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Because there is evidence that ethanol (EtOH) induces release of free radicals, cytokines and inflammatory mediators we examined BBB integrity and matrix metalloproteinase (MMP) activity in postmortem human alcoholic brain and investigated the role of TLR4 signaling in BBB permeability in TLR4\u2010knockout mice under a binge\u2010like EtOH drinking protocol.<\/jats:p><jats:p>Immunohistochemical studies showed reduced immunoreactivity of the basal lamina protein, collagen\u2010IV and of the tight junction protein, claudin\u20105 in dorsolateral prefrontal cortex of alcoholics. There was also increased MMP\u20109 activity and expression of phosphorylated ERK1\/2 and p\u201038. Greater number of CD45+ IR cells were observed associated with an enhanced neuroinflammatory response reflected by increased GFAP and Iba\u20101 immunostaining. To further explore effects of high EtOH consumption on BBB integrity we studied TLR4\u2010knockout mice exposed to the drinking in the dark paradigm. Repetitive EtOH exposure in wild\u2010type mice decreased hippocampal expression of laminin and collagen\u2010IV and increased IgG immunoreactivity, indicating IgG extravasation. Western blot analysis also revealed increased MyD88 and p\u2010ERK1\/2 levels. None of these changes was observed in TLR4\u2010knockout mice. Collectively, these findings indicate that chronic EtOH increases degradation of tight junctions and extracellular matrix in postmortem human brain and induces a neuroinflammatory response associated with activation of ERK1\/2 and p\u201038 and greater MMP\u20109 activity. The EtOH\u2010induced effects on BBB impairment are not evident in the hippocampus of TLR4\u2010knockout mice, suggesting the involvement of TLR4 signaling in the underlying mechanism leading to BBB disruption in mice.<\/jats:p>","DOI":"10.1111\/adb.12376","type":"journal-article","created":{"date-parts":[[2016,3,7]],"date-time":"2016-03-07T08:52:38Z","timestamp":1457340758000},"page":"1103-1116","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":117,"title":["Disruption of blood\u2013brain barrier integrity in postmortem alcoholic brain: preclinical evidence of TLR4 involvement from a binge\u2010like drinking model"],"prefix":"10.1111","volume":"22","author":[{"given":"Ana","family":"Rubio\u2010Araiz","sequence":"first","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Medicina Universidad Complutense, Instituto de Investigaci\u00f3n Sanitaria Hospital 12 de Octubre  Spain"},{"name":"Red de Trastornos 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