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EFFECTS OF CHRONIC ETHANOL DRINKING ON THE BLOOD–BRAIN BARRIER AND ENSUING NEURONAL TOXICITY IN AL

EFFECTS OF CHRONIC ETHANOL DRINKING ON THE BLOOD–BRAIN BARRIER AND ENSUING NEURONAL TOXICITY IN AL

  1. YIPMAN
    Alcohol & Alcoholism Vol. 42, No. 5, pp. 385–399, 2007 | doi:10.1093/alcalc/agl120
    Advance Access publication 6 March 2007

    EFFECTS OF CHRONIC ETHANOL DRINKING ON THE BLOOD–BRAIN BARRIER AND ENSUING NEURONAL TOXICITY IN ALCOHOL-PREFERRING RATS SUBJECTED TO INTRAPERITONEAL LPS INJECTION

    ASHOK K SINGH*, YIN JIANG, SHVETA GUPTA and ELHABIB BENLHABIB

    Department of Veterinary Population Medicine, University of Minnesota, Twin Cities Campus, St Paul, MN 55108, USA

    (Received 10 October 2006; in revised form 6 December 2006; accepted 8 December 2006; advance access publication 6 March 2007)

    Abstract — Aims: Although alcohol drinking impairs the blood–brain barrier (BBB), the underlying mechanism is not fully understood. Thus, the effects of chronic ethanol drinking on the BBB were studied in vivo.

    Methods: Alcohol-preferring rats were given for 70 days free choice water and 15% ethanol. Then, they received LPS by i.p. injection. Efflux of [14C]sucrose or [14C]dextran was measured by their microinjection into the brain. Endothelial cells and neurons were isolated from the brain and analysed for mitogen-activated protein kinase (MAPK) and the tight-junction (TJ) protein phosphorylation, NFkB activation, mRNA levels of TJ proteins, inducible nitric oxide synthase, tumour necrosis factor a, interleukin-1 b (IL-1b), IL-10, CASPASE-8, and DNA damage.

    Results: LPS transiently increased [14C]sucrose efflux in water drinking, while it caused a lasting increase in [14C]sucrose and [14C]dextran efflux in ethanol-drinking rats. The time-course of changes in the TJ correlated with (i) an increase in extracellular signal-regulated kinase (ERK), p38mapk Jun-N-terminal Kinase (JNK), and TJ protein phosphorylation, (ii) RelA-p50 and p50-p50 activation, and (iii) a decrease in the TJ proteins’ mRNA levels in endothelial cells and neurons. Apoptotic cells were detected in water drinking and LPS (WC-LPS) neurons at 24 h after LPS exposure. Neurons from Et-LPS rats did not exhibit apoptosis.

    Conclusions: LPS injection in WC-LPS rats transiently disrupted the BBB. Lack of JNK activation and CASPASE-8 may be responsible for lack of apoptosis in endothelial cells and vice versa in neurons. Chronic alcohol drinking in ethanol drinking and LPS (Et-LPS) rats augmented and dysregulated the LPS-induced BBB abnormalities but suppressed apoptosis in neurons.