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Alcohol and Alcoholism Advance Access originally published online on March 6, 2007
Alcohol and Alcoholism 2007 42(5):385-399; doi:10.1093/alcalc/agl120
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Copyright © The Author 2007. Published by Oxford University Press on behalf of the Medical Council on Alcohol.

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

* Author to whom correspondence should be addressed at: Department of Population Diagnostic Medicine, College of Veterinary Medicine, 1333 Gortner Av., St Paul, MN 55108, USA; Tel.: 01 612 625 6782; Fax: 01 612 624 8707; E-mail: singh001{at}umn.edu

Received 10 October 2006; first review notified 6 December 2006; ; accepted 8 December 2006


  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, NF{kappa}B activation, mRNA levels of TJ proteins, inducible nitric oxide synthase, tumour necrosis factor {alpha}, interleukin-1 ß (IL-1ß), 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.


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