Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson's Disease

Abstract

Quercetin, one of the major flavonoids in plants, has been recently reported to have neuroprotective effects against neurodegenerative processes. However, since the molecular signaling mechanisms governing these effects are not well clarified, we evaluated quercetin’s effect on the neuroprotective signaling events in dopaminergic neuronal models and further tested its efficacy in the MitoPark transgenic mouse model of Parkinson’s disease (PD). Western blotting analysis revealed that quercetin significantly induced the activation of two major cell survival kinases, protein kinase D1 (PKD1) and Akt in MN9D dopaminergic neuronal cells. Furthermore, pharmacological inhibition or siRNA knockdown of PKD1 blocked the activation of Akt, suggesting that PKD1 acts as an upstream regulator of Akt in quercetin-mediated neuroprotective signaling. Quercetin also enhanced CREB phosphorylation and expression of the CREB target gene BDNF. Results from qRT-PCR, Western blot analysis, mtDNA content analysis, and MitoTracker assay experiments revealed that quercetin augmented mitochondrial biogenesis. Quercetin also increased mitochondrial bioenergetics capacity and protected MN9D cells against 6-OHDA-induced neurotoxicity. To further evaluate the neuroprotective efficacy of quercetin against the mitochondrial dysfunction underlying PD, we used the progressive dopaminergic neurodegenerative MitoPark transgenic mouse model of PD. Oral administration of quercetin significantly reversed behavioral deficits, striatal dopamine depletion, and TH neuronal cell loss in MitoPark mice. Together, our findings demonstrate that quercetin activates PKD1-Akt cell survival signaling axis and suggest that further exploration of quercetin as a promising neuroprotective agent for treating PD may offer clinical benefits.

Quercetin prevents spinal motor neuron degeneration induced by chronic excitotoxic stimulus by a sirtuin 1-dependent mechanism

“…In a model of hypobaric-hypoxic brain injury in vivo, QCT prevented cognitive deterioration through SIRT1 upregulation and consequent activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), one of the master regulators of mitochondrial biogenesis [ 23 ]. Further, in an in vitro model of dopaminergic neuronal death induced by 6-hydroxydopamine and MitoPark, QCT prevented neuronal death through the activation of the protein kinase D/cAMP response element binding protein/PGC1-α axis, which led to the augmentation of mitochondrial biogenesis and function [ 54 ]. These studies suggest that QCT may exert its beneficial effects ultimately improving neuronal energetic state irrespective of its molecular targets.…”

Neuroprotective Effects of Quercetin in Alzheimer’s Disease

“…A study using drug screening in Caenorhabditis elegans nematodes with neuronal expression of human exon-1 huntingtin (128Q) and mutant Htt striatal cells derived from knock-in HD mice, concluded that isoquercetin improved motor functions in acute spinal cord injury, reduced α-synuclein fibrillization, reduced hippocampal neuronal cell death, improved synaptic plasticity, and reversed histopathological hallmarks of AD [112]. Quercetin also protects against mitochondrial dysfunction and progressive dopaminergic neurodegeneration by activating PKD1-Akt cell survival signaling axis Cell Culture and MitoPark transgenic mouse models of Parkinson's disease [113].…”

Adult‐onset brain tumors and neurodegeneration: Are polyphenols protective?

“…In accordance with these findings, another study showed that the administration of quercetin reduced ROS production, increased mitochondrial manganese-dependent superoxide dismutase (MnSOD) activity and the ratio of B-cell CLL/lymphoma 2 (BCL-2) to BCL2 associated X (BAX) in aluminum-induced oxidative stress rat model (Sharma et al, 2016). Prasad et al (2013) (Ay et al, 2017).…”