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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
Author(s) -
Ay Muhammet,
Luo Jie,
Langley Monica,
Jin Huajun,
Anantharam Vellareddy,
Kanthasamy Arthi,
Kanthasamy Anumantha G.
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14033
Subject(s) - neuroprotection , protein kinase b , dopaminergic , neurodegeneration , biology , microbiology and biotechnology , pharmacology , phosphorylation , dopamine , neuroscience , medicine , 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 blot analysis revealed that quercetin significantly induced the activation of two major cell survival kinases, protein kinase D1 ( PKD 1) and Akt in MN 9D dopaminergic neuronal cells. Furthermore, pharmacological inhibition or si RNA knockdown of PKD 1 blocked the activation of Akt, suggesting that PKD 1 acts as an upstream regulator of Akt in quercetin‐mediated neuroprotective signaling. Quercetin also enhanced cAMP response‐element binding protein phosphorylation and expression of the cAMP response‐element binding protein target gene brain‐derived neurotrophic factor. Results from qRT ‐ PCR , Western blot analysis, mt DNA content analysis, and MitoTracker assay experiments revealed that quercetin augmented mitochondrial biogenesis. Quercetin also increased mitochondrial bioenergetics capacity and protected MN 9D cells against 6‐hydroxydopamine‐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 the PKD 1‐Akt cell survival signaling axis and suggest that further exploration of quercetin as a promising neuroprotective agent for treating PD may offer clinical benefits.