title: The systemic administration of oleoylethanolamide exerts neuroprotection of the nigrostriatal system in experimental Parkinsonism.
abstract: 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.
authors.affiliation: Instituto Cajal (CSIC), Avenida Doctor Arce, 37, 28002 Madrid, Spain.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Gonzalez-Aparicio
authors.affiliation: Laboratorio de Medicina Regenerativa, IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario Carlos Haya, Avenida Carlos Haya, 82, 29010 Málaga, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Blanco
authors.affiliation: Laboratorio de Medicina Regenerativa, IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario Carlos Haya, Avenida Carlos Haya, 82, 29010 Málaga, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
authors.affiliation: Laboratorio de Medicina Regenerativa, IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario Carlos Haya, Avenida Carlos Haya, 82, 29010 Málaga, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Pavon
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 92037 La Jolla, California, USA.
authors.forename: Loren H
authors.initials: LH
authors.lastname: Parsons
authors.affiliation: Laboratorio de Neurofarmacología, Department de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Calle Doctor Aiguader, 88, 08003 Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.affiliation: Laboratorio de Neurofarmacología, Department de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Calle Doctor Aiguader, 88, 08003 Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Robledo
authors.affiliation: Instituto Cajal (CSIC), Avenida Doctor Arce, 37, 28002 Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Fernandez-Espejo
authors.affiliation: Laboratorio de Medicina Regenerativa, IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario Carlos Haya, Avenida Carlos Haya, 82, 29010 Málaga, Spain.
authors.forename: Fernando Rodriguez
authors.initials: FR
authors.lastname: de Fonseca
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009498:Neurotoxins / Q000633:toxicity; D009829:Oleic Acids / Q000008:administration & dosage*; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D063388:Endocannabinoids; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009829:Oleic Acids; D016708:Synaptophysin; C488250:oleoylethanolamide; D016627:Oxidopamine; D007770:L-Lactate Dehydrogenase; D051547:Heme Oxygenase-1; D014446:Tyrosine 3-Monooxygenase