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.
Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy.
Carmen
C
Avagliano
Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy.
Roberto
R
Russo
Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy.
Carmen
C
De Caro
Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy.
Claudia
C
Cristiano
Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy.
Giovanna
G
La Rana
Department of Veterinary Medicine and Animal Production, University of Naples "Federico II", 80137 Naples, Italy.
Giuseppe
G
Piegari
Department of Veterinary Medicine and Animal Production, University of Naples "Federico II", 80137 Naples, Italy.
Orlando
O
Paciello
Department of Health Sciences, School of Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy.
Rita
R
Citraro
Department of Health Sciences, School of Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy.
Emilio
E
Russo
Department of Health Sciences, School of Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy.
Giovambattista
G
De Sarro
Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy.
Rosaria
R
Meli
Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy. Electronic address: mattace@unina.it.
Giuseppina
G
Mattace Raso
Department of Pharmacy, University of Naples "Federico II", 80131, Naples, Italy.
Antonio
A
Calignano
D000577:Amides; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004983:Ethanolamines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology*; D047493:PPAR alpha / Q000378:metabolism; D010169:Palmitic Acids / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000577:Amides; D004983:Ethanolamines; D018696:Neuroprotective Agents; D047493:PPAR alpha; D010169:Palmitic Acids; D017382:Reactive Oxygen Species; C005958:palmidrol; D016627:Oxidopamine; D019001:Nitric Oxide Synthase; D014446:Tyrosine 3-Monooxygenase; D051546:Cyclooxygenase 2; D013482:Superoxide Dismutase; D004298:Dopamine
Apoptosis; Endoplasmic reticulum stress; Oxidative stress; PPAR-α; Palmitoylethanolamide; Parkinson's disease