Abstract
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-1α is 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-1α levels. However, the therapeutic benefit 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 of a new HIF-PHI, FG-4592, which is currently in phase 3 clinical trials to treat anemia in patients with chronic kidney diseases (CKD) in PD models. FG-4592 attenuates 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-γ coactivator-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.
Highlights
Parkinson’s disease (PD) is the second major neurodegenerative disease after Alzheimer’s disease and the estimated prevalence of PD in people older than 60 years is 1.0%, and 3.0% in those aged 80 years and older (Tanner and Goldman, 1996)
The role of HIF in the pathogenesis of PD is well documented by our previous study and other groups; but the therapeutic potential of this pathway remains poorly explored
HIF heterodimer consisting of a constitutively expressed β subunit and an oxygen-regulated α subunit (Hackenbeck et al, 2011). These two subunits are constantly made in most cell in the body, but the function of HIF is kept in check by degradation after hydroxylation by prolyl hydroxylases (PHD) under normal oxygen conditions
Summary
Parkinson’s disease (PD) is the second major neurodegenerative disease after Alzheimer’s disease and the estimated prevalence of PD in people older than 60 years is 1.0%, and 3.0% in those aged 80 years and older (Tanner and Goldman, 1996). Accumulating evidence appears to suggest that mitochondrial dysfunction, oxidative stress, and dysregulation of autophagy and apoptosis play an important role in the pathogenesis of PD. It is well-established that severe and prolonged hypoxia contributes to the brain damage (Sharp and Bernaudin, 2004), but exposure to moderate hypoxia alone does not cause neuronal death as long as cerebral blood flow is maintained (Teli and Rajanikant, 2013). Since HIF-1α is the master transcriptional regulator of cellular responses to hypoxia, it may be one major pathway involved in neuroprotection (Ran et al, 2005). Previous studies have shown that HIFPH inhibitors (HIF-PHI) have neuroprotective effects on PD
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