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.

Behavioral Phenotyping for Autism Spectrum Disorders in Mice

“…Animals with increased repetitive tendencies (such as autism and OCD mouse models; Kirsten et al 2012; Naviaux et al 2014; Xue et al 2016; Favre et al 2015), or with deficits in spatial working memory (e.g. mouse models of Alzheimer’s disease; D’Agostino et al 2012; Peng et al 2014) usually exhibit a higher number of repetitive entries into the same arm. As an alternative, the Y-maze could be used in a similar protocol, as the Y-shaped maze provides a more natural turning angle (Lainiola et al 2014).…”

Cannabinoid activation of peroxisome proliferator‐activated receptors: an update and review of the physiological relevance

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

“…Since the 1990s, interest in the therapeutic potential of PEA has increased owing to the discovery of the effects of PEA in many preclinical paradigms for pain and chronic inflammation [2]. PEA has antinociceptive properties in several animal models [3][4][5], prevents neurotoxicity and neurodegeneration [6][7][8], and inhibits peripheral inflammation and mast cell degranulation [9,10]. These effects of PEA are not only observed when used as a drug (i.e., after direct administration) [11,12], but also when its endogenous levels are increased by blocking its catabolism [13].…”