Palmitoylethanolamide protects mice against 6-OHDA-induced neurotoxicity and endoplasmic reticulum stress: In vivo and in vitro evidence.
Several pathogenetic factors have been involved in the onset and progression of Parkinson's disease (PD), including inflammation, oxidative stress, unfolded protein accumulation, and apoptosis. Palmitoylethanolamide (PEA), an endogenous N-acylethanolamine, has been shown to be a neuroprotective and anti-inflammatory molecule, acting as a peroxisome proliferator activated receptor (PPAR)-α agonist. In this study we investigated the effects of PEA on behavioral alterations and the underlying pathogenic mechanisms in the 6-hydroxydopamine (6-OHDA)-induced model of PD in male mice. Additionally, we showed the involvement of PPAR-α in PEA protective effect on SH-SY5Y neuroblastoma against 6-OHDA damage. Here, we report that PEA (3-30mg/kg/days.c.) improved behavioral impairments induced by unilateral intrastriatal injection of 6-OHDA. This effect was accompanied by a significant increase in tyrosine hydroxylase expression at striatal level, indicating PEA preserving effect on dopaminergic neurons. Moreover, we found a reduction in the expression of pro-inflammatory enzymes, i.e. inducible nitric oxide synthase and cyclooxygenase-2, a modulation between pro- and anti-apoptotic markers, suggestive of PEA capability in controlling neuroinflammation and cell death. Interestingly, PEA also showed protective scavenging effect, through superoxide dismutase induction, and dampened unfolding protein response, interfering on glucose-regulated protein 78 expression and PERK-eIF2α pathway. Similar data were found in in vitro studies, where PEA treatment was found to rescue SH-SY5Y neuroblastoma cells from 6-OHDA-induced damage and death, partly by inhibiting endoplasmic reticulum stress detrimental response. Therefore, PEA, counteracting the pathogenetic aspects involved in the development of PD, showed its therapeutic potential, possibly integrating current treatments correcting dopaminergic deficits and motor dysfunction.
['Avagliano|Carmen|C|', 'Russo|Roberto|R|', 'De Caro|Carmen|C|', 'Cristiano|Claudia|C|', 'La Rana|Giovanna|G|', 'Piegari|Giuseppe|G|', 'Paciello|Orlando|O|', 'Citraro|Rita|R|', 'Russo|Emilio|E|', 'De Sarro|Giovambattista|G|', 'Meli|Rosaria|R|', 'Mattace Raso|Giuseppina|G|', 'Calignano|Antonio|A|']
D000577:Amides D000818:Animals D017209:Apoptosis D016923:Cell Death D051546:Cyclooxygenase 2 D004195:Disease Models, Animal D004298:Dopamine D059290:Dopaminergic Neurons D059865:Endoplasmic Reticulum Stress D004983:Ethanolamines D008297:Male D051379:Mice D009447:Neuroblastoma D018696:Neuroprotective Agents D020258:Neurotoxicity Syndromes D019001:Nitric Oxide Synthase D018384:Oxidative Stress D016627:Oxidopamine D047493:PPAR alpha D010169:Palmitic Acids D017382:Reactive Oxygen Species D013482:Superoxide Dismutase D014446:Tyrosine 3-Monooxygenase
Palmitoylethanolamide Endoplasmic reticulum stress Parkinson's disease Oxidative stress Apoptosis PPAR-α