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.

Systemic Administration of Oleoylethanolamide Protects from Neuroinflammation and Anhedonia Induced by LPS in Rats

“…Growing evidence indicates that OEA and PEA may have neuroprotective properties in neurological disorders such as stroke ( Sun et al, 2007 ; Zhou et al, 2012 ; Ahmad et al, 2012a ), traumatic brain injury ( Ahmad et al, 2012b ), Parkinson′s disease ( Gonzalez-Aparicio et al, 2013 ; Gonzalez-Aparicio and Moratalla, 2013 ), or addiction ( Melis et al, 2008 ; Plaza-Zabala et al, 2010 ; Bilbao et al, 2013 ; Coppola and Mondola, 2013 ). Some of the mechanisms implicated are the modulation of antioxidant responses, neuroinflammation, glial cell proliferation/differentiation, neurogenesis, and neurotransmission.…”

Oleoylethanolamide prevents neuroimmune HMGB1/TLR4/NF‐kB danger signaling in rat frontal cortex and depressive‐like behavior induced by ethanol binge administration

“…We reported previously that OEA reduced both plasma and frontal cortex TNF‐α under neuroinflammatory experimental conditions (Sayd et al ) and it has been proven that OEA crosses the blood brain barrier after i.p. administration (Gonzalez‐Aparicio et al ). Nevertheless, plasma cytokine alterations are known to induce brain cytokine responses.…”

“…OEA was first discovered as a satiety factor with no activity at traditional cannabinoid receptors (Rodriguez de Fonseca et al ; Fu et al ), and growing evidence indicates that it mediates a variety of different actions through activation of peroxisome proliferator‐activated receptor‐alpha (PPAR‐α). Current studies in animal models indicate that OEA may have putative neuroprotective properties against CNS disorders such as stroke (Sun et al ), Parkinson's disease (Gonzalez‐Aparicio et al ), depression (Jin et al ) or addiction (Melis et al ; Bilbao et al , ).…”

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing–Remitting Multiple Sclerosis

“…Thus, the effects observed here upon um-PEA administration can be due to PEA activating its molecular targets, and also to PEA favoring the actions of other NAEs (e.g., AEA and OEA). Indeed, anti-inflammatory, neuroprotective, and analgesic effects have been reported for AEA and OEA in several preclinical models [69][70][71][72][73].…”