Moderate blood alcohol and brain neurovulnerability: Selective depletion of calcium‐independent phospholipase A2, omega‐3 docosahexaenoic acid, and its synaptamide derivative as a potential harbinger of deficits in anti‐inflammatory reserve. (16th November 2021)

• Record Type: Journal Article
• Authors: Schreiber, Jennifer A.; Tajuddin, Nuzhath F.; Kouzoukas, Dimitrios E.; Kevala, Karl; Kim, Hee‐Yong; Collins, Michael A.
• Is Part Of: Alcoholism. Volume 45:Number 12(2021)
• Page Start: 2506
• Page End: 2517
• Publication Date: 2021-11-16
• Subjects: arachidonic acid -- docosahexaenoic acid -- ethanol -- neurodegeneration -- neuroinflammation -- phospholipase A2; Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.14734
• Languages: English
• ISSNs: 0145-6008

Abstract

Abstract: Background: Repetitive, highly elevated blood alcohol (ethanol) concentrations (BACs) of 350 to 450 mg/dl over several days cause brain neurodegeneration and coincident neuroinflammation in adult rats localized in the hippocampus (HC), temporal cortex (especially the entorhinal cortex; ECX), and olfactory bulb (OB). The profuse neuroinflammation involves microgliosis, increased proinflammatory cytokines, and elevations of Ca +2 ‐dependent phospholipase A2 (cPLA2) and secretory PLA2 (sPLA2), which both mobilize proinflammatory ω‐6 arachidonic acid (ARA). In contrast, Ca +2 ‐independent PLA2 (iPLA2) and anti‐inflammatory ω‐3 docosahexaenoic acid (DHA), a polyunsaturated fatty acid regulated primarily by iPLA2, are diminished. Furthermore, supplemented DHA exerts neuroprotection. Given uncertainties about the possible effects of lower circulating BACs that are common occurring during short‐ term binges, we examined how moderate BACs affected the above inflammatory events, and the impact of supplemented DHA. Methods and results: Young adult male rats sustaining upper‐moderate BACs (~150 mg/dl) from once‐daily alcohol intubations were sacrificed with appropriate controls after 1 week. The HC, ECX and OB were quantitatively examined using immunoblotting, neurodegeneration staining, and lipidomics assays. Whereas neurodegeneration, increases in cPLA2 IVA, sPLA2 IIA, and ARA, and microglial activation were not detected, the HC and ECX regions demonstrated significantly reduced iPLA2 levels. Levels of DHA and synaptamide, its anti‐inflammatory N‐docosahexaenoylethanolamide derivative, also were lower in HC, and DHA supplementation prevented the iPLA2 decrements in HC. Additionally, adult mice maintaining upper‐moderate BACs from limited alcohol binges had reduced midbrain iPLA2 levels. Conclusions: The apparently selective depletion by moderate BACs of the metabolically linked anti‐inflammatory triad of hippocampal iPLA2, DHA, and synaptamide, and of iPLA2 in the ECX, potentially indicates an unappreciated deficit in brain anti‐inflammatory reserve that may be a harbinger of regional neurovulnerability. Abstract : Animal studies have shown that highly elevated BACs from severe repetitive binges promote multiple neuroinflammatory processes and neuronal death in hippocampus, entorhinal cortex and olfactory bulb. Here we report that more moderate, non‐neurotoxic binge BACs selectively deplete an anti‐inflammatory hippocampal pathway involving Ca 2+ ‐independent phospholipase A2, omega‐3 docosahexaenoic acid (DHA), and the novel cannabinoidal DHA derivative, synaptamide. Reduction of this suspected neuroprotective triad could be a harbinger of future brain damage by high BACs. However, DHA supplementation is partially restorative.