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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.

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 (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 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, 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-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 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.

SUBMITTER: Ay M

PROVIDER: S-EPMC5643047 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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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.

Ay Muhammet M Luo Jie J Langley Monica M Jin Huajun H Anantharam Vellareddy V Kanthasamy Arthi A Kanthasamy Anumantha G AG

Journal of neurochemistry 20170509 5

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 signif ...[more]

PMID: 28376279

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Project description:Mitochondrial dysfunction has been implicated as a key player in the pathogenesis of Parkinson's disease (PD). The MitoPark mouse, a transgenic mitochondrial impairment model developed by specific inactivation of TFAM in dopaminergic neurons, spontaneously exhibits progressive motor deficits and neurodegeneration, recapitulating several features of PD. Since nonmotor symptoms are now recognized as important features of the prodromal stage of PD, we comprehensively assessed the clinically relevant motor and nonmotor deficiencies from ages 8-24 wk in both male and female MitoPark mice and their littermate controls. As expected, motor deficits in MitoPark mice began around 12-14 wk and became severe by 16-24 wk. Interestingly, MitoPark mice exhibited olfactory deficits in the novel and social scent tests as early as 10-12 wk as compared to age-matched littermate controls. Additionally, male MitoPark mice showed spatial memory deficits before female mice, beginning at 8 wk and becoming most severe at 16 wk, as determined by the Morris water maze. MitoPark mice between 16 and 24 wk spent more time immobile in forced swim and tail suspension tests, and made fewer entries into open arms of the elevated plus maze, indicating a depressive and anxiety-like phenotype, respectively. Importantly, depressive behavior as determined by immobility in forced swim test was reversible by antidepressant treatment with desipramine. Neurochemical and mechanistic studies revealed significant changes in CREB phosphorylation, BDNF, and catecholamine levels as well as neurogenesis in key brain regions. Collectively, our results indicate that MitoPark mice progressively exhibit deficits in olfactory discrimination, cognitive learning and memory, and anxiety- and depression-like behaviors as well as key neurochemical signaling associated with nonmotor deficits in PD. Thus, MitoPark mice can serve as an invaluable model for studying nonmotor deficits in addition to studying the motor deficits related to pathology in PD.

Project description:Gastrointestinal (GI) disturbances are one of the earliest symptoms affecting most patients with Parkinson's disease (PD). In many cases, these symptoms are observed years before motor impairments become apparent. Hence, the molecular and cellular underpinnings that contribute to this early GI dysfunction in PD have actively been explored using a relevant animal model. The MitoPark model is a chronic, progressive mouse model recapitulating several key pathophysiological aspects of PD. However, GI dysfunction and gut microbiome changes have not been categorized in this model. Herein, we show that decreased GI motility was one of the first non-motor symptoms to develop, evident as early as 8 weeks with significantly different transit times from 12 weeks onwards. These symptoms were observed well before motor symptoms developed, thereby paralleling PD progression in humans. At age 24 weeks, we observed increased colon transit time and reduced fecal water content, indicative of constipation. Intestinal inflammation was evidenced with increased expression of iNOS and TNFα in the small and large intestine. Specifically, iNOS was observed mainly in the enteric plexi, indicating enteric glial cell activation. A pronounced loss of tyrosine hydroxylase-positive neurons occurred at 24 weeks both in the mid-brain region as well as the gut, leading to a corresponding decrease in dopamine (DA) production. We also observed decreased DARPP-32 expression in the colon, validating the loss of DAergic neurons in the gut. However, the total number of enteric neurons did not significantly differ between the two groups. Metabolomic gas chromatography-mass spectrometry analysis of fecal samples showed increased sterol, glycerol, and tocopherol production in MitoPark mice compared to age-matched littermate controls at 20 weeks of age while 16 s microbiome sequencing showed a transient temporal increase in the genus Prevotella. Altogether, the data shed more light on the role of the gut dopaminergic system in maintaining intestinal health. Importantly, this model recapitulates the chronology and development of GI dysfunction along with other non-motor symptoms and can become an attractive translational animal model for pre-clinical assessment of the efficacy of new anti-Parkinsonian drugs that can alleviate GI dysfunction in PD.

Project description:Parkinson's disease (PD) patients have excessive iron depositions in substantia nigra (SN). Neuroinflammation characterized by microglial activation is pivotal for dopaminergic neurodegeneration in PD. However, the role and mechanism of microglial activation in iron-induced dopaminergic neurodegeneration in SN remain unclear yet. This study aimed to investigate the role and mechanism of microglial ?-nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) activation in iron-induced selective and progressive dopaminergic neurodegeneration. Multiple primary midbrain cultures from rat, NOX2+/+ and NOX2-/- mice were used. Dopaminergic neurons, total neurons, and microglia were visualized by immunostainings. Cell viability was measured by MTT assay. Superoxide (O2·-) and intracellular reactive oxygen species (iROS) were determined by measuring SOD-inhibitable reduction of tetrazolium salt WST-1 and DCFH-DA assay. mRNA and protein were detected by real-time PCR and Western blot. Iron induces selective and progressive dopaminergic neurotoxicity in rat neuron-microglia-astroglia cultures and microglial activation potentiates the neurotoxicity. Activated microglia produce a magnitude of O2·- and iROS, and display morphological alteration. NOX2 inhibitor diphenylene iodonium protects against iron-elicited dopaminergic neurotoxicity through decreasing microglial O2·- generation, and NOX2-/- mice are resistant to the neurotoxicity by reducing microglial O2·- production, indicating that iron-elicited dopaminergic neurotoxicity is dependent of NOX2, a O2·--generating enzyme. NOX2 activation is indicated by the increased mRNA and protein levels of subunits P47 and gp91. Molecules relevant to NOX2 activation include PKC-?, P38, ERK1/2, JNK, and NF-?BP65 as their mRNA and protein levels are enhanced by NOX2 activation. Iron causes selective and progressive dopaminergic neurodegeneration, and microglial NOX2 activation potentiates the neurotoxicity. PKC-?, P38, ERK1/2, JNK, and NF-?BP65 are the potential molecules relevant to microglial NOX2 activation.

Dataset Information

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.

Publications

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.

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