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. doi: 10.1089/ars.2016.6905. Epub 2017 Apr 4.

Abstract

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.

Keywords: Mito-apocynin; Parkinson's disease; apocynin; mitochondria; neuroprotection.

MeSH terms

  • Acetophenones / administration & dosage*
  • Acetophenones / chemistry
  • Acetophenones / pharmacology
  • Administration, Oral
  • Animals
  • Antioxidants / administration & dosage*
  • Antioxidants / pharmacology
  • Cells, Cultured
  • DNA-Binding Proteins / genetics*
  • Disease Models, Animal
  • Gene Knockout Techniques
  • High Mobility Group Proteins / genetics*
  • Humans
  • Mice
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • NADPH Oxidase 2 / metabolism
  • Oxidative Stress / drug effects*
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / metabolism

Substances

  • Acetophenones
  • Antioxidants
  • DNA-Binding Proteins
  • High Mobility Group Proteins
  • Tfam protein, mouse
  • acetovanillone
  • Cybb protein, mouse
  • NADPH Oxidase 2