title: Mito-Apocynin Prevents Mitochondrial Dysfunction, Microglial Activation, Oxidative Damage, and Progressive Neurodegeneration in MitoPark Transgenic Mice.
abstract: OBJECTIVE
  Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor deficits and degeneration of dopaminergic neurons. Caused by a number of genetic and environmental factors, mitochondrial dysfunction and oxidative stress play a role in neurodegeneration in PD. By selectively knocking out mitochondrial transcription factor A (TFAM) in dopaminergic neurons, the transgenic MitoPark mice recapitulate many signature features of the disease, including progressive motor deficits, neuronal loss, and protein inclusions. In the present study, we evaluated the neuroprotective efficacy of a novel mitochondrially targeted antioxidant, Mito-apocynin, in MitoPark mice and cell culture models of neuroinflammation and mitochondrial dysfunction.
  
  
  RESULTS
  Oral administration of Mito-apocynin (10 mg/kg, thrice a week) showed excellent central nervous system bioavailability and significantly improved locomotor activity and coordination in MitoPark mice. Importantly, Mito-apocynin also partially attenuated severe nigrostriatal degeneration in MitoPark mice. Mechanistic studies revealed that Mito-apo improves mitochondrial function and inhibits NOX2 activation, oxidative damage, and neuroinflammation.
  
  
  METHODS
  The properties of Mito-apocynin identified in the MitoPark transgenic mouse model strongly support potential clinical applications for Mito-apocynin as a viable neuroprotective and anti-neuroinflammatory drug for treating PD when compared to conventional therapeutic approaches.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University , Ames, Iowa.
authors.forename: Monica
authors.initials: M
authors.lastname: Langley
authors.affiliation: 1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University , Ames, Iowa.
authors.forename: Anamitra
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: 1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University , Ames, Iowa.
authors.forename: Adhithiya
authors.initials: A
authors.lastname: Charli
authors.affiliation: 1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University , Ames, Iowa.
authors.forename: Souvarish
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: 1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University , Ames, Iowa.
authors.forename: Muhammet
authors.initials: M
authors.lastname: Ay
authors.affiliation: 1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University , Ames, Iowa.
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.affiliation: 2 Department of Biophysics, Medical College of Wisconsin , Milwaukee, Wisconsin.
authors.forename: Jacek
authors.initials: J
authors.lastname: Zielonka
authors.affiliation: 3 Department of Chemical and Biological Engineering, Iowa State University , Ames, Iowa.
authors.forename: Timothy
authors.initials: T
authors.lastname: Brenza
authors.affiliation: 4 Department of Physics, Marquette University , Milwaukee, Wisconsin.
authors.forename: Brian
authors.initials: B
authors.lastname: Bennett
authors.affiliation: 1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University , Ames, Iowa.
authors.forename: Huajun
authors.initials: H
authors.lastname: Jin
authors.affiliation: 1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University , Ames, Iowa.
authors.forename: Shivani
authors.initials: S
authors.lastname: Ghaisas
authors.affiliation: 3 Department of Chemical and Biological Engineering, Iowa State University , Ames, Iowa.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schlichtmann
authors.affiliation: 1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University , Ames, Iowa.
authors.forename: Dongsuk
authors.initials: D
authors.lastname: Kim
authors.affiliation: 1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University , Ames, Iowa.
authors.forename: Vellareddy
authors.initials: V
authors.lastname: Anantharam
authors.affiliation: 1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University , Ames, Iowa.
authors.forename: Arthi
authors.initials: A
authors.lastname: Kanthasamy
authors.affiliation: 3 Department of Chemical and Biological Engineering, Iowa State University , Ames, Iowa.
authors.forename: Balaji
authors.initials: B
authors.lastname: Narasimhan
authors.affiliation: 2 Department of Biophysics, Medical College of Wisconsin , Milwaukee, Wisconsin.
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
authors.affiliation: 1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University , Ames, Iowa.
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D006609:High Mobility Group Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000074662:NADPH Oxidase 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C081930:Tfam protein, mouse; C056165:acetovanillone; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2
keywords: Mito-apocynin; Parkinson's disease; apocynin; mitochondria; neuroprotection