Moderate blood alcohol and brain neurovulnerability: Selective depletion of calcium-independent PLA2, omega-3 docosahexaenoic acid and its synaptamide derivative as a potential harbinger of deficits in anti-inflammatory reserve. Journal Article

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Authors: Schreiber, JA; Tajuddin, NF; Kouzoukas, DE; Kevala, K; Kim, HY; Collins, MA
Article Title: Moderate blood alcohol and brain neurovulnerability: Selective depletion of calcium-independent PLA2, omega-3 docosahexaenoic acid and its synaptamide derivative as a potential harbinger of deficits in anti-inflammatory reserve.
Abstract: BACKGROUND: Repetitive, highly elevated blood alcohol (ethanol) concentrations (BACs) of 350-450 mg/dl over several days cause brain neurodegeneration and coincident neuroinflammation in adult rats that is localized in hippocampus (HC), temporal cortex (esp. entorhinal cortex; ECX), and olfactory bulb (OB). The profuse neuroinflammation involves microgliosis, increased pro-inflammatory cytokines, and elevations of Ca -dependent phospholipase A2 (cPLA2) and secretory PLA2 (sPLA2) that both mobilize pro-inflammatory ?-6 arachidonic acid (ARA). In contrast, Ca -independent PLA2 (iPLA2) and anti-inflammatory ?-3 docosahexaenoic acid (DHA), a polyunsaturated fatty acid believed to be primarily regulated by iPLA2, are diminished. Furthermore, supplemented DHA exerts neuroprotection. Given uncertainties about possible effects of relatively common lower circulating levels 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 one 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, as well as of iPLA2 in the ECX, potentially indicates an unrecognized deficit in brain anti-inflammatory reserve that may be a harbinger of regional neurovulnerability.
Journal Title: Alcoholism, Clinical and Experimental Research
ISSN: 1530-0277; 0145-6008
Publisher: Unknown  
Date Published: 2021