title: Neuroinflammation and neurodegeneration in adult rat brain from binge ethanol exposure: abrogation by docosahexaenoic acid.
abstract: Evidence that brain edema and aquaporin-4 (AQP4) water channels have roles in experimental binge ethanol-induced neurodegeneration has stimulated interest in swelling/edema-linked neuroinflammatory pathways leading to oxidative stress. We report here that neurotoxic binge ethanol exposure produces comparable significant effects in vivo and in vitro on adult rat brain levels of AQP4 as well as neuroinflammation-linked enzymes: key phospholipase A2 (PLA2) family members and poly (ADP-ribose) polymerase-1 (PARP-1). In adult male rats, repetitive ethanol intoxication (3 gavages/d for 4 d, ∼ 9 g/kg/d, achieving blood ethanol levels ∼ 375 mg/dl; "Majchrowicz" model) significantly increased AQP4, Ca+2-dependent PLA2 GIVA (cPLA2), phospho-cPLA2 GIVA (p-cPLA2), secretory PLA2 GIIA (sPLA2) and PARP-1 in regions incurring extensive neurodegeneration in this model--hippocampus, entorhinal cortex, and olfactory bulb--but not in two regions typically lacking neurodamage, frontal cortex and cerebellum. Also, ethanol reduced hippocampal Ca+2-independent PLA2 GVIA (iPLA2) levels and increased brain "oxidative stress footprints" (4-hydroxynonenal-adducted proteins). For in vitro studies, organotypic cultures of rat hippocampal-entorhinocortical slices of adult age (∼ 60 d) were ethanol-binged (100 mM or ∼ 450 mg/dl) for 4 d, which augments AQP4 and causes neurodegeneration (Collins et al. 2013). Reproducing the in vivo results, cPLA2, p-cPLA2, sPLA2 and PARP-1 were significantly elevated while iPLA2 was decreased. Furthermore, supplementation with docosahexaenoic acid (DHA; 22:6n-3), known to quell AQP4 and neurodegeneration in ethanol-treated slices, blocked PARP-1 and PLA2 changes while counteracting endogenous DHA reduction and increases in oxidative stress footprints (3-nitrotyrosinated proteins). Notably, the PARP-1 inhibitor PJ-34 suppressed binge ethanol-dependent neurodegeneration, indicating PARP upstream involvement. The results with corresponding models support involvement of AQP4- and PLA2-associated neuroinflammatory pro-oxidative pathways in the neurodamage, with potential regulation by PARP-1 as well. Furthermore, DHA emerges as an effective inhibitor of these binge ethanol-dependent neuroinflammatory pathways as well as associated neurodegeneration in adult-age brain.
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, United States of America.
authors.forename: Nuzhath
authors.initials: N
authors.lastname: Tajuddin
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, United States of America.
authors.forename: Kwan-Hoon
authors.initials: KH
authors.lastname: Moon
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: S Alex
authors.initials: SA
authors.lastname: Marshall
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Nixon
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, United States of America.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Neafsey
authors.affiliation: Laboratory of Molecular Signaling, NIAAA, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Hee-Yong
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Collins
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D018728:Entorhinal Cortex / Q000187:drug effects* / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D054467:Phospholipases A2 / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051401:Aquaporin 4; D004281:Docosahexaenoic Acids; D000431:Ethanol; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D054467:Phospholipases A2