Pioglitazone ameliorates the phenotype of a novel Parkinson's disease mouse model by reducing neuroinflammation

Mol Neurodegener. 2016 Apr 2;11:25. doi: 10.1186/s13024-016-0090-7.


Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The cause of the motor symptoms is the loss of dopaminergic neurons in the substantia nigra with consequent depletion of dopamine in the striatum. Although the etiology of PD is unknown, mitochondrial dysfunctions, including cytochrome c oxidase (Complex IV) impairment in dopaminergic neurons, have been associated with the disease's pathophysiology. In order to analyze the role of Complex IV in PD, we knocked out Cox10 (essential for the maturation of COXI, a catalytic subunit of Complex IV) in dopaminergic neurons. We also tested whether the resulting phenotype was improved by stimulating the PPAR-γ pathway.

Results: Cox10/DAT-cre mice showed decreased numbers of TH+ and DAT+ cells in the substantia nigra, early striatal dopamine depletion, motor defects reversible with L-DOPA treatment and hypersensitivity to L-DOPA with hyperkinetic behavior. We found that chronic pioglitazone (PPAR-γ agonist) treatment ameliorated the motor phenotype in Cox10/DAT-cre mice. Although neither mitochondrial function nor the number of dopaminergic neurons was improved, neuroinflammation in the midbrain and the striatum was decreased.

Conclusions: By triggering a mitochondrial Complex IV defect in dopaminergic neurons, we created a new mouse model resembling the late stages of PD with massive degeneration of dopaminergic neurons and striatal dopamine depletion. The motor phenotypes were improved by Pioglitazone treatment, suggesting that targetable secondary pathways can influence the development of certain forms of PD.

Keywords: Mitochondria; Neuroinflammation; Pioglitazone.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / metabolism
  • Inflammation / metabolism*
  • Mesencephalon / drug effects
  • Mesencephalon / metabolism
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / genetics
  • Phenotype
  • Pioglitazone
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism
  • Thiazolidinediones / pharmacology*


  • Thiazolidinediones
  • Dopamine
  • Pioglitazone