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Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

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Abstract

Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson’s disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP+)-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP+-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in cellular and pre-clinical animal models of PD by attenuating oxidative damage and neuroinflammatory processes.

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Acknowledgments

This study was funded by NIH grant R01 NS039958 (to B.K. and A.K.), U.S. Army Medical Research and Materiel Command (grant no. W81XWH-11-1-0700) and by the Harry R. and Angeline E. Quadracci Chair Endowment (B.K.). The W. Eugene and Linda Lloyd Endowed Chair to A.G.K. is also acknowledged. A.G.K., V.A., and B.N. are grateful to the Iowa State Nanovaccine Initiative and B.N. acknowledges the Vlasta Klima Balloun Professorship. We thank Mr. Gary Zenitsky for his assistance in preparing this manuscript.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA, 50011, USA

    Anamitra Ghosh, Monica R. Langley, Dilshan S. Harischandra, Matthew L Neal, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy & Anumantha G. Kanthasamy

  2. Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA

    Joy Joseph & Balaraman Kalyanaraman

  3. Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA

    Timothy Brenza & Balaji Narasimhan

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  1. Anamitra Ghosh
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  2. Monica R. Langley
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  4. Matthew L Neal
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  12. Anumantha G. Kanthasamy
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Correspondence to Anumantha G. Kanthasamy.

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A.G.K. and B.K. hold a patent entitled “Neuroprotective Compounds and Their Use” for the Mitoapocynin treatment of Parkinson’s disease. The other authors have no conflicts of interest.

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Ghosh, A., Langley, M.R., Harischandra, D.S. et al. Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease. J Neuroimmune Pharmacol 11, 259–278 (2016). https://doi.org/10.1007/s11481-016-9650-4

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