Disinhibition-Like Behavior Correlates with Frontal Cortex Damage in an Animal Model of Chronic Alcohol Consumption and Thiamine Deficiency

Abstract

Wernicke–Korsakoff syndrome (WKS) is induced by thiamine deficiency (TD) and mainly related to alcohol consumption. Frontal cortex dysfunction has been associated with impulsivity and disinhibition in WKS patients. The pathophysiology involves oxidative stress, excitotoxicity and inflammatory responses leading to neuronal death, but the relative contributions of each factor (alcohol and TD, either isolated or in interaction) to these phenomena are still poorly understood. A rat model was used by forced consumption of 20% (w/v) alcohol for 9 months (CA), TD hit (TD diet + pyrithiamine 0.25 mg/kg, i.p. daily injections the last 12 days of experimentation (TDD)), and both combined treatments (CA+TDD). Motor and cognitive performance and cortical damage were examined. CA caused hyperlocomotion as a possible sensitization of ethanol-induced excitatory effects and recognition memory deficits. In addition, CA+TDD animals showed a disinhibited-like behavior which appeared to be dependent on TDD. Additionally, combined treatment led to more pronounced alterations in nitrosative stress, lipid peroxidation, apoptosis and cell damage markers. Correlations between injury signals and disinhibition suggest that CA+TDD disrupts behaviors dependent on the frontal cortex. Our study sheds light on the potential disease-specific mechanisms, reinforcing the need for neuroprotective therapeutic approaches along with preventive treatments for the nutritional deficiency in WKS.

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

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

“…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 chronic alcohol 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 disinhibition-like behavior in animals (Moya et al, 2022), which is a core symptom of the pathology. Similarly, 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 postmortem brain of an alcohol-induced WE case.…”

“…Experimental Groups. The experimental design and all the procedures of this animal study are described in detail and can be viewed at (Moya et al, 2022). Briefly, to explore the different conditions that contribute to develop WE, the following experimental groups were used:…”

“…Western Blot Analysis. Frontal cortex and cerebellar hemisphere samples were processed and analyzed by western blot following the methodology previously detailed in (Moya et al, 2022).…”

“…However, some authors pointed out to 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, in cognition and in 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, behavioral inhibition, including cognitive processes, social behavior and inhibition of motor responses.…”