Neuroprotective effects of the PPARβ/δ antagonist GSK0660 in in vitro and in vivo Parkinson's disease models

BackgroundThe underlying mechanism of Parkinson's disease are still unidentified, but excitotoxicity, oxidative stress, and neuroinflammation are considered key actors. Proliferator activated receptors (PPARs) are transcription factors involved in the control of numerous pathways. Specifically, PPAR beta/delta is recognized as an oxidative stress sensor, and we have previously reported that it plays a detrimental role in neurodegeneration.MethodsBasing on this concept, in this work, we tested the potential effects of a specific PPAR beta/delta antagonist (GSK0660) in an in vitro model of Parkinson's disease. Specifically, live-cell imaging, gene expression, Western blot, proteasome analyses, mitochondrial and bioenergetic studies were performed. Since we obtained promising results, we tested this antagonist in a 6-hydroxydopamine hemilesioned mouse model. In the animal model, behavioral tests, histological analysis, immunofluorescence and western blot of substantia nigra and striatum upon GSK0660 were assayed.ResultsOur findings suggested that PPAR beta/delta antagonist has neuroprotective potential due to neurotrophic support, anti-apoptotic and anti-oxidative effects paralleled to an amelioration of mitochondria and proteasome activity. These findings are strongly supported also by the siRNA results demonstrating that by silencing PPAR beta/delta a significative rescue of the dopaminergic neurons was obtained, thus indicating an involvement of PPAR beta/delta in PD's pathogenesis. Interestingly, in the animal model, GSK0660 treatment confirmed neuroprotective effects observed in the in vitro studies. Neuroprotective effects were highlighted by the behavioural performance and apomorphine rotation tests amelioration and the reduction of dopaminergic neuronal loss. These data were also confirmed by imaging and western blotting, indeed, the tested compound decreased astrogliosis and activated microglia, concomitant with an upregulation of neuroprotective pathways.ConclusionsIn summary, PPAR beta/delta antagonist displayed neuroprotective activities against 6-hydroxydopamine detrimental effects both in vitro and in vivo models of Parkinson's disease, suggesting that it may represent a novel therapeutic approach for this disorder.