title: Neuroinflammatory pathways in binge alcohol-induced neuronal degeneration: oxidative stress cascade involving aquaporin, brain edema, and phospholipase A2 activation.
abstract: Chronic binge alcohol exposure in adult rat models causes neuronal degeneration in the cortex and hippocampus that is not reduced by excitotoxic receptor antagonists, but is prevented by antioxidants. Neuroinflammatory (glial-neuronal) signaling pathways are believed to underlie the oxidative stress and brain damage. Based on our experimental results as well as increased knowledge about the pro-neuroinflammatory potential of glial water channels, we propose that induction of aquaporin-4 can be a critical initiating factor in alcohol's neurotoxic effects, through the instigation of cellular edema-based neuroinflammatory cascades involving increased phospholipase A2 activities, polyunsaturated fatty acid release/membrane depletion, decreased prosurvival signaling, and oxidative stress. A testable scheme for this pathway is presented that incorporates recent findings in the alcohol-brain literature indicating a role for neuroimmune activation (upregulation of NF-kappaB, proinflammatory cytokines, and toll-like receptors). We present the argument that such neuroimmune activation could be associated with or even dependent on increased aquaporin-4 and glial swelling as well.
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Stritch School of Medicine, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA. mcollin@lumc.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Collins
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Neafsey
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism*; D001929:Brain Edema / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000431:Ethanol / Q000633:toxicity*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D054467:Phospholipases A2 / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
chemical_list: D051401:Aquaporin 4; D000431:Ethanol; D054467:Phospholipases A2