Oleoylethanolamide, Neuroinflammation, and Alcohol Abuse

Abstract

Neuroinflammation is a complex process involved in the physiopathology of many central nervous system diseases, including addiction. Alcohol abuse is characterized by induction of peripheral inflammation and neuroinflammation, which hallmark is the activation of innate immunity toll-like receptors 4 (TLR4). In the last years, lipid transmitters have generated attention as modulators of parts of the addictive process. Specifically, the bioactive lipid oleoylethanolamide (OEA), which is an endogenous acylethanolamide, has shown a beneficial profile for alcohol abuse. Preclinical studies have shown that OEA is a potent anti-inflammatory and antioxidant compound that exerts neuroprotective effects in alcohol abuse. Exogenous administration of OEA blocks the alcohol-induced TLR4-mediated pro-inflammatory cascade, reducing the release of proinflammatory cytokines and chemokines, oxidative and nitrosative stress, and ultimately, preventing the neural damage in frontal cortex of rodents. The mechanisms of action of OEA are discussed in this review, including a protective action in the intestinal barrier. Additionally, OEA blocks cue-induced reinstatement of alcohol-seeking behavior and reduces the severity of withdrawal symptoms in animals, together with the modulation of alcohol-induced depression-like behavior and other negative motivational states associated with the abstinence, such as the anhedonia. Finally, exposure to alcohol induces OEA release in blood and brain of rodents. Clinical evidences will be highlighted, including the OEA release and the correlation of plasma OEA levels with TLR4-dependent peripheral inflammatory markers in alcohol abusers. In base of these evidences we hypothesize that the endogenous release of OEA could be a homeostatic signal to counteract the toxic action of alcohol and we propose the exploration of OEA-based pharmacotherapies to treat alcohol-use disorders.

A systematic review of the effects of oleoylethanolamide, a high‐affinity endogenous ligand of PPAR‐α, on the management and prevention of obesity

“…In fact, GPR119 does not mediate the anorectic effects of OEA . OEA can also interact with another receptor, named as TRPV1, which is also known as the capsaicin receptor . TRPV1 receptors have been reported to exhibit analgesic and thermosensation properties.…”

“…62 OEA can also interact with another receptor, named as TRPV1, which is also known as the capsaicin receptor. 35,64 TRPV1 receptors have been reported to exhibit analgesic and thermosensation properties. In addition, TRPV1 receptors may be involved in energy homeostasis by regulating food intake and EE.…”

Symmetrically substituted dichlorophenes inhibit N-acyl-phosphatidylethanolamine phospholipase D

“…For instance, re-feeding of rodents leads to an increase in jejunal C18:1NAE levels, but also leads to a decrease in jejunal C20:4NAE levels (32), despite the notion that both NAEs theoretically share the same biosynthetic machinery. Modulating the NAE-biosynthetic enzymes with appropriate tool compounds should help elucidate the contribution of individual enzymes to the biosynthesis of individual NAEs under various physiological and pathophysiological conditions and could lead to the development of effective therapies for a range of clinical conditions including obesity, inflammation, chronic pain, and addiction (33)(34).…”

Indoleamine-2,3-Dioxygenase Mediates Emotional Deficits by the Kynurenine/Tryptophan Pathway in the Ethanol Addiction/Withdrawal Mouse Model

“…It has been demonstrated that moderate drinking is beneficial to health. For example, it can reduce cardiovascular disease mortality and increase life expectancy (Guzmán et al, 2004;Orio et al, 2019). However, alcohol is also a widely used psychoactive drug which causes many public health problems in our society.…”