title: Toll-like receptor 4 participates in the myelin disruptions associated with chronic alcohol abuse.
abstract: Alcohol abuse and alcoholism can cause brain damage, loss of white matter, myelin fiber disruption, and even neuronal injury. The underlying mechanisms of these alterations remain elusive. We have shown that chronic ethanol intake, by activating glial toll-like receptor 4 (TLR4) receptors, triggers the production of inflammatory mediators and can cause brain damage. Because neuroinflammation may be associated with demyelination and neuronal damage, we evaluate whether the ethanol-induced TLR4-dependent proinflammatory environment in the brain could be involved in the myelin disruptions observed in alcoholics. Using brains from wild-type (WT) and TLR4 knockout (KO, TLR4(-/-) ) mice, we demonstrate that chronic ethanol treatment downregulated proteins involved in myelination [proteolipid protein (PLP), myelin basic protein (MBP), myelin-oligodendrocyte glycoprotein, 2,3-cyclic-nucleotide-3-phosphodiesterase, and myelin-associated glycoprotein], while increased chondroitin sulfate proteoglycan NG2 (NG2)-proteoglycan in several brain regions of ethanol-treated WT mice. The immunohistochemistry analysis also revealed that ethanol-treatment-altered myelin morphology reduced the number of MBP-positive fibers and caused oligodendrocyte death, as demonstrated by an increase in caspase-3-positive oligodendrocytes. The in vivo imaging system further confirmed that chronic ethanol intake markedly reduced the PLP in WT mice. Most myelin alterations were not observed in brains from ethanol-treated TLR4(-/-) mice. Electron microscopy studies revealed that although 41-47% of axons showed myelin sheath disarrangements in the cerebral cortex and corpus callosum of WT ethanol-treated mice, respectively, small focal fiber disruptions were noticed in these brain areas of ethanol-treated TLR4(-/-) mice. In summary, the present results suggest that ethanol-induced neuroinflammation might be involved in myelin disruptions and white matter loss observed in human alcoholics.
authors.affiliation: Department of Cellular Pathology, Príncipe Felipe Research Centre, Avda. Autopista del Saler 16, Valencia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Alfonso-Loeches
authors.forename: Maria
authors.initials: M
authors.lastname: Pascual
authors.forename: Ulises
authors.initials: U
authors.lastname: Gómez-Pinedo
authors.forename: Maya
authors.initials: M
authors.lastname: Pascual-Lucas
authors.forename: Jaime
authors.initials: J
authors.lastname: Renau-Piqueras
authors.forename: Consuelo
authors.initials: C
authors.lastname: Guerri
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000437:Alcoholism / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D000941:Antigens / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D007211:Indoles; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D009836:Oligodendroglia / Q000473:pathology; D009930:Organic Chemicals; D011509:Proteoglycans / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism*; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D000941:Antigens; D053148:Caspase 3; D002492:Central Nervous System Depressants; D000431:Ethanol; D005452:Fluoresceins; D007211:Indoles; D009185:Myelin Proteins; D009930:Organic Chemicals; D011509:Proteoglycans; D051197:Toll-Like Receptor 4; D000099216:Chondroitin Sulfate Proteoglycan 4; C493487:Tlr4 protein, mouse; C435731:fluoro jade; C018588:Luxol Fast Blue MBS