Alcohol, phospholipase A2-associated neuroinflammation, and ω3 docosahexaenoic acid protection.
Chronic alcohol (ethanol) abuse causes neuroinflammation and brain damage that can give rise to alcoholic dementia. Insightfully, Dr. Albert Sun was an early proponent of oxidative stress as a key factor in alcoholism-related brain deterioration. In fact, oxidative stress has proven to be critical to the hippocampal and temporal cortical neurodamage resulting from repetitive "binge" alcohol exposure in adult rat models. Although the underlying mechanisms are uncertain, our immunoelectrophoretic and related assays in binge alcohol experiments in vivo (adult male rats) and in vitro (rat organotypic hippocampal-entorhinal cortical slice cultures) have implicated phospholipase A(2) (PLA(2))-activated neuroinflammatory pathways, release of pro-oxidative arachidonic acid (20:4 ω6), and elevated oxidative stress adducts (i.e., 4-hydroxynonenal-protein adducts). Also, significantly increased by the binge alcohol treatments was aquaporin-4 (AQP4), a water channel enriched in astrocytes that, when augmented, may trigger brain (esp. cellular) edema and neuroinflammation; of relevance, glial swelling is known to provoke increased PLA(2) activities or levels. Concomitant with PLA(2) activation, the results have further implicated binge alcohol-elevated poly (ADP-ribose) polymerase-1 (PARP-1), an oxidative stress-responsive DNA repair enzyme linked to parthanatos, a necrotic-like neuronal death process. Importantly, supplementation of the brain slice cultures with docosahexaenoic acid (22:6 ω3) exerted potent suppression of the induced changes in PLA(2) isoforms, AQP4, PARP-1 and oxidative stress footprints, and prevention of the binge alcohol neurotoxicity, by as yet unknown mechanisms. These neuroinflammatory findings from our binge alcohol studies and supportive rat binge studies in the literature are reviewed.
Department of Molecular Pharmacology & Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, 60153, USA, mcollin@lumc.edu.
Michael A
MA
Collins
Nuzhath
N
Tajuddin
Kwan-Hoon
KH
Moon
Hee-Yong
HY
Kim
Kimberly
K
Nixon
Edward J
EJ
Neafsey
D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D000431:Ethanol; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D054467:Phospholipases A2 / Q000378:metabolism*; D051381:Rats
D051401:Aquaporin 4; D004281:Docosahexaenoic Acids; D000431:Ethanol; D054467:Phospholipases A2