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 (1μM) increased the detrimental effect of 1-methyl-4-phenylpyridinium iodide (MPP+) on cell viability, which was reversed by co-treatment with agonist GW0742 (1μM). 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 (30mg/kg for 5 consecutive days) compared to saline-treated mice. PPARδ heterozygous mice were not protected against MPTP toxicity. Intra-striatal infusion of GW0742 (84μg/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.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disease (Dauer and Przedborski, 2003)
The cytotoxicity of MPP+ was unaffected by treatment with GW0742, but was increased in the presence of 100 nM GSK0660 as measured by a reduction in cell viability compared to MPP+ alone (p = 0.008 analysis of variance (ANOVA), Student–Newman– Keuls post hoc test; Fig. 1C)
Despite these alterations in cell viability neither 100 nM GSK0660, 10 nM GW0742 or the co-treatments had any effects on MPP+-induced cytotoxicity as measured by lactate dehydrogenase (LDH) release (Fig. 1D), suggesting that inhibition of PPARd may affect cellular metabolic status, altering MTT conversion to its insoluble formazan, this does not lead to an alteration in cell death in this model
Summary
Parkinson’s disease (PD) is a common neurodegenerative disease (Dauer and Przedborski, 2003). Its primary neuropathogical feature is the loss of dopaminergic nigrostriatal neurons, which results in the disabling motor abnormalities that characterise PD: rigidity, bradykinesia, resting tremor and postural instability (Dauer and Przedborski, 2003). There are three PPAR isoforms – a, c and d ( known as b), each with varying tissue distributions and ligand affinities (Desvergne and Wahli, 1999). The majority of the studies on the role of PPARs in neurodegenerative diseases have focussed on PPARc, as it is known to be a negative regulator of macrophage, microglia and astrocyte function (Ricote et al, 1999; Storer et al, 2005; Xu et al, 2005, 2006).
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