title: Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson's Disease.
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.
authors.affiliation: Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Anamitra
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Monica R
authors.initials: MR
authors.lastname: Langley
authors.affiliation: Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Dilshan S
authors.initials: DS
authors.lastname: Harischandra
authors.affiliation: Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Neal
authors.affiliation: Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Huajun
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Vellareddy
authors.initials: V
authors.lastname: Anantharam
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Joseph
authors.affiliation: Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Brenza
authors.affiliation: Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA.
authors.forename: Balaji
authors.initials: B
authors.lastname: Narasimhan
authors.affiliation: Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA, 50011, USA.
authors.forename: Arthi
authors.initials: A
authors.lastname: Kanthasamy
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
authors.affiliation: Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA, 50011, USA. akanthas@iastate.edu.
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
mesh_terms: D000098:Acetophenones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000098:Acetophenones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D018836:Inflammation Mediators; C056165:acetovanillone
keywords: Drug therapy; Microglia; Mito-apocynin; Mitochondria; Neuroprotection; Parkinson’s disease
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