Alcohol abuse and glycoconjugate metabolism

The relationship between alcohol consumption and glycoconjugate metabolism is complex and multidimensional. This review summarizes the advances in basic and clinical research on the molecular and cellular events involved in the metabolic effects of alcohol on glycoconjugates (glycoproteins, glycolipids, and proteoglycans). We summarize the action of ethanol, acetaldehyde, reactive oxygen species (ROS), nonoxidative metabolite of alcohol — fatty acid ethyl esters (FAEEs), and the ethanol-water competition mechanism, on glycoconjugate biosynthesis, modification, transport and secretion, as well as on elimination and catabolism processes. As the majority of changes in the cellular metabolism of glycoconjugates are generally ascribed to alterations in synthesis, transport, glycosylation and secretion, the degradation and elimination processes, of which the former occurs also in extracellular matrix, seem to be underappreciated. The pathomechanisms are additionally complicated by the fact that the effect of alcohol intoxication on the glycoconjugate metabolism depends not only on the duration of ethanol exposure, but also demonstrates dose- and regional-sensitivity. Further research is needed to bridge the gap in transdisciplinary research and enhance our understanding of alcohol- and glycoconjugate-related diseases

Cerebral Metabolism of Ethanol-Derived Acetate: A Metabolic Basis for Dependence?

Alcoholism is a tremendous health problem throughout the world. Ethanol is a unique drug that is consumed in large quantities for pharmacologic effect, reaching blood concentrations as high as 100mM. Ethanol is eliminated almost exclusively via oxidation to acetate in the liver, and nearly all of the ethanol-derived acetate is released into the blood where it travels to other organs, including the brain, for use as an energy source. Thus ethanol directly alters metabolism in the liver, and causes the production of large amounts of acetate which may serve as a substrate for brain, possibly contributing to intoxication and dependence. This dissertation describes two separate approaches to study the metabolic effects of ethanol. First, 1H NMR-based metabolomic analysis of endogenous metabolites revealed decreased lactate and alanine, and increased acetate and ketone bodies due to ethanol. These results provided new insights regarding the effect of ethanol on gluconeogenesis. In addition, we determined that ethyl glucuronide (EtG), a unique metabolite of ethanol, produces a characteristic NMR signal. EtG is formed within hours of ethanol dosing, and remains elevated during a 4 day binge exposure. The antioxidant BHT appears to reduce formation of EtG during a 4 day exposure to ethanol. Our second approach used 13C-enriched tracers along with 13C NMR to measure brain metabolism of ethanol-derived acetate. Our hypothesis was that cerebral metabolism of acetate released from the liver during ethanol oxidation perturbs cerebral metabolism, and thereby contributes to neuroadaptation associated with alcohol dependence and withdrawal. Using a single dose of [2-13C] ethanol intragastrically, we found carbons derived from ethanol are rapidly incorporated into brain amino acids glutamate, glutamine, and GABA. Next, we investigated whether a 10 day exposure to ethanol would increase cerebral utilization of acetate. We found that acetate metabolism was not increased, most likely because transport into brain astrocytes was not increased. We did find, however, that ethanol induced significant changes in metabolism of GABA, and we speculate that this may reflect neuroadaptations that produce tolerance to ethanol

Profiling the neurovascular cell interactions in alcohol exposure and HIV-1 infection

Alcohol use is known to exacerbate the progression of human immunodeficiency virus associated acquired immunodeficiency syndrome or HIV/AIDS in the brain, known as the NeuroAIDS. The mechanisms of this accelerated progression are still poorly understood. The purpose of my thesis is to review the parameters contributing to the co-morbid effects of alcohol in the progression of NeuroAIDS. The first aim will evaluate the exacerbating effects of alcohol on HIV-1 transmission, infection, and the role of metabolic energy imbalance during NeuroAIDS progression, which will enable me to formulate the possible mechanism for NeuroAIDS progression. The second aim will help me establish the technique of rat embryonic neuronal isolation, which will be used for testing the neurotoxicity of HIV proteins (Tat, gp120) in the setting of interactive neuroimmune cell culture (brain endothelial cells, astrocytes, microglia, and neurons) with or without the presence of alcohol. The synergistic effect of alcohol on HIV associated neurotoxicity will pave the future research path to examine the unique mechanism for HIV/AIDS progression and a possible cure for HIV/AIDS with active antiretroviral drug(s)

ETHANOL INDUCED NEUROTOXICITY THROUGH DYSREGULATION OF AMPK IN A FETAL ALCOHOL SYNDROME MODEL

Ethanol consumption during pregnancy is rising in the U.S., including the rate of binge drinking. It is reported around 1 in 27 women engage in binge drinking activities while pregnant. The third trimester is a sensitive period of neuronal growth in which ethanol induced neurotoxicity can cause many harmful effects including Fetal Alcohol Spectrum Disorders. It has been shown that ethanol decreases the activity of AMPK through increasing lipid peroxidation, both of which are correlated to neurotoxicity. AICAR is a synthetic analog of AMP which significantly increases AMPK activity and may have beneficial effects in an organotypic hippocampal model of third trimester binge drinking. The purpose of this study is to evaluate if pharmacologically increasing the activity of AMPK could reduce the degree of ethanol induced neurotoxicity to provide a potential therapeutic target for Fetal Alcohol Spectrum Disorders

Acute alcohol intoxication: a clinical overview

Alcohol is a legal and yet detrimental psychoactive substance, capable of establishing addiction and impacting the physical, mental, social, and economic health of people. Alcohol intake causes a large variety of tissue damages severely impacting the nervous system, digestive and cardiovascular systems and causing oral cavity, oropharyngeal, hypopharyngeal, esophageal, colon-rectal, laryngeal, liver and intrahepatic bile duct, and breast cancers. Alcohol can also play a role in the pathogenesis of diabetes mellitus, cardiomyopathy and hemorrhagic strokes. When drunk during pregnancy it is proved to be responsible for serious damage to fetuses causing a wide range of pathological conditions from miscarriage to Fetal Alcoholic Spectrum Disorder (FASD). Acute ethanol intoxication happens when the amount of alcohol consumed is greater than the disposal capacity of the liver, causing an accumulation of its metabolites displayed by initial dysphoria and disinhibition. Nausea, vomiting, memory loss could happen. Although, it can lead to more serious conditions like impaired speaking, impaired coordination, unstable gait, nystagmus, stupor, or coma. Respiratory depression and death could also happen in such cases. Unfortunately, diagnosis of acute alcohol intoxication is difficult because most of the drinkers deny or minimize their assumption. It is dramatically important to assess when the last intake happened to avoid withdrawal syndrome. Alcohol acute intoxication can be considered a serious harm to health and a relevant issue for healthcare provid-ers working in emergency rooms. Differential diagnosis is crucial to avoid serious outcomes. There is no consensus about therapies for acute intoxication, but supportive and symptomatic treatments were proved effective. The repercussions of alcohol misuse over drinkers' social, familiar, economical and working life enhance the importance of a multidisciplinary approach in such cases

The effect of alcohol intoxication on haemodynamic physiology of acute cardiac tamponade

It is generally accepted that alcohol impairs haemodynamic physiology in normal subjects. Alcohol is also thought to have a detrimental effect in shock states. However, most research has concentrated on haemorrhagic shock, whereas in cardiac tamponade, the pathophysiology of shock is very different. Although some studies have mentioned alcohol as a negative factor in patients with cardiac tamponade, none have adequately assessed its effect. In a clinical study of 50 patients who presented to Groote Schuur Hospital Trauma Unit with acute cardiac tamponade due to penetrating chest injury, those who were intoxicated fared the same as their sober counterparts. Although more patients in the intoxicated group were "moribund" or "in extremis" on admission, this did not lead to a higher overall mortality. Haemodynamic parameters and results of special investigations in the two groups were also similar. These findings suggested that intoxicated patients with cardiogenic shock, specifically acute cardiac tamponade, behaved differently from intoxicated patients with haemorrhagic shock. However, the multitude of variables and the stress involved in treating patients with life-threatening acute conditions, makes studies such as this difficult. Because of these limitations, an animal model of acute cardiac tamponade was developed, so that actions of alcohol on haemodynamic physiology could be studied in a controlled environment. Fourteen young pigs were randomly assigned to receive either 30% alcohol or tap-water via a gastrostomy. The former resulted in blood alcohol levels which were compatible with moderate to severe intoxication. Cardiac tamponade was then induced by instilling warmed plasmalyte-8 into the pericardia! sac using a pressure-cycled system. Despite the fact that animals in the tamponade/alcohol group were more hypotensive, and reflex increase in heart rate was inhibited, cardiac output was similar in the two groups. The actions of alcohol in isolation were also studied in eight sham-operated pigs. The only noticeable effect in this instance were higher pulmonary artery wedge pressures in the sham/non-alcohol group. In other words, cardiac performance in both the tamponade/alcohol and sham/alcohol groups was at least equal to, or even better than that in animals that did not receive alcohol. It would seem therefore, that alcohol does not have a negative effect on haemodynamic physiology of acute cardiac tamponade. Theoretically, alcohol may "protect" patients with acute cardiac tamponade by decreasing peripheral vascular resistance and "afterload". It is also possible that inhibitory actions on the respiratory centre may prevent hyperpnoea or tachypnoea, and thereby diminish competitive filling of the right and left ventricles. However, further studies of cardiac function in intoxicated subjects with tamponade using more sophisticated techniques are necessary, before mechanisms will become apparent. In practice, an aggressive approach should be adopted towards moribund patients with penetrating chest injuries; if they have acute cardiac tamponade and are intoxicated, their prognosis is not necessarily dismal. This is of particular relevance in Cape Town, where both alcohol abuse and assault are endemic. As for a therapeutic effect of alcohol, these studies do not support its use for pharmacological manipulation of cardiac tamponade

Focal Thalamic Degeneration from Ethanol and Thiamine Deficiency is Associated with Neuroimmune Gene Induction, Microglial Activation, and Lack of Monocarboxylic Acid Transporters

BackgroundWernicke's encephalopathy-Korsakoff syndrome (WE-KS) is common in alcoholics, caused by thiamine deficiency (TD; vitamin B1) and associated with lesions to the thalamus (THAL). Although TD alone can cause WE, the high incidence in alcoholism suggests that TD and ethanol (EtOH) interact.MethodsMice in control, TD, or EtOH groups alone or combined were studied after 5 or 10 days of treatment. THAL and entorhinal cortex (ENT) histochemistry and mRNA were assessed.ResultsCombined EtOH-TD treatment for 5 days (EtOH-TD5) showed activated microglia, proinflammatory gene induction and THAL neurodegeneration that was greater than that found with TD alone (TD5), whereas 10 days resulted in marked THAL degeneration and microglial-neuroimmune activation in both groups. In contrast, 10 days of TD did not cause ENT degeneration. Interestingly, in ENT, TD10 activated microglia and astrocytes more than EtOH-TD10. In THAL, multiple astrocytic markers were lost consistent with glial cell loss. TD blocks glucose metabolism more than acetate. Acetate derived from hepatic EtOH metabolism is transported by monocarboxylic acid transporters (MCT) into both neurons and astrocytes that use acetyl-CoA synthetase (AcCoAS) to generate cellular energy from acetate. MCT and AcCoAS expression in THAL is lower than ENT prompting the hypothesis that focal THAL degeneration is related to insufficient MCT and AcCoAS in THAL. To test this hypothesis, we administered glycerin triacetate (GTA) to increase blood acetate and found it protected the THAL from TD-induced degeneration.ConclusionsOur findings suggest that EtOH potentiates TD-induced THAL degeneration through neuroimmune gene induction. The findings support the hypothesis that TD deficiency inhibits global glucose metabolism and that a reduced ability to process acetate for cellular energy results in THAL focal degeneration in alcoholics contributing to the high incidence of Wernicke-Korsakoff syndrome in alcoholism