Disinhibited-Like Behavior Correlates With Frontal Cortex Damage in Alcohol-Induced Wernicke-Korsakoff Syndrome

Moya, Marta; López-Valencia, Leticia; García‐Bueno, Borja; Orío, Laura

doi:10.20944/preprints202111.0484.v1

Cited by 1 publication

(8 citation statements)

References 49 publications

(66 reference statements)

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“…However, since the main documented cause of WE is alcohol consumption, it is needed to explore more complex animal models, in which we can combine TD and CA consumption and explore the specific contribution of each factor to the pathophysiology of the disease. Indeed, in a very recent publication of our group we described the contribution of both factors (TD and alcohol abuse) to the induction of neuronal damage in the frontal cortex and how the combination of both (CA + TDD) correlates with Frontiers in Pharmacology frontiersin.org disinhibition-like behavior in animals (Moya et al, 2022), which is a core symptom of the pathology. Likewise, in the present study, we used the same combined animal models to explore the specific role of TLR4 in the induction of a neuroinflammatory cascade in the frontal cortex and cerebellum and added the description of the TLR4/MyD88 upregulation in the postmortem brain of an alcohol-induced WE case.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma thiamine levels were measured in all animals in our study. In brief, after 9 months of alcohol exposure and after TDD treatment, we found a trend toward a decrease in total thiamine levels due to an alcohol effect [for detailed results see (Moya et al, 2022)].…”

Section: Thiamine Levelsmentioning

confidence: 98%

“…The experimental design and all the procedures of this animal study are described in detail and can be viewed in Moya et al (2022).…”

Section: Experimental Groupsmentioning

confidence: 99%

“…Frontal cortex and cerebellar hemisphere samples were processed and analyzed using western blotting following the methodology previously detailed in Moya et al (2022).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…However, some authors pointed out the presence of damage in other structures less studied in this pathology, such as the frontal cortex (Jacobson and Lishman, 1990;Jernigan et al, 1991;Paller et al, 1997;Aupée et al, 2001;Gibson et al, 2016) and the cerebellum (Mulholland, 2006;Manzo et al, 2014). In our previous preclinical studies about WE, we selected these less studied frontal cortex and cerebellum (Moya et al, 2021(Moya et al, , 2022 as structures of great interest to be investigated, since both participate in motor function control, cognition, and emotional responses (Baillieux et al, 2008;Molinari et al, 2008;Rudebeck et al, 2008;Leggio et al, 2011;Clausi et al, 2017). Indeed, the frontal cortex is particularly important in executive control tasks and behavioral inhibition, including cognitive processes, social behavior, and inhibition of motor responses.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2022

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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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Section: Discussionmentioning

confidence: 99%

Section: Thiamine Levelsmentioning

confidence: 98%

“…The experimental design and all the procedures of this animal study are described in detail and can be viewed in Moya et al (2022).…”

Section: Experimental Groupsmentioning

confidence: 99%

“…Frontal cortex and cerebellar hemisphere samples were processed and analyzed using western blotting following the methodology previously detailed in Moya et al (2022).…”

Section: Western Blot Analysismentioning

confidence: 99%