Gingerol‐Induced Hypoxia‐Inducible Factor 1 Alpha Inhibits Human Prion Peptide‐Mediated Neurotoxicity

Abstract

Prion diseases are a family member of neurodegenerative disorders caused by the accumulation of misfolded-prion proteins (scrapie form of PrP, PrP(Sc)). The accumulation of PrP(Sc) in the brain leads to neurotoxicity by the induction of mitochondrial-apoptotic pathways. Recent studies implicated gingerol in protection against neurodegeneration. However, the basis of the neuroprotection in prion disease remains unclear. Thus, we investigated the influence of gingerol on prion peptide-induced neuronal damage. Gingerol blocked PrP(106-126)-mediated neurotoxicity by protecting mitochondrial function. Moreover, the protective effect of gingerol against PrP(106-126)-induced mitochondrial damage was associated with hypoxia-inducible factor 1 alpha (HIF-1α) expression. Gingerol-induced HIF-1α expression inhibited the PrP(106-126)-induced mitochondrial dysfunction. On the other hand, inhibition of gingerol-induced HIF-1 α expression attenuated the gingerol-mediated neuroprotective effect. Here, we demonstrate for the first time that treatment with gingerol prevents prion peptide-mediated neuronal cell death and that the neuroprotection is induced by HIF-1α-mediated signals. This study suggests that treatment with gingerol may provide a novel therapeutic strategy for prion-mediated neurotoxicity.

Gingerols and shogaols: Important nutraceutical principles from ginger

“…The compound was also found to block prion peptide-mediated neurotoxicity by protecting mitochondrial function, which is associated with the expression of hypoxia-inducible factor 1a (Jeong et al, 2013). 6-Gingerol and SG were predicted in silico to be strong antidepressants, using Argus lab 4.0.1 docking software, when compared to the standard drug, imipramine (Ittiyavirah and Paul, 2013).…”

HIF-1α-induced β-catenin activation prevents prion-mediated neurotoxicity

“…It has been shown that hypoxia regulates β-catenin activation through the modulation of HIF-1α stabilization (26,31) and that HIF-1α protects neuronal cells against PrP (106-126)induced mitochondrial damage (11). Therefore, in this study, we assessed whether HIF-1α has an effect on PrP (106-126)-mediated mitochondrial toxicity by activating β-catenin signals.…”

“…effects of HIF-1α are associated with the regulation of mitochondrial functions (11,35). In this study, we demonstrate that HIF-1α prevents prion-mediated mitochondrial neurotoxicity by regulating β-catenin signaling pathways.…”

“…Previously it has been shown that treatment with gingerol prevents PrP (106-126)-mediated mitochondrial neurotoxicity through the regulation of hypoxia-inducible factor-1α (HIF-1α) activation (11). Xie et al (12) also demonstrated that exposing neurons to low oxygen activated HIF-1α and inhibited the activation of the mitochondrial apoptotic pathway induced by nerve growth factor (NGF) deprivation.…”

“…It has previously been demonstrated that gingerol protects neuronal cells against PrP (106-126)-induced neurotoxicity; the protective effects were associated with HIF-1α activation and correlated with the regulation of mitochondrial homeostasis (11). The activation of β-catenin signals has been suggested to protect neuronal cells from 6-OHDA-induced mitochondrial damage (32).…”