title: Pharmacological manipulation of peroxisome proliferator-activated receptor γ (PPARγ) reveals a role for anti-oxidant protection in a model of Parkinson's disease.
abstract: Peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ, however, there is increasing evidence that anti-oxidant mechanisms may also contribute. This study explored the impact of the PPARγ agonist rosiglitazone and the PPARγ 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 PPARγ activation is not required. The localisation of PPARγ in vivo to dopaminergic neurons of the substantia nigra pars compacta (SNpc) was established by immunohistochemistry and PPARγ levels were found to be upregulated 7 days after MPTP treatment. The importance of PPARγ 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 PPARγ agonists in neurodegenerative diseases, but indicates that these effects may be independent of PPARγ activation. It also demonstrates the importance of PPARγ activity for neuronal survival within the SNpc.
authors.affiliation: School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, UK.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Martin
authors.forename: Ross B
authors.initials: RB
authors.lastname: Mounsey
authors.forename: Sarah
authors.initials: S
authors.lastname: Mustafa
authors.forename: Kinnari
authors.initials: K
authors.lastname: Sathe
authors.forename: Peter
authors.initials: P
authors.lastname: Teismann
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism / Q000517:prevention & control*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000975:Antioxidants; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone