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Alcohol Alcohol. 2007 Sep-Oct;42(5):385-99. Epub 2007 Mar 6.

Effects of chronic ethanol drinking on the blood brain barrier and ensuing neuronal toxicity in alcohol-preferring rats subjected to intraperitoneal LPS injection.

Author information

1
Department of Population Diagnostic Medicine, College of Veterinary Medicine, University of Minnesota-Twin Cities Campus, 1333 Gortner Avenue, St Paul, MN 55108, USA. singh001@umn.edu

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 [(14)C]sucrose or [(14)C]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, NFkappaB activation, mRNA levels of TJ proteins, inducible nitric oxide synthase, tumour necrosis factor alpha, interleukin-1 beta (IL-1beta), IL-10, CASPASE-8, and DNA damage.

RESULTS:

LPS transiently increased [(14)C]sucrose efflux in water drinking, while it caused a lasting increase in [(14)C]sucrose and [(14)C]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), p38(mapk) 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.

PMID:
17341516
DOI:
10.1093/alcalc/agl120
[Indexed for MEDLINE]

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