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

Peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR alpha have shown neuroprotective effects in models of Parkinson's disease (PD). The role of the third, more ubiquitous isoform PPAR delta has not been fully explored. This study investigated the role of PPAR delta 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 PPAR delta antagonist GSK0660 (1 mu M) increased the detrimental effect of 1-methyl-4-phenylpyridinium iodide (MPP+) on cell viability, which was reversed by co-treatment with agonist GW0742 (1 mu M). GW0742 alone did not affect MPP+ toxicity. PPAR delta was expressed in the nucleus of dopaminergic neurons and in astrocytes. Striatel PPAR delta levels were increased (over two-fold) immediately after MPTP treatment (30 mg/kg for 5 consecutive days) compared to saline-treated mice. PPAR delta heterozygous mice were not protected against MPTP toxicity. Intra-striatal infusion of GW0742 (84 mu g/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 PPAR delta provides protection against MPTP toxicity, in agreement with the effects of other PPAR agonists. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.