Oleoylethanolamide (OEA) is an agonist of the peroxisome proliferator-activated receptor α (PPARα) and has been described to exhibit neuroprotective properties when administered locally in animal models of several neurological disorder models, including stroke and Parkinson's disease. However, there is little information regarding the effectiveness of systemic administration of OEA on Parkinson's disease. In the present study, OEA-mediated neuroprotection has been tested on in vivo and in vitro models of 6-hydroxydopamine (6-OH-DA)-induced degeneration. The in vivo model was based on the intrastriatal infusion of the neurotoxin 6-OH-DA, which generates Parkinsonian symptoms. Rats were treated 2 h before and after the 6-OH-DA treatment with systemic OEA (0.5, 1, and 5 mg/kg). The Parkinsonian symptoms were evaluated at 1 and 4 wk after the development of lesions. The functional status of the nigrostriatal system was studied through tyrosine-hydroxylase (TH) and hemeoxygenase-1 (HO-1, oxidation marker) immunostaining as well as by monitoring the synaptophysin content. In vitro cell cultures were also treated with OEA and 6-OH-DA. As expected, our results revealed 6-OH-DA induced neurotoxicity and behavioural deficits; however, these alterations were less severe in the animals treated with the highest dose of OEA (5 mg/kg). 6-OH-DA administration significantly reduced the striatal TH-immunoreactivity (ir) density, synaptophysin expression, and the number of nigral TH-ir neurons. Moreover, 6-OH-DA enhanced striatal HO-1 content, which was blocked by OEA (5 mg/kg). In vitro, 0.5 and 1 µm of OEA exerted significant neuroprotection on cultured nigral neurons. These effects were abolished after blocking PPARα with the selective antagonist GW6471. In conclusion, systemic OEA protects the nigrostriatal circuit from 6-OH-DA-induced neurotoxicity through a PPARα-dependent mechanism.

This work was supported by grants to EFE, RM and FRF from Fundació La Marató TV3, and Red de Trastornos Adictivos (Instituto de Salud Carlos III, RD06/0001/0002, RD06/0001/0001, RD06/0001/0005, and FEDER funds) and to EFE from Delegación del Gobierno para el Plan Nacional sobre Drogas (PNSD2009I039) and Junta de Andalucía (BIO127, PAIDI). EB is a recipient of a ‘Marie Curie’ COFUND Fellowship (U-Mobility, number 246550) from the University of Málaga and the 7th Framework Program (FP7). The authors thank Beatriz Galan-Rodriguez, Mara Guerra and Silvia Castellano for animal care and technical assistance, and Juan Luis Ribas (Servicio de Microscopia, CITIUS, University of Seville) for stereological advice