Alcoholic Damage Research Articles

Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics.

Cytochrome P450 (CYP) 2D6 is expressed in liver, brain and other extrahepatic tissues where it metabolizes a range of centrally acting drugs and toxins. As ethanol can induce CYP2D in rat brain, we hypothesized that CYP2D6 expression is higher in brains of human alcoholics. We examined regional and cellular expression of CYP2D6 mRNA and protein by RT-PCR, Southern blotting, slot blotting, immunoblotting and immunocytochemistry. A significant correlation was found between mean mRNA and CYP2D6 protein levels across 13 brain regions. Higher expression was detected in 13 brain regions of alcoholics (n = 8) compared to nonalcoholics (n = 5) (anovap < 0.0001). In hippocampus this was localized in CA1-3 pyramidal cells and dentate gyrus granular neurons. In cerebellum this was localized in Purkinje cells and their dendrites. Both of these brain regions, and these same cell-types, are known to be susceptible to alcohol damage. For one case, a poor metabolizer (CYP2D6*4/*4), there was no detectable CYP2D6 protein, confirming the specificity of the antibody used. These data suggest that in alcoholics elevated brain CYP2D6 expression may contribute to altered sensitivity to centrally acting drugs and to the mediation of neurotoxic and behavioral effects of alcohol.

Midline corpus callosum is a neuroanatomical focus of fetal alcohol damage.

Prenatal exposure to high levels of alcohol often induces birth defects that combine morphological stigmata with neurological or neuropsychological deficits. But it has proved problematic to diagnose these syndromes in adolescents and adults, in whom the morphological signs are absent or attenuated, the behavioral deficits nonspecific, and the exposure history often difficult to reconstruct. Localizing the associated brain abnormalities might circumvent most of these difficulties. To this end, three-dimensional (3D) locations were recorded for 67 homologous points on or near the corpus callosum in magnetic resonance (MR) brain images from 60 adolescents and adults who were normal, 60 diagnosed with fetal alcohol syndrome, and 60 diagnosed with fetal alcohol effects. We combined the standard statistical approach to this type of geometric data, Procrustes analysis, with a multivariate strategy focusing on differences in variability. In this data set, the shape of the corpus callosum and its vicinity proves systematically much more variable in the alcohol-affected brains than in those of the normal subjects. From this excess variability follows a promising classification rule, having both high sensitivity (100 out of 117) and high specificity (49 out of 60) in this sample. The discrimination uses four landmark points and two summary scores of callosal outline shape. The information from the corpus callosum and vicinity, as viewed in MR brain images of full-grown subjects, may serve as a permanent record of the prenatal effects of alcohol, even in patients who are first suspected of these syndromes relatively late in life or who lack the facial signs of prenatal alcohol damage. The statistical pattern underlying the callosal diagnosis also leads to speculations on mechanisms of the prenatal damage.

Excited to death: different ways to lose your neurones.

The selective loss of neurones in a range of neurodegenerative diseases is widely thought to involve the process of excitotoxicity, in which glutamate-mediated neuronal killing is elaborated through the excessive stimulation of cell-surface receptors. Every such disease exhibits a distinct regional and subregional pattern of neuronal loss, so processes must be locally triggered to different extents to account for this. We have studied several mechanisms which could lead to excitotoxic glutamate pathophysiology and compared them in different diseases. Our data suggest that glutamate can reach toxic extracellular levels in Alzheimer disease by malfunctions in cellular transporters, and that the toxicity may be exacerbated by continued glutamate release from presynaptic neurones acting on hypersensitive postsynaptic receptors. Thus the excitotoxicity is direct. In contrast, alcoholic brain damage arises in regions where GABA-mediated inhibition is deficient, and fails properly to dampen trans-synaptic excitation. Thus the excitotoxicity is indirect. A variety of such mechanisms is possible, which may combine in different ways.

Effects of Abstinence on the Brain: Quantitative Magnetic Resonance Imaging and Magnetic Resonance Spectroscopic Imaging in Chronic Alcohol Abuse

Background: Structural brain damage, especially to white matter, is well documented in chronic alcohol abuse. There is also evidence for brain metabolic abnormalities in this condition. It is unknown, however, to what extent these structural and metabolic changes are present in treated alcohol abusers who achieve long-term abstinence versus treatment-naïve, heavily drinking individuals. Methods: This study compared 12 recovering alcoholics with 8 actively heavily drinking subjects. Participants underwent magnetic resonance (MR) imaging and proton MR spectroscopic imaging of the brain. Semiautomated image segmentation techniques yielded volumes for gray matter, white matter, white matter lesions, and cerebral spinal fluid in multiple brain regions defined by Talairach stereotaxic coordinates. Automated spectral processing methods yielded gray and white matter concentrations of the metabolites N-acetylaspartate, creatine, and choline for the same regions. Results: Recovering alcoholics had greater volumes of frontal white matter, but the opposite was true for white matter in a “remainder” region encompassing the basal frontal and temporal lobes, the cerebellum, and the brainstem. Recovering alcoholics also had smaller volumes of white matter lesions in whole brain, in occipital and mesial parietal regions, and in the remainder region. Recovering alcoholics had greater gray matter volumes in the orbital frontal pole and postcentral gyrus, but smaller gray matter volumes in the anterior cingulate. Whole-brain and regional metabolite concentrations did not differ significantly between the two groups. Conclusions: White and gray matter volumes in different regions of the brain were greater or smaller in recovering, treated alcoholics. The findings suggest region-specific structural recovery from chronic alcohol–induced brain injury, but also region-specific long-term structural damage in abstinent alcoholics. White matter lesions were widespread in active drinkers and may partly resolve during long-term abstinence. Proton MR spectroscopic measures, as applied in this cross-sectional study, were largely ineffective in revealing metabolic effects of abstinence on the alcohol-damaged brain.

Effects of Abstinence on the Brain: Quantitative Magnetic Resonance Imaging and Magnetic Resonance Spectroscopic Imaging in Chronic Alcohol Abuse

Structural brain damage, especially to white matter, is well documented in chronic alcohol abuse. There is also evidence for brain metabolic abnormalities in this condition. It is unknown, however, to what extent these structural and metabolic changes are present in treated alcohol abusers who achieve long-term abstinence versus treatment-naïve, heavily drinking individuals. This study compared 12 recovering alcoholics with 8 actively heavily drinking subjects. Participants underwent magnetic resonance (MR) imaging and proton MR spectroscopic imaging of the brain. Semiautomated image segmentation techniques yielded volumes for gray matter, white matter, white matter lesions, and cerebral spinal fluid in multiple brain regions defined by Talairach stereotaxic coordinates. Automated spectral processing methods yielded gray and white matter concentrations of the metabolites N-acetylaspartate, creatine, and choline for the same regions. Recovering alcoholics had greater volumes of frontal white matter, but the opposite was true for white matter in a "remainder" region encompassing the basal frontal and temporal lobes, the cerebellum, and the brainstem. Recovering alcoholics also had smaller volumes of white matter lesions in whole brain, in occipital and mesial parietal regions, and in the remainder region. Recovering alcoholics had greater gray matter volumes in the orbital frontal pole and postcentral gyrus, but smaller gray matter volumes in the anterior cingulate. Whole-brain and regional metabolite concentrations did not differ significantly between the two groups. White and gray matter volumes in different regions of the brain were greater or smaller in recovering, treated alcoholics. The findings suggest region-specific structural recovery from chronic alcohol-induced brain injury, but also region-specific long-term structural damage in abstinent alcoholics. White matter lesions were widespread in active drinkers and may partly resolve during long-term abstinence. Proton MR spectroscopic measures, as applied in this cross-sectional study, were largely ineffective in revealing metabolic effects of abstinence on the alcohol-damaged brain.

Geometric morphometrics of corpus callosum and subcortical structures in the fetal-alcohol-affected brain.

Although experienced clinicians have been diagnosing fetal alcohol syndrome (FAS) for nearly 30 years, the rest of the spectrum of fetal alcohol damage is not being classified effectively. This article describes a quantification of neuroanatomical structure that may supply a useful discriminator of prenatal brain damage from alcohol. It is demonstrated in a data set of adults of both sexes. Ninety adults (45 males) were examined by magnetic resonance imaging (MRI). These subjects were group-matched for age and ethnicity across three diagnoses: FAS, fetal alcohol effects (FAE), and normals. All FAS and FAE were heavily alcohol-exposed in utero; normals were not. From T(1)-weighted MR brain images, we extracted 3D morphometric representations of shape for 33-landmark point configurations and 40-point outlines of the corpus callosum along its midline (a slightly nonplanar structure). There are striking differences between exposed and unexposed in the statistical distributions of these two shapes. The differences are better characterized by excess variance in the exposed group than by any change in average landmark or outline shape. For each sex, combining the callosal outline data with the landmark data leads to a powerful quadratic discriminator of exposed from unexposed. The discriminating features include the relationship of brain stem to diencephalon, and localized variabilities of callosal outline shape, but not diagnosis (FAS vs. FAE). Statistical analysis of brain shape is a powerful new source of information relevant to fetal alcohol spectrum nosology and etiology. Patients with FAS and FAE do not differ in these brain shape features, but both differ from the unexposed. The aspects of brain shape that are especially variable may be entailed in the underlying neuroteratogenetic mechanisms.

Direct and Indirect Effects of Prenatal Alcohol Damage on Executive Function

Patients with Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Effects (FAE) often have difficulty functioning appropriately in everyday life and seem to employ poor problem-solving strategies. Tests of executive function are relevant for quantifying the functional deficits and underlying real-life problems associated with prenatal alcohol exposure. This study considers two pathways for the effects of prenatal alcohol on executive function: a direct effect and an indirect effect through prenatal alcohol's effect on IQ. We compared 30 men who had been diagnosed with FAS or FAE with young adults participating in a longitudinal prospective study (n = 419) and 15 control participants that comprised a comparison group. This study is unique in its analysis of the same battery of assessments of executive function in both a large low dose longitudinal study sample and a clinically diagnosed group. Participants were evaluated on 9 tests (including 58 scores) of executive function. For some but not all of the tests in this executive function battery, the decrement in the alcohol exposure group is greater than would be predicted from their IQ scores. We found that 3 of 6 Stroop scores, 2 of 4 Trails scores, 9 of 16 Wisconsin Card Sorting scores, 1 of 2 Ruff's Figural Fluency scores, and 2 of 4 Consonant Trigrams scores appear to be particularly sensitive to the direct effects of prenatal alcohol damage for patients with FAS and FAE. The findings suggest that these executive function tests would be particularly useful in clinical evaluations of persons suspected of fetal alcohol damage because they would not simply reflect deficits in IQ or facial stigmata.

The heterozygosis in the genetic mutation for HFE is not associated with an increased risk of liver damage in alcoholics

The heterozygosis in the genetic mutation for HFE is not associated with an increased risk of liver damage in alcoholics

Alcohol and DNA damage

Alcohol and DNA damage

Stability properties of human brain apo‐transketolase

Stability properties of human brain apo-transketolase were investigated by studying the effect of a range of pH (6.25 to 8.20) at 37°C on it as well as the effect of storage for different time intervals ranging from 10 to 210 min. The results show that initial rate of loss of enzyme activity is pH dependent, being minimal at a pH value of 7.6 at 37°C (which is equivalent to pH 8.0 at room temperature of 20°C). This optimum pH for human brain apo-transketolase in vitro is close to that likely to exist in vivo as well as that for rat brain enzyme reported previously. The findings on the stability of the brain enzyme during storage suggest that the human apo-transketolase is more stable than the rat apo-transketolase since 20% of enzyme activity is lost in approximately 180 min of incubation compared to 50% loss reported in the rat brain. Hence, it can be concluded that although the human brain apo-transketolase is identical to the rat enzyme in that they both an optimum pH of 7.6 of 37°C, the human brain enzyme appears to be more stable than the rat enzyme. The instability of the human brain apo-transketolase, together with the variant forms of the human erythrocyte transketolase, provides further support for the role of transketolase in the genesis of alcoholic brain damage.

A New Clue to How Alcohol Damages Brains

On page 1056, researchers report the first possible explanation for how alcohol damages the developing brain. They show that alcohol works through the receptors for two of the brain9s neurotransmitters, glutamate and GABA, to kill brain neurons in rat pups. In addition to carrying an important message for the public about the dangers of alcohol use during pregnancy, the work could provide a first step toward controlling that damage, possibly with drugs that block alcohols9 effects on the receptors.

Homocysteine and alcoholism.

Chronic alcohol consumption can induce alterations in the function and morphology of most if not all brain systems and structures. However, the exact mechanism of brain damage in alcoholics remains unknown. Partial recovery of brain function with abstinence suggests that a proportion of the deficits must be functional in origin (i.e. plastic changes of nerve cells) while neuronal loss from selected brain regions indicates permanent and irreversible damage. There is growing evidence that chronic alcoholism is associated with a derangement in the sulfur amino acid metabolism. Recently, it has been shown that excitatory amino acid (EAA) neurotransmitters and homocysteine levels are elevated in patients who underwent withdrawal from alcohol. Furthermore, it has been found that homocysteine induces neuronal cell damage by stimulating NMDA receptors as well as by producing free radicals. Homocysteine neurotoxicity via overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both brain shrinkage and withdrawal seizures linked to alcoholism.

Short-term ethanol exposure increases the expression of Kupffer cell CD14 receptor and lipopolysaccharide binding protein in rat liver.

Gut-derived endotoxins (lipopolysaccharide, LPS) complexed to LPS-binding protein (LBP) activate liver Kupffer cells via their CD14 receptor. Pro-inflammatory cytokines are released and this is postulated to promote liver injury. We previously demonstrated enhanced expression of CD14 endotoxin receptor after 2 weeks of alcohol administration. A similar result, based on 6 weeks of ethanol treatment, was recently reported and suggested to correlate with alcohol-induced liver injury. To establish whether this occurs prior to or after the initiation of damage, we investigated the temporal effect of continuous ethanol exposure on the expression of CD14 and the associated LBP. In addition, we studied the effect of treatment with gadolinium chloride (GdCl3) that inactivates Kupffer cells and alleviates alcohol-induced liver damage. The amount of CD14 and LBP mRNA, as determined by reverse transcriptase-polymerase chain reaction (RT-PCR), was unchanged 4-8 h after intragastric ethanol administration. However, after 24-48 h of repeated ethanol administration, CD14 and LBP mRNA both increased significantly and reached a level similar to that observed after 6 weeks of ethanol exposure by liquid diet. Immunostaining experiments with ED2 antibody demonstrated that GdCl3 efficiently inactivated Kupffer cells. However, there was no concomitant reduction in the expression of CD14 mRNA, suggesting that compensatory infiltration by ED2-negative, but CD14-positive, macrophages had occurred. Our results demonstrate that soon after the initiation of ethanol exposure, i.e. within 24-48 h, the hepatic expression of both the CD14 receptor and LBP is increased. This suggests that these increases could contribute to the initiation of alcoholic damage rather than being a consequence of the injury.

Indicators of inflammation and cellular damage in chronic asymptomatic or oligosymptomatic alcoholics: correlation with alteration of bilirubin and hepatic and pancreatic enzymes.

Biochemical and hematimetric indicators of inflammation and cell damage were correlated with bilirubin and hepatic and pancreatic enzymes in 30 chronic male alcoholics admitted into psychiatric hospital for detoxification and treatment of alcoholism. Aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, and total bilirubin were altered, respectively, in 90%, 63%, 87%, 23% and 23% of the cases. None of the indicators of inflammation (lactic dehydrogenase, altered in 16% of the cases; alpha-1 globulin, 24%; alpha-2 globulin, 88%; leucocyte counts, 28%) was correlated with alterations of bilirubin or liver enzymes. Lactic dehydrogenase was poorly sensitive for detection of hepatocytic or muscular damage. Alterations of alpha-globulins seemed to have been due more to alcohol metabolism-induced increase of lipoproteins than to inflammation. Among indicators of cell damage, serum iron, increased in 40% of the cases, seemed to be related to liver damage while creatine phosphokinase, increased in 84% of the cases, related to muscle damage. Hyperamylasemia was found in 20% of the cases and significantly correlated with levels of bilirubin, alkaline phosphatase and gamma-glutamyltransferase. It was indicated that injuries of liver, pancreas, salivary glands, and muscle occurred in asymptomatic or oligosymptomatic chronic alcoholics.

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For nearly two decades, the concept of alcoholism as a disease has been unpopular. During this time, those unfortunate people suffering from one of the various forms of alcohol poisoning, alcohol damage or dependence were collectively labelled as having an alcohol problem or of being a problem drinker. The view that alcoholism was a disease or illness was met with derision and refute, usually by those who have a psychological, social or behavioural training.

Alcohol Abuse, Alcoholism, and Damage to the Immune System???A Review

Alcohol Abuse, Alcoholism, and Damage to the Immune System???A Review

Alcohol Abuse, Alcoholism, and Damage to the Immune System—A Review

Chronic alcohol abuse exacts a major social and medical toll in the United States and other Western countries. One of the least appreciated medical complications of alcohol abuse is altered immune regulation leading to immunodeficiency and autoimmunity. The consequences of the immunodeficiency include increased susceptibility to bacterial pneumonia, tuberculosis, and other infectious diseases. In addition, the chronic alcoholic often has circulating autoantibodies, and recent investigations indicate that the most destructive complications of alcoholism, such as liver disease and liver failure, may have a component of autoimmunity. Current research on altered cytokine balance produced by alcohol is leading to new insights on the regulation of the immune system in the chronic alcoholic. There is also recent development of exciting new techniques designed to improve or restore immune function by manipulation of cytokine balance. Although much remains to be learned, both in the abnormalities produced by alcohol and in the techniques to reverse those abnormalities, current progress reflects a rapidly improving understanding of the basic immune disorders of the alcoholic.

Cell Death Mediated by Amino Acid Transmitter Receptors in Human Alcoholic Brain Damage: Conflicts in the Evidencea.

Human alcoholics have reduced neuronal counts in certain brain regions, such as superior frontal cortex (SFC), where the form and quantity of synaptic γ-aminobutyric acid type A (GABAA) receptor sites are atypical. We measured the expression of GABAA receptor isoform mRNA and protein, since GABAA receptor pharmacology is strongly influenced by its subunit composition. Cortex samples were obtained at autopsy; whole-tissue extracts were assayed for mRNA by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), while synaptic membranes were studied for both GABAA receptor pharmacology and subunit protein levels by Western blots with isoform-specific antibodies. Although α1 and α3 mRNA species were more strongly expressed in alcoholics irrespective of cirrhosis than in controls, α1 protein differed little between case groups, and α3 protein showed some complex variations. Differences in GABAA pharmacology conformed more closely with differences in protein levels than with altered mRNA expression.

The neuropathology of alcohol-specific brain damage, or does alcohol damage the brain?

The aim of this review is to identify neuropathological changes that are directly related to the long-term use of excessive amounts of alcohol (ethanol). There is still debate as to whether alcohol per se causes brain damage. The main problem has been to identify those lesions caused by alcohol itself and those caused by other common alcohol-related factors, principally thiamin deficiency. Careful selection and classification of alcoholic cases into those with and without these complications, together with detailed quantitative neuropathological analyses, has provided us with useful data. There is brain shrinkage in uncomplicated alcoholics which can largely be accounted for by loss of white matter. Some of this damage appears to be reversible. However, alcohol-related neuronal loss has been documented in specific regions of the cerebral cortex (superior frontal association cortex), hypothalamus (supraoptic and paraventricular nuclei), and cerebellum. The data is conflicting for several regions: the hippocampus, amygdala and locus ceruleus. No change is found in the basal ganglia, nucleus basalis, or serotonergic raphe nuclei. Many of the regions that are normal in uncomplicated alcoholics are damaged in those with the Wernicke-Korsakoff syndrome. Dendritic and synaptic changes have been documented in uncomplicated alcoholics and these, together with receptor and transmitter changes, may explain functional changes and cognitive deficits that precede the more severe structural neuronal changes. The pattern of damage appears to be somewhat different and species-specific in animal models of alcohol toxicity. Pathological changes that have been found to correlate with alcohol intake include white matter loss and neuronal loss in the hypothalamus and cerebellum.

Selective damage to the cerebellar vermis in chronic alcoholism: a contribution from neurotoxicology to an old problem of selective vulnerability

The curiously consistent localization of cerebellar cortical damage in chronic alcoholism is re-evaluated in the light of selective damage, with a similar topography in the cerebellar vermal region, in superficial siderosis in man and in experimental animals exposed to certain toxic substances. Attention is drawn to the capacity for Purkinje cell dendrites and Bergmann glia to extract materials from the CSF, and to the close anatomical relationships of the susceptible lobules I-II, IX and X to the roof of the IVth ventricle and to the cistern of the great cerebral veins. This restriction of damage to vermis and paravermis may reflect some compartmentalization of CSF flow within leptomeninges, consistently increasing exposure of these cerebellar surfaces to materials circulating in the CSF. In other circumstances when this pattern of damage is encountered it raises the question as to whether other environmental agents, gaining access to the CSF, may be similarly distributed.