title: A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease.
abstract: Peroxisome proliferator-activated receptor (PPAR)-γ and PPARα have shown neuroprotective effects in models of Parkinson's disease (PD). The role of the third, more ubiquitous isoform PPARδ has not been fully explored. This study investigated the role of PPARδ in PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model the dopaminergic neurodegeneration of PD. In vitro administration of the PPARδ antagonist GSK0660 (1 μM) increased the detrimental effect of 1-methyl-4-phenylpyridinium iodide (MPP⁺) on cell viability, which was reversed by co-treatment with agonist GW0742 (1 μM). GW0742 alone did not affect MPP⁺ toxicity. PPARδ was expressed in the nucleus of dopaminergic neurons and in astrocytes. Striatal PPARδ levels were increased (over two-fold) immediately after MPTP treatment (30 mg/kg for 5 consecutive days) compared to saline-treated mice. PPARδ heterozygous mice were not protected against MPTP toxicity. Intra-striatal infusion of GW0742 (84 μg/day) reduced the MPTP-induced loss of dopaminergic neurons (5036±195) when compared to vehicle-infused mice (3953±460). These results indicate that agonism of PPARδ provides protection against MPTP toxicity, in agreement with the effects of other PPAR agonists.
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: H L
authors.initials: HL
authors.lastname: Martin
authors.forename: R B
authors.initials: RB
authors.lastname: Mounsey
authors.forename: K
authors.initials: K
authors.lastname: Sathe
authors.forename: S
authors.initials: S
authors.lastname: Mustafa
authors.forename: M C
authors.initials: MC
authors.lastname: Nelson
authors.forename: R M
authors.initials: RM
authors.lastname: Evans
authors.forename: P
authors.initials: P
authors.lastname: Teismann
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid; D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine; D004305:Dose-Response Relationship, Drug; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D047494:PPAR delta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D051381:Rats; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000627:therapeutic use*; D013876:Thiophenes / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine; D005904:Glial Fibrillary Acidic Protein; D016177:Macrophage-1 Antigen; D018696:Neuroprotective Agents; D047494:PPAR delta; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; D014446:Tyrosine 3-Monooxygenase; C529769:GSK0660; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds