Oleoylethanolamide prevents neuroimmune HMGB1/TLR4/NF‐kB danger signaling in rat frontal cortex and depressive‐like behavior induced by ethanol binge administration

• Published in: Addiction biology Vol. 22; no. 3; pp. 724 - 741
• Main Authors: Antón, María, Alén, Francisco, Gómez de Heras, Raquel, Serrano, Antonia, Pavón, Francisco Javier, Leza, Juan Carlos, García‐Bueno, Borja, Rodríguez de Fonseca, Fernando, Orio, Laura
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.05.2017
• Subjects: Alcohol binge; Animals; Binge Drinking - complications; Depressive Disorder - chemically induced; Depressive Disorder - prevention & control; Disease Models, Animal; Endocannabinoids - pharmacology; Ethanol - pharmacology; Frontal Lobe - drug effects; Frontal Lobe - metabolism; HMGB1; HMGB1 Protein - drug effects; HMGB1 Protein - genetics; HMGB1 Protein - metabolism; Male; Mice; Neuroimmunomodulation - drug effects; neuroinflammation; neuroprotection; NF-kappa B - drug effects; NF-kappa B - metabolism; Oleic Acids - pharmacology; oleoylethanolamide; Rats, Wistar; Signal Transduction - drug effects; TLR4; Toll-Like Receptor 4 - drug effects; Toll-Like Receptor 4 - metabolism; Alcohol binge; HMGB1; neuroinflammation; TLR4; neuroprotection; oleoylethanolamide
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.12365

Alcohol abuse is frequently characterized by a specific pattern of intake in binge drinking episodes, inducing neuroinflammation and brain damage. Here, we characterized the temporal profile of neuroinflammation in rats exposed to intragastric binge ethanol administrations (3 times/day × 4 days) and tested the anti‐inflammatory/neuroprotective properties of the satiety factor oleoylethanolamide (OEA). Pre‐treatment with OEA (5 mg/kg, i.p.) previous each alcohol gavage blocked the expression of high mobility group box 1 (HMGB1) danger signal and the innate immunity Toll‐like receptors 4 (TLR4) in frontal cortex, and inhibited the nuclear factor‐kappa B (NF‐kB) proinflammatory cascade induced by alcohol binge administration. OEA reduced the levels of interleukin‐1beta (IL‐1β), the monocyte chemoattractant protein‐1 (MCP‐1), and the enzymes cyclooxygenase‐2 (COX‐2) and inducible nitric oxide synthase (iNOS) in ethanol binged animals. Elevations in plasma tumor necrosis factor alpha (TNF‐α) and IL‐1β after ethanol were also inhibited by OEA. OEA also prevented ethanol‐induced lipid peroxidation, caspase‐8 and pro‐apoptotic caspase‐3 activation in frontal cortex. Additionally, OEA blocked the rise in blood corticosterone levels after ethanol with no alteration in blood ethanol levels and may affect ethanol‐induced gut permeability for endotoxin. Finally, OEA, administered as a pre‐treatment during the ethanol binge, exerted antidepressant‐like effects during acute withdrawal. Altogether, results highlight a beneficial profile of OEA as a potent anti‐inflammatory, antioxidant, neuroprotective and antidepressant‐like compound to treat alcohol abuse. In this study, we reported a beneficial role for the lipid oleoylethanolamide (OEA) to treat alcohol binge drinking because of its antiinflammatory, antioxidant, neuroprotective and antidepressant‐like effects. Pre‐treatment with OEA during binging episodes blocked the expression of HMGB1/TLR4 cell danger signaling and inhibited the nuclear factor‐kappa B‐related cascade of proinflammatory mediators, affording protection against ethanol‐induced lipid peroxidation and apoptosis in frontal cortex. Additionally, OEA blocked the rise in blood corticosterone induced by alcohol binge and had antidepressant‐like actions during early withdrawal.