N-acetylcysteine relieves neurologic signs of acute ethanol hangover in rats

Introduction: Alcohol abuse is one of the grave social and medical problems in many countries, including Russia. Alcohol not only negatively affects health, social and family relationships, but also a person’s performance. Hangover, which is a one of the negative consequences of alcohol intake, is a complex of neurological and somatic symptoms that occur when ethanol is almost completely metabolized to acetaldehyde. This condition, despite the severity and potential economic damage, remains poorly understood, and there are no effective medicines to treat it. Aim: to provide an experimental basis for the possibility of using N-acetylcysteine (NAC), a precursor of glutathione, as a medicine for prevention of the neurological and cognitive impairments due to alcohol intoxication. Materials and Methods: The study used male Wistar rats, which were intraperitoneally injected with ethanol at a dose of 3 g/kg to simulate acute ethanol intoxication. Sixty minutes before the injection, the animals from the experimental groups were gavaged with NAC (1 g/kg) or with an equivalent volume of saline. Immediately after awakening and 3 h after it, the animals were assessed for neurological deficits, motor skills, spontaneous motor activity, and cognitive functions. After the completion of the behavioral tests, the animals were euthanized to assess the level of glutathione, triglycerides (TGs), and malonic dialdehyde (MDA) in liver homogenates, and to determine the activity of enzymatic antioxidant systems and serum aminotransferases. Results and Discussion: The ethanol intoxication in the animals from the control group was associated with pronounced signs of neurological and cognitive impairments, including low spontaneous motor and exploratory activity, impaired fine motor skills in the adhesive test, and cognitive function decline in the Morris water maze test. The rats which had received NAC before ethanol injection demonstrated better fine motor skills in the adhesive test, a higher level of spontaneous motor activity and better performance in the Morris water maze test (in comparison to the animals treated with saline before alcohol intoxication). In the animals which had received NAC, the levels of glutathione, MDA, and TGs, as well as the activity of liver antioxidant enzymes, were closer to the values of the intact rats to a greater extent than in the animals that had been injected with ethanol and received saline. Conclusion: Orally administered NAC before acute ethanol intoxication led to a decrease in the severity of neurological deficiency in rats and reduced the amnesic effect of ethanol. This could be due to an improvement of ethanol metabolism and a decrease in the severity of disorders associated with oxidative stress and liver dysfunction.

Ethanol Disrupts Hormone-Induced Calcium Signaling in Liver

Receptor-coupled phospholipase C (PLC) is an important target for the actions of ethanol. In the ex vivo perfused rat liver, concentrations of ethanol >100 mM were required to induce a rise in cytosolic calcium (Ca2+) suggesting that these responses may only occur after binge ethanol consumption. Conversely, pharmacologically achievable concentrations of ethanol (≤30 mM) decreased the frequency and magnitude of hormone-stimulated cytosolic and nuclear Ca2+ oscillations and the parallel translocation of protein kinase C-β to the membrane. Ethanol also inhibited gap junction communication resulting in the loss of coordinated and spatially organized intercellular Ca2+ waves in hepatic lobules. Increasing the hormone concentration overcame the effects of ethanol on the frequency of Ca2+ oscillations and amplitude of the individual Ca2+ transients; however, the Ca2+ responses in the intact liver remained disorganized at the intercellular level, suggesting that gap junctions were still inhibited. Pretreating hepatocytes with an alcohol dehydrogenase inhibitor suppressed the effects of ethanol on hormone-induced Ca2+ increases, whereas inhibiting aldehyde dehydrogenase potentiated the inhibitory actions of ethanol, suggesting that acetaldehyde is the underlying mediator. Acute ethanol intoxication inhibited the rate of rise and the magnitude of hormone-stimulated production of inositol 1,4,5-trisphosphate (IP3), but had no effect on the size of Ca2+ spikes induced by photolysis of caged IP3. These findings suggest that ethanol inhibits PLC activity, but does not affect IP3 receptor function. We propose that by suppressing hormone-stimulated PLC activity, ethanol interferes with the dynamic modulation of [IP3] that is required to generate large, amplitude Ca2+ oscillations.

Morphometric Methods for Examining the Liver in the Diagnosis of Acute and Chronic Alcohol Intoxication

The article presents the results of a morphometric study of the liver of persons who died from acute ethanol intoxication and chronic alcohol intoxication in persons with alcohol-induced liver pathology. The aim of the work was to carry out morphometry of the main vascular and parenchymal structural components of the liver, reflecting its morphological and functional state. Data were obtained on a decrease in the area of the vascular bed, cyto- and karyometric parameters, which reflect an increase in dystrophic processes in hepatocytes and inflammatory-proliferative processes in the connective tissue and indicate the tension of capillary-connective tissue structures, impaired blood circulation, bile and lymph outflow in the liver in chronic alcohol intoxication, especially with hepatitis and cirrhosis. The obtained morphometric data can be used as a comparison in studying the pathomorphological features of the liver in other pathological conditions.

SPECIFICS OF ALCOHOL USE DISORDER IN PRE-HOSPITAL PRACTICES AND EMERGENCY UNIT

Ethanol intoxication is analyzed from the point of ethanol interaction with receptors and enzymes. Ethanol dependence is based on neurochemical misbalance, which is different in acute ethanol intoxication and withdrawal. It is shown that the clinical manifestation of ethanol intoxication and its complications depends on ligand-receptor and enzyme imbalances. Pharmacological approaches to the treatment of acute ethanol intoxication and its complications at the pre-hospital stage and in the emergency, unit are discussed.

EFFECT OF POLYMORPHISM OF THE GABRA2 GENE ON THE DEGREE OF RAT POISONING IN ACUTE ETHANOL INTOXICATION

Four polymorphic GABRA2 gene variations: rs105733011, rs8168342, rs198286814, rs198837638 that can influence the formation of different biological effects of the organism when exposed to ethanol have been investigated. For rs105733011 polymorphism the frequency of occurrence of the CT genotype was found to be significantly higher (p < 0,05) among animals with «severe intoxication» – 37,0% than with «mild intoxication» – 14,0%. For rs198286814 polymorphism the tendency to the most frequent occurrence of the AG genotype in the group of animals with «severe intoxication» was established. Significant differences in the distribution of occurrence frequencies of the GG/AG genotypes in the studied groups for polymorphic loci rs8168342 and rs198837638 were not revealed. It was concluded that the rs105733011 polymorphism can be one of the genetic markers allowing to predict the degree of inhibitory action of ethanol in acute alcohol intoxication.

Acute ethanol intoxication induces preferred loss of presynaptic boutons devoid of mitochondria in vivo

Acute alcohol intoxication is frequently observed in modern societies and carries a vast burden, ranging from traffic accidents to transient memory loss. Despite years of intense research, the effects of acute ethanol intoxication on brain function remain incompletely understood. Here, we studied the effect of acute ethanol intoxication on axonal organelle trafficking and presynaptic structure using in vivo two photon microscopy in anesthetized mice. After a single intraperitoneal injection of ethanol, inducing a blood alcohol concentration of roughly 250 mg/dl, the axonal mitochondrial mobility was doubled while dense core vesicle mobility remained unaffected. Simultaneously imaging mitochondria and presynaptic boutons revealed that unoccupied presynaptic boutons perished more frequently after ethanol exposure, while boutons stably occupied with mitochondria mostly persisted. Our results define a novel mechanism of ethanol action and may explain difficulties in permanently storing new memories after episodes of intense ethanol consumption with a loss of synapses.