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

Aims: Although alcohol drinking impairs the blood–brainbarrier (BBB), the underlying mechanism is not fully understood.Thus, the effects of chronic ethanol drinking on the BBB werestudied in vivo. Methods: Alcohol-preferring rats were givenfor 70 days free choice water and 15% ethanol. Then, they receivedLPS by i.p. injection. Efflux of [¹⁴C]sucrose or [¹⁴C]dextranwas measured by their microinjection into the brain. Endothelialcells and neurons were isolated from the brain and analysedfor mitogen-activated protein kinase (MAPK) and the tight-junction(TJ) protein phosphorylation, NFB activation, mRNA levels ofTJ proteins, inducible nitric oxide synthase, tumour necrosisfactor , 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 lastingincrease in [¹⁴C]sucrose and [¹⁴C]dextran efflux in ethanol-drinkingrats. 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 inthe 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 ratsdid not exhibit apoptosis. Conclusions: LPS injection in WC-LPSrats transiently disrupted the BBB. Lack of JNK activation andCASPASE-8 may be responsible for lack of apoptosis in endothelialcells and vice versa in neurons. Chronic alcohol drinking inethanol drinking and LPS (Et-LPS) rats augmented and dysregulatedthe LPS-induced BBB abnormalities but suppressed apoptosis inneurons.