The Neuroprotection Of Upregulation HIF-1α By FG-4592 And Its Mechanism In Dopaminergic Neuronal Injury In Parkinson’s Disease

As the main transcription factor that regulates the cellular responses to hypoxia,Hypoxia-inducible factor-1α(HIF-1α)plays an important role in the pathogenesis of Parkinson’s disease(PD).HIF-1αis normally degraded through ubiquitination after hydroxylation by prolyl hydroxylases(PHD).Emerging evidence has suggested that HIF PHD inhibitors(HIF-PHI)may have neuroprotective effects on PD through increasing HIF-1αlevels.However,the therapeutic potential of HIF-PHI for PD remains poorly explored due to the lack of proper clinical compounds and understanding of the underlying molecular mechanisms.In this study,we examined the therapeutic benefit in PD models using a new HIF-PHI,FG-4592,which is currently in phase 3 clinical trials to treat anemia in patients with chronic kidney diseases(CKD).FG-4592 attenuated MPP~+-induced apoptosis and loss of tyrosine hydroxylase(TH)in SH-SY5Y cells.Pretreatment with FG-4592 mitigates MPP~+-induced loss of mitochondrial membrane potential(MMP),mitochondrial oxygen consumption rate(OCR),production of reactive oxygen species(ROS)and ATP.Furthermore,FG-4592 counterbalances the oxidative stress through up-regulating nuclear factor erythroid 2 p45-related factor 2(Nrf-2),heme oxygenase-1(HO-1)and superoxide dismutase 2(SOD2).FG-4592 treatment also induces the expression of Peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α)through increasing the phosphorylation of AMP-activated protein kinase(AMPK).In MPTP-treated mice,FG-4592 protects against MPTP-induced loss of TH-positive neurons of substantia nigra and attenuates behavioral impairments.Collectively,our study demonstrates that FG-4592 is a promising therapeutic strategy for PD through improving the mitochondrial function under oxidative stress.