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

Aims: Although alcohol drinking impairs the bloodbrain 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 [C-14]sucrose or [C-14]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, NFB activation, mRNA levels of TJ proteins, inducible nitric oxide synthase, tumour necrosis factor , interleukin-1 beta(IL-1 beta), IL-10, CASPASE-8, and DNA damage. Results: LPS transiently increased [C-14]sucrose efflux in water drinking, while it caused a lasting increase in [C-14]sucrose and [C-14]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. Conclusion: 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.