Mito-Apocynin Prevents Mitochondrial Dysfunction, Microglial Activation, Oxidative Damage, and Progressive Neurodegeneration in MitoPark Transgenic Mice. Antioxid Redox Signal 2017 Nov 10;27(14):1048-1066
Date
04/05/2017Pubmed ID
28375739Pubmed Central ID
PMC5651937DOI
10.1089/ars.2016.6905Scopus ID
2-s2.0-85019331880 (requires institutional sign-in at Scopus site) 111 CitationsAbstract
AIMS: 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.
INNOVATION: 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.
CONCLUSION: 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.
Author List
Langley M, Ghosh A, Charli A, Sarkar S, Ay M, Luo J, Zielonka J, Brenza T, Bennett B, Jin H, Ghaisas S, Schlichtmann B, Kim D, Anantharam V, Kanthasamy A, Narasimhan B, Kalyanaraman B, Kanthasamy AGAuthors
Brian Bennett D.Phil. Professor and Chair in the Physics department at Marquette UniversityBalaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AcetophenonesAdministration, Oral
Animals
Antioxidants
Cells, Cultured
DNA-Binding Proteins
Disease Models, Animal
Gene Knockout Techniques
High Mobility Group Proteins
Humans
Mice
Mice, Transgenic
Mitochondria
NADPH Oxidase 2
Oxidative Stress
Parkinson Disease
