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Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: Findings in preclinical models and in a postmortem human case

Wernicke’s encephalopathy (WE) is a neurologic disease caused by vitamin B1 or thiamine deficiency (TD), being the alcohol use disorder its main risk factor. WE patients present limiting motor, cognitive, and emotional alterations related to a selective cerebral vulnerability. Neuroinflammation has...

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Autores principales: Moya, Marta, Escudero, Berta, Gómez-Blázquez, Elena, Rebolledo-Poves, Ana Belen, López-Gallardo, Meritxell, Guerrero, Carmen, Marco, Eva M., Orio, Laura
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9549119/
https://www.ncbi.nlm.nih.gov/pubmed/36225571
http://dx.doi.org/10.3389/fphar.2022.866574
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author Moya, Marta
Escudero, Berta
Gómez-Blázquez, Elena
Rebolledo-Poves, Ana Belen
López-Gallardo, Meritxell
Guerrero, Carmen
Marco, Eva M.
Orio, Laura
author_facet Moya, Marta
Escudero, Berta
Gómez-Blázquez, Elena
Rebolledo-Poves, Ana Belen
López-Gallardo, Meritxell
Guerrero, Carmen
Marco, Eva M.
Orio, Laura
author_sort Moya, Marta
collection PubMed
description Wernicke’s encephalopathy (WE) is a neurologic disease caused by vitamin B1 or thiamine deficiency (TD), being the alcohol use disorder its main risk factor. WE patients present limiting motor, cognitive, and emotional alterations related to a selective cerebral vulnerability. Neuroinflammation has been proposed to be one of the phenomena that contribute to brain damage. Our previous studies provide evidence for the involvement of the innate immune receptor Toll-like (TLR)4 in the inflammatory response induced in the frontal cortex and cerebellum in TD animal models (animals fed with TD diet [TDD] and receiving pyrithiamine). Nevertheless, the effects of the combination of chronic alcohol consumption and TD on TLR4 and their specific contribution to the pathogenesis of WE are currently unknown. In addition, no studies on TLR4 have been conducted on WE patients since brains from these patients are difficult to achieve. Here, we used rat models of chronic alcohol (CA; 9 months of forced consumption of 20% (w/v) alcohol), TD hit (TDD + daily 0.25 mg/kg i.p. pyrithiamine during 12 days), or combined treatment (CA + TDD) to check the activation of the proinflammatory TLR4/MyD88 pathway and related markers in the frontal cortex and the cerebellum. In addition, we characterized for the first time the TLR4 and its coreceptor MyD88 signature, along with other markers of this proinflammatory signaling such as phospo-NFκB p65 and IκBα, in the postmortem human frontal cortex and cerebellum (gray and white matter) of an alcohol-induced WE patient, comparing it with negative (no disease) and positive (aged brain with Alzheimer’s disease) control subjects for neuroinflammation. We found an increase in the cortical TLR4 and its adaptor molecule MyD88, together with an upregulation of the proinflammatory signaling molecules p-NF-ĸB and IĸBα in the CA + TDD animal model. In the patient diagnosed with alcohol-induced WE, we observed cortical and cerebellar upregulation of the TLR4/MyD88 pathway. Hence, our findings provide evidence, both in the animal model and the human postmortem brain, of the upregulation of the TLR4/MyD88 proinflammatory pathway in alcohol consumption–related WE.
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spelling pubmed-95491192022-10-11 Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: Findings in preclinical models and in a postmortem human case Moya, Marta Escudero, Berta Gómez-Blázquez, Elena Rebolledo-Poves, Ana Belen López-Gallardo, Meritxell Guerrero, Carmen Marco, Eva M. Orio, Laura Front Pharmacol Pharmacology Wernicke’s encephalopathy (WE) is a neurologic disease caused by vitamin B1 or thiamine deficiency (TD), being the alcohol use disorder its main risk factor. WE patients present limiting motor, cognitive, and emotional alterations related to a selective cerebral vulnerability. Neuroinflammation has been proposed to be one of the phenomena that contribute to brain damage. Our previous studies provide evidence for the involvement of the innate immune receptor Toll-like (TLR)4 in the inflammatory response induced in the frontal cortex and cerebellum in TD animal models (animals fed with TD diet [TDD] and receiving pyrithiamine). Nevertheless, the effects of the combination of chronic alcohol consumption and TD on TLR4 and their specific contribution to the pathogenesis of WE are currently unknown. In addition, no studies on TLR4 have been conducted on WE patients since brains from these patients are difficult to achieve. Here, we used rat models of chronic alcohol (CA; 9 months of forced consumption of 20% (w/v) alcohol), TD hit (TDD + daily 0.25 mg/kg i.p. pyrithiamine during 12 days), or combined treatment (CA + TDD) to check the activation of the proinflammatory TLR4/MyD88 pathway and related markers in the frontal cortex and the cerebellum. In addition, we characterized for the first time the TLR4 and its coreceptor MyD88 signature, along with other markers of this proinflammatory signaling such as phospo-NFκB p65 and IκBα, in the postmortem human frontal cortex and cerebellum (gray and white matter) of an alcohol-induced WE patient, comparing it with negative (no disease) and positive (aged brain with Alzheimer’s disease) control subjects for neuroinflammation. We found an increase in the cortical TLR4 and its adaptor molecule MyD88, together with an upregulation of the proinflammatory signaling molecules p-NF-ĸB and IĸBα in the CA + TDD animal model. In the patient diagnosed with alcohol-induced WE, we observed cortical and cerebellar upregulation of the TLR4/MyD88 pathway. Hence, our findings provide evidence, both in the animal model and the human postmortem brain, of the upregulation of the TLR4/MyD88 proinflammatory pathway in alcohol consumption–related WE. Frontiers Media S.A. 2022-09-26 /pmc/articles/PMC9549119/ /pubmed/36225571 http://dx.doi.org/10.3389/fphar.2022.866574 Text en Copyright © 2022 Moya, Escudero, Gómez-Blázquez, Rebolledo-Poves, López-Gallardo, Guerrero, Marco and Orio. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Moya, Marta
Escudero, Berta
Gómez-Blázquez, Elena
Rebolledo-Poves, Ana Belen
López-Gallardo, Meritxell
Guerrero, Carmen
Marco, Eva M.
Orio, Laura
Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: Findings in preclinical models and in a postmortem human case
title Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: Findings in preclinical models and in a postmortem human case
title_full Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: Findings in preclinical models and in a postmortem human case
title_fullStr Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: Findings in preclinical models and in a postmortem human case
title_full_unstemmed Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: Findings in preclinical models and in a postmortem human case
title_short Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: Findings in preclinical models and in a postmortem human case
title_sort upregulation of tlr4/myd88 pathway in alcohol-induced wernicke’s encephalopathy: findings in preclinical models and in a postmortem human case
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9549119/
https://www.ncbi.nlm.nih.gov/pubmed/36225571
http://dx.doi.org/10.3389/fphar.2022.866574
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