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- W2783304412 abstract "Using rat adult-age hippocampal-entorhinal cortical (HEC) slice cultures, we examined the role of poly [ADP-ribose] polymerase (PARP) in binge ethanol'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 ω6 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 (↑PAR), 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'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→phospholipid→ARA and HMGB1→TLR4→proinflammatory cytokines) that are complicit in binge ethanol-induced neurodegeneration." @default.
- W2783304412 created "2018-01-26" @default.
- W2783304412 creator A5021439072 @default.
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- W2783304412 date "2018-01-16" @default.
- W2783304412 modified "2023-10-14" @default.
- W2783304412 title "PARP Inhibition Prevents Ethanol-Induced Neuroinflammatory Signaling and Neurodegeneration in Rat Adult-Age Brain Slice Cultures" @default.
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- W2783304412 doi "https://doi.org/10.1124/jpet.117.245290" @default.
- W2783304412 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5830636" @default.
- W2783304412 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29339456" @default.
- W2783304412 hasPublicationYear "2018" @default.
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