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.
Highlights
Alcohol is one of the most widely used psychoactive drugs worldwide, whose consumption originates major public health problems in our society including alcohol use disorder (AUD)
With the start of the thiamine deficiency (TD) diet, the four corresponding groups were fully shaped, and significant weight loss was observed in the TDD and Chronic alcohol (CA)+TDD animals at the end of the protocol (Figure 2A, upper right box; two-way repeated measures (RM) ANOVA, interaction: F (3, 32) = 4.742, p = 0.0076; effect of time: F (1, 32) = 30.24, p < 0.0001; effect of treatment: F (3, 32) = 8.26, p = 0.0003; both groups: p = 0.0002)
Our findings showed that the combination of CA with the TDD induced an increase in the HSP70 and high-mobility group box 1 protein (HMGB1) cortical levels
Summary
Alcohol is one of the most widely used psychoactive drugs worldwide, whose consumption originates major public health problems in our society including alcohol use disorder (AUD) (reviewed in [1]). The confluence of nutritional deficiency in AUD patients is of particular interest, in the case of thiamine deficiency (TD), as this can result in Wernicke–Korsakoff syndrome (WKS). WKS is often characterized by ataxia, oculomotor disturbances, severe memory impairment, global confusion, executive dysfunction and apathy, mainly seen in chronic alcohol consumption cases. 75% of TD cases are undiagnosed in AUD patients (reviewed in [3]). Other causes inducing the pathology, independent of alcohol, include chronic malnutrition caused by prolonged fasting and hyperemesis gravidarum, bariatric and gastrointestinal surgeries, acute pancreatitis and hemodialysis [4,5]
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