Oleoylethanolamide (OEA), marketed mainly as an appetite regulator in weight loss supplement formulas, has nowadays been proven to have anti-inflammatory and antioxidant functions, showing neuroprotective effects in fighting against alcohol abuse in preclinical studies.

What is alcohol use disorders (AUDs)? 

AUD is a highly prevalent condition in the world population that causes medical, psychological, personal, social and economic problems. The most severe dimension of AUDs is alcohol dependence, a condition in which individuals lose control over alcohol intake despite the negative consequences.

Although some medications have been approved for this purpose, existing pharmacotherapies are not effective for all people due to the heterogeneity of AUDs. Oleoylethanolamide is the latest ingredient found to be effective for alcohol abuse and AUDs.

Oleoylethanolamide (OEA) as a candidate for treating alcohol-induced neuroinflammation/neurotoxicity and AUDs:

During the last decades, emerging investigations have focused on the role of lipid transmitters, instead of traditional neurotransmitters, as targets for many neuropsychiatric disorders. Lipid transmitters are small molecules that are primarily generated enzymatically by the cleavage of phospholipids, which are structural components of the cell membrane. Among lipid transmitters, acylethanolamides such as OEA and palmitoylethanolamide have been shown to be upregulated in several brain disorders and to exert neuroprotective properties though the modulation of oxidative stress, neuroinflammation, glial cell proliferation or neurotransmission. The disorders in which these acylethanolamides participate include stroke, multiple sclerosis, Parkinson’s disease, traumatic brain injury, Hungtington’s disease, post-traumatic stress disorder, depression or substance use disorders, among others.

Mechanism of Action of Oleoylethanolamide in alcohol abuse

Study research shows that OEA supplementation 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.

OLEOYLETHANOLAMIDE IS A MEMBER OF THE ANTI-INFLAMMATORY AND NEUROPROTECTANT ACYLETHANOLAMIDE FAMILY

The acylethanolamides (also known as N-acylethanolamines) are a class of naturally occurring lipid mediators involved in the regulation of a great deal of homeostatic functions (Orio et al., 2013). The endocannabinoid AEA is structurally an acylethanolamide, and other bioactive acylethanolamides are the anorexic lipid mediator OEA (Rodriguez de Fonseca et al., 2001) and the anti-nociceptive mediator palmitoylethanolamide (PEA) (Calignano et al., 2001; Figure 2). In this review, we will summarize the anti-inflammatory and neuroprotectant actions of these three acylethanolamides and we will focus on the specific role of OEA in neuroinflammation and alcohol abuse.

MECHANISMS BY WHICH OEA REDUCES ALCOHOL-INDUCED NEUROINFLAMMATION

Exogenous administration of OEA has proven to exert potent anti-inflammatory, antioxidant, and neuroprotective effects in animals exposed to alcohol binges (Antón et al., 2017a). Specifically, OEA pre-treatment before alcohol binges inhibits alcohol-induced increases in TLR4 expression (Figure 3A) and activation of the NF-κB canonical inflammatory pathway. As a result, OEA inhibits the release of the pro-inflammatory cytokine IL-1β, chemokine MCP-1, and danger molecule HMGB1 (Figure 3B), and the activity of the enzymes COX-2 and iNOS, preventing ethanol-induced lipid peroxidation and apoptotic mechanisms in prefrontal cortex (Antón et al., 2017a; Figure 1). The mechanisms by which OEA reduce innate immunity activation and neuroinflammation induced by alcohol abuse are discussed in the following lines.

OEA in Alcohol Metabolism Since ethanol administration induces a rapid release of OEA in the intestine and liver (remember that also in the brain), it could be argued that the satiety factor OEA interferes in the absorption of ethanol. Lower blood ethanol levels would mean decreased ethanol-induced effects, including its action on immune receptors and inflammation.

The anti-inflammatory actions of OEA could be related to its PPARα agonism within the brain, since activation of this nuclear receptor has been shown to induce changes in inflammatory-related genes by repressing the nuclear factors NF-κB and AP-1 (reviewed in Stahel et al., 2008).

EFFECTS OF OEA IN ALCOHOL CONSUMPTION AND NEGATIVE BEHAVIORS ASSOCIATED WITH THE ABSTINENCE OEA Decreases Alcohol Intake and Relapse

The beneficial actions of OEA in alcohol abuse have been tested in animal models of chronic alcohol consumption (Bilbao et al., 2016) and binge drinking (Antón et al., 2017a). Regarding chronic alcohol consumption, OEA was able to decrease alcohol self-administration relative to controls at doses of 5 and 20 mg/kg i.p. In a two-bottle choice paradigm, OEA-treated animals showed decreased voluntary drinking relative to controls at different time points, indicating that OEA serves as a regulator of voluntary alcohol intake (Figure 4). Oleoylethanolamide decreased also alcohol-induced operant responses after a period of drug deprivation, with has important implications for relapse to alcohol. Specifically, OEA was capable of blocking cue-conditioned reinstatement of alcohol-seeking behavior, an animal model of relapse (Bilbao et al., 2016).

The mechanisms by which OEA reduces voluntary alcohol consumption and alcohol relapse have been studied. As mentioned before, OEA is a PPARα agonist and a great deal of its effects are absent in PPARα knock-out mice (Fu et al., 2003; Guzmán et al., 2004). Then, the effects of OEA on alcohol consumption have been compared with the effects of PPARα agonists and antagonists. The i.p. injection of Wy14643, a PPARα agonist, imitated the actions of decreasing alcohol self-administration, cue-induced reinstatement, or alcohol deprivation effect, and the compound GW6471, a PPARα antagonist, reverted the actions of OEA decreasing alcohol intake in the two-bottle choice paradigm. Additionally, deafferentation by capsaicin reverted the actions of Wy14643 on self-administration, similar to the OEA-induced effects.

CONCLUSION AND CLINICAL RELEVANCE: THE HOMEOSTATIC ROLE OF OEA IN ALCOHOL ABUSE

Data presented in this review indicate that OEA has a beneficial role to counteract many responses related to alcohol consumption and abuse, so OEA-based pharmacotherapies emerge as future perspectives to treat AUDs.

In particular, there is strong evidence that endogenous OEA is released as counteracted response to alcohol abuse. First of all, animal studies showed that acute i.p. administrations of ethanol induce a rapid release of OEA (in 45–90 min) in the small intestine, the liver, and also in brain areas such as the nucleus accumbens and cerebellum. Elevations of OEA in plasma after alcohol i.p. administration occurred in an interval of 90–240 min, parallel to the time in which blood alcohol levels are elevated after the administration. Chronic alcohol consumption maintains elevated levels of OEA in plasma during the alcohol liquid diet that remains elevated in the period in which blood ethanol levels are detectable (6 h of withdrawal approximately). Thus, the presence of OEA in blood persisted, at least, as long as the ethanol is also present, and starts to decrease after removing alcohol (Ferrer et al., 2007; Bilbao et al., 2016), strengthening the homeostatic role of OEA in the organism.

Secondly, results in animals are in agreement with recent studies in alcohol-dependent patients. OEA concentration was found elevated during early abstinence in those patients relative to controls, and the concentration of OEA was gradually decreasing as advanced the duration of abstinence, approaching the control group (Garcia-Marchena et al., 2016). Thus, OEA plasma levels were negatively correlated to the duration of abstinence, suggesting that OEA may serve also as a potential marker to predict length of alcohol abstinence.

Thirdly, human studies revealed that OEA is released after different patterns of alcohol or cocaine abuse, and correlates with inflammatory markers. For example, regular alcohol binge drinkers showed during abstinence elevated plasma levels of OEA and other related biolipids, compared with little or no drinkers (Antón et al., 2018). These elevated levels of OEA correlate with key peripheral inflammatory makers found in these young drinkers, such as the innate immunity receptors TLR4, pro-inflammatory cytokines IL-1β and IL-6, or pro-inflammatory enzyme COX-2 (Orio et al., 2017; Antón et al., 2018). Higher plasma HMBG1 and other pro-inflammatory cytokines correlate with worse scores on episodic memory and executive functioning task in female regular binge drinkers and, interestingly, that increase in the danger-related molecule HMGB1 correlates also with OEA plasma levels in such female binge drinkers (Antón et al., 2017b), in favor of the mentioned homeostatic role of OEA. In summary, preclinical and clinical evidence point-out to the beneficial actions of OEA to treat many negative aspects of alcohol abuse, including neuroinflammation, cognitive decline, withdrawal responses, or motivation and relapse to drinking. OEA-based pharmacotherapies emerge as future perspectives to treat AUDs.

OEA Reference (downloadable):

 

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