PARP Inhibition Prevents Ethanol-Induced Neuroinflammatory Signaling and Neurodegeneration in Rat Adult-Age Brain Slice Cultures Journal Article

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Authors: Tajuddin, N.; Kim, H. Y.; Collins, M. A.
Article Title: PARP Inhibition Prevents Ethanol-Induced Neuroinflammatory Signaling and Neurodegeneration in Rat Adult-Age Brain Slice Cultures
Abstract: Using rat adult-age hippocampal-entorhinal cortical (HEC) slice cultures, we examined the role of poly [ADP-ribose] polymerase (PARP) in binge ethanol#39;s brain inflammatory and neurodegenerative mechanisms. Activated by DNA strand breaks, PARP (principally PARP1 in the brain) promotes DNA repair via poly [ADP-ribose] (PAR) products, but PARP overactivation triggers regulated neuronal necrosis (e.g., parthanatos). Previously, we found that brain PARP1 levels were upregulated by neurotoxic ethanol binges in adult rats and HEC slices, and PARP inhibitor PJ34 abrogated slice neurodegeneration. Binged HEC slices also exhibited increased Ca(+2)-dependent phospholipase A2 (PLA2) isoenzymes (cPLA2 IVA and sPLA2 IIA) that mobilize proinflammatory omega6 arachidonic acid (ARA). We now find in 4-day-binged HEC slice cultures (100 mM ethanol) that PARP1 elevations after two overnight binges precede PAR, cPLA2, and sPLA2 enhancements by 1 day and high-mobility group box-1 (HMGB1), an ethanol-responsive alarmin that augments proinflammatory cytokines via toll-like receptor-4 (TLR4), by 2 days. After verifying that PJ34 effectively blocks PARP activity ( upward arrowPAR), we demonstrated that, like PJ34, three other PARP inhibitors-olaparib, veliparib, and 4-aminobenzamide-provided neuroprotection from ethanol. Importantly, PJ34 and olaparib also prevented ethanol#39;s amplification of the PLA2 isoenzymes, and two PLA2 inhibitors were neuroprotective-thus coupling PARP to PLA2, with PLA2 activity promoting neurodegeneration. Also, PJ34 and olaparib blocked ethanol-induced HMGB1 elevations, linking brain PARP induction to TLR4 activation. The results provide evidence in adult brains that induction of PARP1 may mediate dual neuroinflammatory pathways (PLA2--gt;phospholipid--gt;ARA and HMGB1--gt;TLR4--gt;proinflammatory cytokines) that are complicit in binge ethanol-induced neurodegeneration.
Journal Title: The Journal of pharmacology and experimental therapeutics
Volume: 365
Issue: 1
ISSN: 1521-0103; 0022-3565
Publisher: Unknown  
Journal Place: United States
Date Published: 2018
Start Page: 117
End Page: 126
Language: eng
DOI/URL:

10.1124/jpet.117.245290
Notes: LR: 20180402; CI: U.S. Government work not protected by U.S. copyright.; GR: U01 AA018279/AA/NIAAA NIH HHS/United States; JID: 0376362; 2017/09/22 00:00 [received]; 2017/12/13 00:00 [accepted]; 2018/01/18 06:00 [pubmed]; 2018/01/18 06:00 [medline]; 2018/01/18 06:00 [entrez]; ppublish