Abstract
N-Palmitoylethanolamide (PEA) is a non-endocannabinoid lipid mediator belonging to the class of the N-acylethanolamine phospolipids and was firstly isolated from soy lecithin, egg yolk, and peanut meal. Either preclinical or clinical studies indicate that PEA is potentially useful in a wide range of therapeutic areas, including eczema, pain, and neurodegeneration. PEA-containing products are already licensed for use in humans as a nutraceutical, a food supplement, or a food for medical purposes, depending on the country. PEA is especially used in humans for its analgesic and anti-inflammatory properties and has demonstrated high safety and tolerability. Several preclinical in vitro and in vivo studies have proven that PEA can induce its biological effects by acting on several molecular targets in both central and peripheral nervous systems. These multiple mechanisms of action clearly differentiate PEA from classic anti-inflammatory drugs and are attributed to the compound that has quite unique anti(neuro)inflammatory properties. According to this view, preclinical studies indicate that PEA, especially in micronized or ultramicronized forms (i.e., formulations that maximize PEA bioavailability and efficacy), could be a potential therapeutic agent for the effective treatment of different pathologies characterized by neurodegeneration, (neuro)inflammation, and pain. In particular, the potential neuroprotective effects of PEA have been demonstrated in several experimental models of Alzheimer’s disease. Interestingly, a single-photon emission computed tomography (SPECT) case study reported that a mild cognitive impairment (MCI) patient, treated for 9 months with ultramicronized-PEA/luteolin, presented an improvement of cognitive performances. In the present review, we summarized the current preclinical and clinical evidence of PEA as a possible therapeutic agent in Alzheimer’s disease. The possible PEA neuroprotective mechanism(s) of action is also described.
Highlights
Neuroinflammation and synaptic dysfunction in Alzheimer’s disease (AD) have been originally considered as epiphenomena with inflammation and altered neurotransmission occurring when damaged neurons provoke glia activation and changes in neuron biology
Neuroinflammation in AD is predominantly linked to central nervous system (CNS)-resident microglia, astroglia, and perivascular macrophages, which have been implicated at the cellular level (Zádori et al, 2018)
The results indicate that PEA treatment attenuated Aβ-induced astrocyte activation, as proven by its effects in reducing astrocyte hypertrophied cell bodies and thickened processes, along with the expression of glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B), two specific markers of astrocyte activity linked to AD pathogenesis
Summary
Neuroinflammation and synaptic dysfunction in Alzheimer’s disease (AD) have been originally considered as epiphenomena with inflammation and altered neurotransmission occurring when damaged neurons provoke glia activation and changes in neuron biology. Changes in neuronal activity/signaling in AD can promote the β-amyloidogenic pathway of amyloid precursor protein (APP) processing, leading to increased Aβ levels and creating a sort of a positive feedback or a vicious cycle to accelerate AD pathogenesis (Herrup, 2010; Wirz et al, 2014; Cai and Tammineni, 2017) These findings indicate that neuroinflammation, oxidative stress, and synaptic dysfunction are integral parts of AD pathogenesis, and not solely consequences of Aβ-induced CNS damage. The relationship between neurodegeneration and neuroinflammation is strictly interdependent, suggesting that compounds able to simultaneously target these processes might be effective therapeutic agents in AD In this context, endocannabinoid signaling and endocannabinoid-related compounds have been demonstrated to modulate the main pathological processes during early AD, including protein misfolding, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress (Aso and Ferrer, 2014; Bedse et al, 2015; Fernández-Ruiz et al, 2015). We report the in vivo and in vitro findings, along with clinical results, supporting the possible role of PEA as a therapeutic agent in AD
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