifeng
authors.initials: N
authors.lastname: Tian
authors.affiliation: Department of Orthopaedics, The Second affiliated hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key laboratory of orthopaedics, Wenzhou, Zhejiang Province, China.
authors.forename: Yaosen
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Orthopaedics, The Second affiliated hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key laboratory of orthopaedics, Wenzhou, Zhejiang Province, China.
authors.forename: Deheng
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, The Second affiliated hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key laboratory of orthopaedics, Wenzhou, Zhejiang Province, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, The Second affiliated hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key laboratory of orthopaedics, Wenzhou, Zhejiang Province, China.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, The Second affiliated hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key laboratory of orthopaedics, Wenzhou, Zhejiang Province, China. Electronic address: spinexu@163.com.
authors.forename: Huazi
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Orthopaedics, The Second affiliated hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key laboratory of orthopaedics, Wenzhou, Zhejiang Province, China. Electronic address: callmeroger@126.com.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016716:PC12 Cells; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007546:Isoquinolines; D018696:Neuroprotective Agents; D005998:Glycine; C584543:roxadustat
keywords: Apoptosis; HIF1α; Prolyl hydroxylase inhibitor; Spinal cord injury