Pharmacological manipulation of peroxisome proliferator-activated receptor γ (PPARγ) reveals a role for anti-oxidant protection in a model of Parkinson's disease

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists have been shown to provide neuroprotection in a number of neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. These protective effects are primarily considered to result from the anti-inflammatory actions of PPAR gamma, however, there is increasing evidence that anti-oxidant mechanisms may also contribute. This study explored the impact of the PPAR gamma agonist rosiglitazone and the PPAR gamma antagonist GW9662 in the MPP+/MPTP (1-methyl-4-phenylpyridinium/1-methyl-4-Phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease, focussing on oxidative stress mechanisms. Rosiglitazone attenuated reactive oxygen species formation induced by MPP+ in SH-SY5Y cells concurrent with an upregulation of glutathione-S-transferase activity, but not superoxide dismutase activity. These responses were not attenuated by cotreatment with GW9662 suggesting that PPAR gamma activation is not required. The localisation of PPAR gamma in vivo to dopaminergic neurons of the substantia nigra pars compacta (SNpc) was established by immunohistochemistry and PPAR gamma levels were found to be upregulated 7 days after MPTP treatment. The importance of PPAR gamma in protecting against MPTP toxicity was confirmed by treating C57BL6 mice with GW9662. Treatment with GW9662 increased MPTP-induced neuronal loss in the SNpc whilst not affecting MPTP-induced reductions in striatal dopamine and 3,4-dihdroxyphenylacetic acid. GW9662 also caused neuronal loss in the SNpc of saline-treated mice. The evidence presented here supports the role of anti-oxidant mechanisms in the protective effects of PPAR gamma agonists in neurodegenerative diseases, but indicates that these effects may be independent of PPAR gamma activation. It also demonstrates the importance of PPAR gamma activity for neuronal survival within the SNpc. (c) 2012 Elsevier Inc. All rights reserved.