Behavioral effects of long-term administration of palmitoylethanolamide on Tg2576 mice

Aim: To date, pharmacological approaches to treat dementia and particularly Alzheimer disease (AD) remain uncertain and unclear. In this context, palmitoylethanolamide (PEA) has been emerging as an important analgesic, anti-inflammatory and neuroprotective mediator, acting at several molecular targets in both central and peripheral nervous systems as well as immune cells, and has demonstrated high safety and tolerability. PEA is present in certain foods we use every day such as egg yolk, corn, peanut and soy oils and is also produced by many cells in our organism. It can be found in high concentrations in brain tissues and is synthesized starting by lipid components of the cellular membranes. In the present study, we sought to investigate the behavioral modifications potentially induced by a chronic administration of ultra-micronized PEA (i.e., a micrometer-sized crystalline form that improves both its pharmacokinetics and bioavailability) for 6-months in transgenic mice expressing mutant APP (Tg2576 mice). These mice express high levels of mutated human APP and with advancing age develop both amyloid peptide accumulation and amyloid plaques in the brain, as well as behavioral and cognitive deficits; thus, they represent a widely accepted animal model of AD. Methods: The 6-month administration of PEA in Tg2576 mice and the wild-type (WT) control group was via a subcutaneous (s.c.) delivery system. Mice were subjected to s.c. implantation of PEA or placebo pellets at 6 months of age. PEA effects on motor, cognitive and emotional performances were monitored longitudinally, by a battery of behavioral tasks, within three different ages, corresponding to a pre-symptomatic phase (T0 = 3 months), a mild-symptomatic phase (T1 = 6.5 months) and a fully symptomatic phase (T2 = 11-12 months; ie., at the end of the chronic supplementation). All mice underwent the behavioral assessment by using the following battery of validated tests: Elevated Plus Maze (EPM), to assess anxiety levels and locomotor skills; Rotarod Test (RT), to assess motor coordination skills; Y-Maze Spontaneous Alternation Test (Y-Maze), to assess working memory skills; Novel Object Recognition Test (NORT), to assess mnestic and discriminative skills; Tail Suspension Test (TST), to assess depressive behaviors. Results: Behavioral analyses performed on our mice demonstrate that chronic PEA supplementation exerts beneficial effects on NORT mnesic performances of Tg2576 mice at T2. Specifically, in Tg2576 mice chronic PEA supplementation restored the novelty recognition memory impaired during the fully symptomatic phase, while did not affect working memory, motor coordination, anxiety, and depressive-like alterations. No PEA effects were observed in WT mice. Conclusions: PEA is able to counteract specific hippocampal-dependent mnesic deficits typical of AD. Our data suggest the likely therapeutic potential of ultra-micronized PEA as an early treatment in AD. These findings should be further investigated to increase knowledge of the effects of PEA as a safe and low-cost nutraceutical tool useful to improve quality of life in AD.