title: Palmitoylethanolamide protects against the amyloid-β25-35-induced learning and memory impairment in mice, an experimental model of Alzheimer disease.
abstract: Alzheimer disease (AD) is the most common form of neurodegenerative dementia. Amyloid-β deposition, neurofibrillary tangle formation, and neuro-inflammation are the major pathogenic mechanisms that in concert lead to memory dysfunction and decline of cognition. Palmitoylethanolamide (PEA) is the naturally occurring lipid amide between palmitic acid and ethanolamine. Despite its clear role in inflammation and pain control, only limited in vitro evidence exist about a role for PEA in neurodegenerative diseases. Here we describe the neuroprotective activities of PEA in mice injected intracerebroventricularly with amyloid-β 25-35 (Ab25-35) peptide (9 nmol). We used spatial and non-spatial memory tasks to evaluate learning and memory dysfunctions. Ab25-35 injection significantly impaired spontaneous alternation performances, water maze spatial reference and working-like memory, and novel object recognition test. PEA was administered once a day (3-30 mg/kg, subcutaneously), starting 3 h after Ab25-35, for 1 or 2 weeks. PEA reduced (10 mg/kg) or prevented (30 mg/kg) behavioral impairments induced by Ab25-35 injection. PEA failed to rescue memory deficits induced by Ab25-35 injection in peroxisome proliferator-activated receptor-α (PPAR-α) null mice. GW7647 (2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid; 5 mg/kg per day), a synthetic PPAR-α agonist, mimicked the effect of PEA. Acute treatment with PEA was ineffective. According with the neuroprotective profile of PEA observed during behavioral studies, experimental molecular and biochemical markers induced by Ab25-35 injection, such as lipid peroxidation, protein nytrosylation, inducible nitric oxide synthase induction, and caspase3 activation, were reduced by PEA treatment. These data disclose novel findings about the therapeutic potential of PEA, unrevealing a previously unknown therapeutic possibility to treat memory deficits associated with AD.
authors.affiliation: Department of Experimental Pharmacology, Faculty of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Agostino
authors.forename: Roberto
authors.initials: R
authors.lastname: Russo
authors.forename: Carmen
authors.initials: C
authors.lastname: Avagliano
authors.forename: Claudia
authors.initials: C
authors.lastname: Cristiano
authors.forename: Rosaria
authors.initials: R
authors.lastname: Meli
authors.forename: Antonio
authors.initials: A
authors.lastname: Calignano
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000577:Amides; D016229:Amyloid beta-Peptides; D000818:Animals; D004195:Disease Models, Animal; D063388:Endocannabinoids; D004983:Ethanolamines; D015227:Lipid Peroxidation / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects*; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D010169:Palmitic Acids / Q000627:therapeutic use*; D010446:Peptide Fragments
chemical_list: D000577:Amides; D016229:Amyloid beta-Peptides; D063388:Endocannabinoids; D004983:Ethanolamines; D010169:Palmitic Acids; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C005958:palmidrol