Mito-Apocynin Prevents Mitochondrial Dysfunction, Microglial Activation, Oxidative Damage, and Progressive Neurodegeneration in MitoPark Transgenic Mice

Langley, Monica R.; Ghosh, Alip; Charli, Adhithiya; Sarkar, Satyapriya; Ay, Muhammet; Luo, Jie; Zielonka, Jacek; Brenza, Timothy M.; Bennett, Brian; Jin, Huajun; Ghaisas, Shivani; Schlichtmann, Benjamin; Kim, Dong-Suk; Anantharam, Vellareddy; Kanthasamy, Anumantha G.; Narasimhan, Balaji; Kalyanaraman, Balaraman

doi:10.1089/ars.2016.6905

Cited by 114 publications

(127 citation statements)

References 77 publications

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“…The large energetic demand along with dopamine metabolism generate high basal levels of reactive oxygen species, suggesting that added oxidative stress from mitochondrial dysfunction could be especially damaging . Indeed, dopamine neurons from MitoPark mice exhibit increased markers of oxidative stress as well as altered morphology in nigral microglia indicative of neuroinflammation . Furthermore, dopamine neurons in MitoPark mice exhibit structurally altered mitochondria that are associated with the intracellular protein aggregates observed with this model .…”

Section: Discussionmentioning

confidence: 95%

Progressively disrupted somatodendritic morphology in dopamine neurons in a mouse Parkinson's model

et al. 2018

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Background: Parkinson’s disease is characterized by the progressive loss of dopamine neurons in the substantia nigra, leading to severe motor deficits. Although the disease likely begins to develop years before observable motor symptoms, the specific morphological and functional alterations involved are poorly understood. Objectives: MitoPark mice lack the gene coding for mitochondrial transcription factor A specifically in dopamine neurons, which over time produces a progressive decline of neuronal function and related behavior that phenotypically mirrors human parkinsonism. Our previous work identified a progressive decrease in cell capacitance in dopamine neurons from MitoPark mice, possibly suggesting reduced membrane surface area. We therefore sought to identify and quantify somatodendritic parameters in this model across age. Methods: We used whole-cell patch clamp and fluorescent labeling to quantify somatodendritic morphology of single, neurobiotin-fllled dopamine neurons in acutely isolated brain slices from MitoPark mice. Results: We found that MitoPark mice exhibit an adultonset, age-dependent reduction of neuritic branching and soma size in dopamine neurons. This decline proceeds similarly in MitoPark mice of both sexes, but does not begin until after the age that early decrements in ion channel physiology and behavior have previously been observed. Conclusions: A progressive and severe decline in somatodendritic morphology occurs prior to cell death, but is not responsible for the subtle decrements observable in the earliest stages of neurodegeneration. This work could help identify the ideal time window for specific treatments to halt disease progression and avert debilitating motor deficits in Parkinson’s patients.

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Section: Discussionmentioning

confidence: 95%

Progressively disrupted somatodendritic morphology in dopamine neurons in a mouse Parkinson's model

et al. 2018

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“…493,494 Also, the short-chain homolog, Mito-Apo 2 , was shown to be safe and neuroprotective in mice treated daily via oral gavage for 12 days at the dosage of 3 mg/kg. 495 …”

Section: Mitochondria-targeted Therapeutics In the Pre-clinical Momentioning

confidence: 99%

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Zielonka¹,

Joseph²,

et al. 2017

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Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the potentials of cell and mitochondrial membranes, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

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“…In our study, we observed that quercetin showed only a modest protective effect in MitoPark mice, possibly because of the fact that the MitoPark mouse is the most severe model of PD. Indeed, although the MitoPark model has been used since 2007 to test the efficacy of various interventions, only a few compounds have shown neuroprotective effects in MitoPark mice (Langley et al, 2017, Marcellino et al 2010. MitoPark mice show changes in electrophysiological parameters and dopamine signaling, even prior to 12 weeks when the onset of motor symptoms occurs (Good et al 2011;Branch et al 2016), which is when we started treating the animals in this study.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Luo

Langley

et al. 2017

Journal of Neurochemistry

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156

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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.

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Mito-Apocynin Prevents Mitochondrial Dysfunction, Microglial Activation, Oxidative Damage, and Progressive Neurodegeneration in MitoPark Transgenic Mice

Abstract: Collectively, our data demonstrate, for the first time, that a novel orally active apocynin derivative improves behavioral, inflammatory, and neurodegenerative processes in a severe progressive dopaminergic neurodegenerative model of PD. Antioxid. Redox Signal. 27, 1048-1066.

Cited by 114 publications

References 77 publications

Progressively disrupted somatodendritic morphology in dopamine neurons in a mouse Parkinson's model

Progressively disrupted somatodendritic morphology in dopamine neurons in a mouse Parkinson's model

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

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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