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.
Highlights
CONCEPTUALIZATION OF NEUROINFLAMMATION AND ITS RELATIONSHIPS WITH NEUROPSYCHIATRIC DISORDERSFramework for Neuroinflammation in central nervous system (CNS) PathologiesImmunopsychiatry is a renewed biomedical discipline in continuous expansion that studies the interaction/s between the brain and the immune system
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 alcohol-use disorders (AUDs)
In line with the results presented in this review, OEA can be considered as an endogenous signal with a homeostatic role in the organism
Summary
Immunopsychiatry is a renewed biomedical discipline in continuous expansion that studies the interaction/s between the brain and the immune system. It is aimed to find new molecular/cellular targets for the development of original therapies for the treatment of psychiatric disorders (Pariante, 2015; Khandaker et al, 2017) It is based on increasing evidences from both preclinical and clinical studies supporting the existence of a “low grade” neuroinflammatory response with relevance in the etiophysiopathology of psychiatric disorders [recently reviewed in Bauer and Teixeira (2018)]. In particular cases such as schizophrenia and other psychotic diseases, this neuroinflammation has been demonstrated by means of brain postmortem evidence and imaging techniques, some authors have alerted about the need for more selective markers of glial activation and the combination with diverse methodologies at molecular/cellular level (Trepanier et al, 2016; Notter et al, 2018). All these alterations can even affect other multifaceted processes, such as monoaminergic and glutamatergic neurotransmission (Ogyu et al, 2018), neuroendocrine responses (Pariante, 2017), cognition (Skaper et al, 2014), and behavior (Dantzer et al, 2008; McCusker and Kelley, 2013)
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