Participation of cAMP/PKA-Mediated Signaling Pathways in Functional Activity of Regeneration-Competent Cells in the Nervous Tissue under Conditions of Ethanol-Induced Neurodegeneration.

We studied the involvement of cAMP/PKA signaling in the realization of the growth potential of neural progenitors and secretion of neurotrophic growth factors by glial elements under conditions of ethanol-induced neurodegeneration in vitro and in vivo. The stimulating role of cAMP and PKA in cell cycle progression of the neural progenitor cells and in production of neurotrophins by the cells in nervous tissue under the optimal conditions to vital activity was demonstrated. Ethanol inverted the role of cAMP/PKA signaling pathways in determination of the proliferation-differentiation status of neural stem cells. Selective blockade of adenylate cyclase or PKA in neural stem cells increased the rate of their division against the background of relative decrease in differentiation rate. In addition, cAMP/PKA signaling does not longer participate in neurotrophin production by glial cells in neurodegeneration. These findings suggest that inhibitors of activity/expression of adenylate cyclase and PKA can be considered as possible drugs with regenerative activity for the treatment of nervous system pathologies provoked by alcohol.

Component processes of memory in alcoholism: pattern of compromise and neural substrates.

Initially, alcohol-related memory deficits were considered only through the prism of Korsakoff's syndrome (KS). It is now clear, however, that chronic alcohol consumption results in memory disorders in alcoholics without ostensible neurologic complications, such as Wernicke's encephalopathy and KS. Most of the principal memory components are affected, including working memory, episodic memory, semantic memory, perceptual memory, and procedural memory. The extent of those cognitive impairments depends on several factors, such as age, gender, nutritional status, and psychiatric comorbidity. While memory disorders, especially episodic memory deficits, are largely definitive in patients with KS, recovery of memory abilities has been described with abstinence in uncomplicated alcoholics. Neuropsychologic impairments, and especially memory disorders, must be evaluated at alcohol treatment entry because they could impede patients from benefiting fully from cognitive and behavioral treatment approaches for alcohol dependence. Screening of memory deficits could also enable clinicians to detect, among alcoholics without ostensible neurologic complications, those at risk of developing permanent and debilitating amnesia that features KS.

Alcoholic metabolic emergencies.

Ethanol intoxication and ethanol use are associated with a variety of metabolic derangements encountered in the Emergency Department. In this article, the authors discuss alcohol intoxication and its treatment, dispel the myth that alcohol intoxication is associated with hypoglycemia, comment on electrolyte derangements and their management, review alcoholic ketoacidosis, and end with a section on alcoholic encephalopathy.

Morphological and glucose metabolism abnormalities in alcoholic Korsakoff's syndrome: group comparisons and individual analyses.

BACKGROUND: Gray matter volume studies have been limited to few brain regions of interest, and white matter and glucose metabolism have received limited research attention in Korsakoff's syndrome (KS). Because of the lack of brain biomarkers, KS was found to be underdiagnosed in postmortem studies. METHODOLOGY/PRINCIPAL FINDINGS: Nine consecutively selected patients with KS and 22 matched controls underwent both structural magnetic resonance imaging and (18)F-fluorodeoxyglucose positron emission tomography examinations. Using a whole-brain analysis, the between-group comparisons of gray matter and white matter density and relative glucose uptake between patients with KS and controls showed the involvement of both the frontocerebellar and the Papez circuits, including morphological abnormalities in their nodes and connection tracts and probably resulting hypometabolism. The direct comparison of the regional distribution and degree of gray matter hypodensity and hypometabolism within the KS group indicated very consistent gray matter distribution of both abnormalities, with a single area of significant difference in the middle cingulate cortex showing greater hypometabolism than hypodensity. Finally, the analysis of the variability in the individual patterns of brain abnormalities within our sample of KS patients revealed that the middle cingulate cortex was the only brain region showing significant GM hypodensity and hypometabolism in each of our 9 KS patients. CONCLUSIONS/SIGNIFICANCE: These results indicate widespread brain abnormalities in KS including both gray and white matter damage mainly involving two brain networks, namely, the fronto-cerebellar circuit and the Papez circuit. Furthermore, our findings suggest that the middle cingulate cortex may play a key role in the pathophysiology of KS and could be considered as a potential in vivo brain biomarker.

Suppression of neuro-inflammatory signaling cascade by tocotrienol can prevent chronic alcohol-induced cognitive dysfunction in rats.

Chronic alcohol intake is known to induce the selective neuronal damage associated with increase oxidative-nitrosative stress and activation of inflammatory cascade finally resulting in neuronal apoptosis and thus dementia. In the present study, we investigated the comparative effect of both the isoforms of vitamin E, alpha-tocopherol and tocotrienol against chronic alcohol-induced cognitive dysfunction in rats. Male Wistar rats were given ethanol (10g/kg; oral gavage) for 10 weeks, and treated with alpha-tocopherol and tocotrienol for the same duration. The learning and memory behavior was assessed using Morris water maze and elevated plus maze test. The rats were sacrificed at the end of 10th week and cytoplasmic fractions of cerebral cortex and hippocampus were prepared for the quantification of acetylcholinesterase activity, oxidative-nitrosative stress parameters, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). From the 6th week onwards, ethanol-treated rats showed significant increase in transfer latency in both the behavioral paradigms which was coupled with enhanced acetylcholinesterase activity, increased oxidative-nitrosative stress, TNF-alpha and IL-1beta levels in different brain regions of ethanol-treated rats. Co-administration of alpha-tocopherol as well as tocotrienol significantly and dose-dependently prevented these behavioral, biochemical and molecular changes in the brains of ethanol-treated rats. However, the effects were more pronounced with tocotrienol. The current study thus demonstrates the possible involvement of oxidative-nitrosative stress mediated activation of inflammatory cascade in chronic alcohol-induced cognitive dysfunction and also suggests the effectiveness of vitamin E isoforms, of which tocotrienol being more potent, in preventing the cognitive deficits associated with chronic alcohol consumption.

Influence of reboxetine on salivary MHPG concentration and cognitive symptoms among patients with alcohol-related Korsakoff's syndrome.

This study is based on the hypothesis of a paraventricular cerebral noradrenaline deficit in alcoholic Korsakoff's syndrome. In a randomized open study the effects of a 4-week treatment with the selective noradrenaline reuptake inhibitor reboxetine on (1) the salivary concentration of the noradrenaline metabolite MHPG and (2) changes in cognitive performance measured by the Mini Mental Status Test were examined. The study group consisted of 105 patients diagnosed with alcohol-related Korsakoff's syndrome (ICD-10: F10.6). Korsakoff's patients showed a reduced concentration of salivary MHPG compared to healthy controls; this reduction did not correlate with the results of the Mini Mental Status Test. An increase in salivary MHPG was found together with an improvement in the Mini Mental Status Test both in the verum group treated with reboxetine and in the control group upon completion of the 4-week study. However, a subgroup with a shorter duration of disease (<1 year) was found to profit significantly from reboxetine treatment, as shown by improvements in cognitive performance.

The role of thiamine deficiency in alcoholic brain disease.

A deficiency in the essential nutrient thiamine resulting from chronic alcohol consumption is one factor underlying alcohol-induced brain damage. Thiamine is a helper molecule (i.e., a cofactor) required by three enzymes involved in two pathways of carbohydrate metabolism. Because intermediate products of these pathways are needed for the generation of other essential molecules in the cells (e.g., building blocks of proteins and DNA as well as brain chemicals), a reduction in thiamine can interfere with numerous cellular functions, leading to serious brain disorders, including Wernicke-Korsakoff syndrome, which is found predominantly in alcoholics. Chronic alcohol consumption can result in thiamine deficiency by causing inadequate nutritional thiamine intake, decreased absorption of thiamine from the gastrointestinal tract, and impaired thiamine utilization in the cells. People differ in their susceptibility to thiamine deficiency, however, and different brain regions also may be more or less sensitive to this condition.

Regional cerebral blood flow and oxygen metabolism in a patient with Korsakoff syndrome.

We report a functional neuroimaging study of a patient clinically diagnosed with Korsakoff syndrome. Positron emission tomography (PET) with the 15O inhalation method showed decreased regional cerebral blood flow (rCBF) and decreased regional cerebral metabolic ratio for oxygen (rCMRO2) in the bilateral fronto-temporal areas and in the left thalamus. These results suggest that dysfunction of the frontal-thalamic neural network plays a role in the disturbance of Korsakoff syndrome.

In vivo localized proton NMR spectroscopy of thiamine-deficient rat brain.

Thiamine deficiency (TD) in rats produces lesions similar to those found in humans suffering from Wernicke's encephalopathy, an organic mental disorder associated with alcoholism. Male Sprague-Dawley rats (n = 29) were deprived of thiamine via a regimen of thiamine-deficient chow and daily intraperitoneal injections of the thiamine antagonist pyrithiamine hydrobromide. Spectra were obtained by using the STEAM sequence. No significant change occurred in the ratio of Cr/NAA, while the ratio of Cho/NAA declined significantly (60 +/- 11%) on Day 14. Eleven rats received intraperitoneal injections of thiamine hydrochloride at the end of 12 days, and dose-dependent recovery in Cho/NAA was observed.

Impaired melatonin secretion in patients with Wernicke-Korsakoff syndrome.

OBJECTIVES: Melatonin (MT) undergoes circadian changes in response to external light conditions and has been implicated in the control of other circadian hormone variations. Alcohol inhibits MT secretion in healthy subjects. The purpose of the present investigation was to elucidate whether patients with Wernicke-Korsakoff syndrome (WKS) also have impaired MT secretion after a period of prolonged alcohol abstention. If so, it would be of interest to find out whether this affects cortisol rhythmicity. DESIGN: Seven patients with WKS and 8 healthy controls were included in the study. Venous blood was sampled every 2nd h between 18.00 and 08.00 hours, and urine collected between 22.00 and 07.00 hours. SETTING: Department of Internal Medicine, Endocrinology Section, Södersjukhuset, Stockholm. MAIN OUTCOME MEASURES: Peak serum MT values during the night, total nocturnal MT secretion (estimated by MT incremental areas), and urinary excretion of MT were determined in each participant. Serum cortisol levels were determined in the patients at 18.00, 02.00 and 08.00 hours. RESULTS: Patients with WKS had a markedly reduced nocturnal secretion of MT compared to healthy volunteers (MT incremental areas 0.33 +/- 0.21 vs. 1.60 +/- 0.29 nmol L-1 h-1, mean +/- SEM; P < 0.005). Amongst the patients, the serum cortisol level was higher in the morning than in the afternoon (331 +/- 46 vs. 240 +/- 52 nmol L-1; P < 0.01), and showed a nadir during the night (138 +/- 45 nmol L-1) as in normal individuals. CONCLUSION: Patients with WKS have markedly reduced nocturnal secretion of MT. The exact mechanism behind this finding has to be further elucidated. However, it is of interest to note that despite the lack of clearcut circadian MT changes. WKS patients retain normal cortisol secretion, thus suggesting that MT rhythm may not be obligatory for the proper control of circadian cortisol rhythmicity.

Pharmacological manipulations of the alpha 2-noradrenergic system. Effects on cognition.

Electrophysiological and neurosurgical lesion studies with experimental animals have implicated the ascending dorsal noradrenergic bundle of the locus coeruleus system in cognitive process such as memory, learning and selective attention. However, it has also been suggested that noradrenaline (norepinephrine) is crucial in certain cognitive functions associated with the frontal lobes, particularly the prevention of distractibility by irrelevant stimuli. The alpha 2-receptors of the prefrontal cortex appear to be of particular importance in this respect. Studies with humans and experimental primates provide substantial support for this view. The aged primate brain is prone to degeneration of the locus coeruleus, as well as profound catecholamine depletion in the prefrontal cortex, and so is ideal for psychopharmacological investigation of the role of noradrenaline in frontal lobe function. Elderly monkeys show deficits in performance of the delayed response task, which can be reversed directly by both the mixed alpha 1/alpha 2-agonist clonidine, the more specific alpha 2-agonist guanfacine and also, indirectly, by the alpha 2-antagonist yohimbine. It is suggested that these results can be explained by an attenuation of the distracting properties of irrelevant stimuli following stimulation of noradrenergic activity. Conversely, distractibility is magnified whenever noradrenergic activity is reduced. This is supported by similar findings in psychopharmacological studies of healthy humans. The exception to this is when the locus coeruleus is likely to be firing, e.g. in times of stress or when novel stimuli are encountered. Clonidine attenuates locus coeruleus firing on such occasions, and so counteracts any beneficial (or deleterious) effects of stress on task performance. alpha 2-Adrenoceptor agents have little therapeutic value in patients with dementia of the Alzheimer's type. However, they may have some clinical use in patients who have a cognitive symptomatology similar to that of patients who have received neurosurgical excisions to the frontal lobes, e.g. deficits in working memory, executive function or focused attention, with relative sparing of episodic short term memory. Patients with Korsakoff's disease, attention deficit disorder or schizophrenia may benefit from treatment with alpha 2-agents. In particular, idazoxan has putative therapeutic effects in patients with a neurodegenerative disorder, namely dementia of frontal type.

Clonidine infusion increases uptake of 99mTc-Exametazime in anterior cingulate cortex in Korsakoff's psychosis.

The effects upon regional brain function of infusing either saline or clonidine (1.5 microgram/kg) has been examined in 18 patients with alcoholic Korsakoff's psychosis using 99mTc-hexamethylpropyleneamineoxime (99mTc-HMPAO or 99mTc-Exametazime) and Single Photon Emission Tomography (SPET or SPECT). The hypothesis tested was that frontal lobe function would be increased by adrenoceptor stimulation. This was confirmed by an increase in the uptake of 99mTc-Exametazime into anterior cingulate regions of the frontal lobes. Patients were scanned before and after saline or clonidine infusion during performance of a verbal fluency task. There was a significantly increased performance of verbal fluency in patients given clonidine. This effect was variable and could not be unequivocably distinguished from increases in performance in the saline treated group. Nevertheless, the increase in neuropsychological performance was also correlated with increased function in left dorsolateral frontal cortex within the clonidine treated group. An exploratory examination of other brain areas suggested that relative increases in posterior cingulate cortex and changes in the symmetry of function within the thalamus may also be produced by acute infusion of clonidine in Korsakoff patients. The findings support the idea that adrenergic mechanisms may modulate cognitive performance by actions on attentional systems within the brain. These appear to be located primarily within limbic cortex. It is, of course, notable that this can occur in patients with profound and disabling amnesia.

Thiamine utilization in the pathogenesis of alcohol-induced brain damage.

There is increasing evidence for the role of thiamine deficiency in ethanol neurotoxicity and in development of alcoholic organic brain disorders other than Wernicke-Korsakoff syndrome [WKS] and cerebellar degeneration. Investigations in humans and in animal models have implicated a reduction in the activities of thiamine-utilizing enzymes as the metabolic basis of tissue injury due to thiamine deficiency. We have investigated the interactions of the thiamine-utilizing enzyme transketolase [Tk], derived from human fibroblasts, lymphoblasts, and various brain regions, with its cofactor, thiamine pyrophosphate [TPP], in an attempt to elucidate the molecular basis of selective brain damage in alcoholism-associated thiamine deficiency. There were no significant differences in the isoelectric pattern of Tk among the nine brain regions (white matter and grey matter) examined. However, Tk activity/mg protein, increase in Tk activity with addition of excess TPP (TPP effect), and TPP-dependent rate of formation of active Tk holoenzyme (tau) varied 2.5-, 6-, and 4-fold, respectively, among these brain regions. These differences in tissue requirements for TPP may contribute to the selective vulnerability of certain brain regions to alcoholism-associated thiamine deficiency, and may influence the pattern of clinical impairment in the individual patient.

[Rationale for alcohol consumption and mitochondrial aldehyde dehydrogenase genotype in the native male population of Chukotka]. / Osobennosti potrebleniia alkogolia i genotip mitokhondrialnoi aldegidrogenazy u korennykh muzhchin Chukotki.

To study the alcohol consumption pattern and mitochondrial aldehyde dehydrogenase (ALDH2) genotype, a random sample consisting of 170 native males (Chukchee and the Eskimo), residents of 4 Chukotka settlements, was studied. According to interviews, most residents (68%) consumed alcohol once or twice a month; however during an alcohol uptake episode they consumed very high (intoxicating) doses exceeding 150 g of pure alcohol. The rates of control loss, alcohol amnesia and withdrawal syndrome were more than 50%. Twelve per cent reported inconsistent facial flushing after drinking and positive ethanol-patch test was found only in 2% of cases. Direct genotyping, using specific oligonucleotide probes, showed no atypical oriental type ALDH2. The normal genotype (ALDH2-1) was present in all the examinees from Chukotka natives (n = 87). These results explain the ability of Chukotka natives to consume high amounts of alcohol per occasion and they are in disagreement with the hypothesis that the drinking pattern among the natives is explained by specific features of alcohol-metabolising enzymes.

Brainstem serotonergic neurons in chronic alcoholics with and without the memory impairment of Korsakoff's psychosis.

There are several lines of evidence to suggest that serotonergic neurons in the brain are detrimentally affected by chronic alcohol consumption. The present study aims to quantify pathological changes in brainstem regions containing serotonergic neurons in chronic alcoholics compared to age-matched non-alcoholic controls. An antibody specific for tryptophan hydroxylase was used to immunohistochemically demonstrate serotonergic neurons in serial sections of postmortem brainstem. The cases analyzed were divided into four groups on the basis of their clinical and pathological presentation; chronic alcoholics with Wernicke's encephalopathy, chronic alcoholics with additional Korsakoff's psychosis, non-alcoholic controls, and a single chronic alcoholic without neurological complications. There was an overall reduction in the number of serotonergic neurons in all alcoholic cases when compared with controls. All brainstem regions were affected, but the largest neuronal loss was found in areas of the medullary and caudal pontine reticular formation (reduced by 80-90%). Alcoholics with Korsakoff's psychosis did not differ in the amount or extent of pathology from the other alcoholic cases analyzed. The data indicate that significant numbers of serotonergic neurons degenerate in chronic alcoholics. Such a loss is likely to have significant clinical consequences.

Increased central immunoreactive beta-endorphin content in patients with Wernicke-Korsakoff syndrome and in alcoholics.

beta-endorphin, adrenocorticotrophin, and alpha-melanocyte stimulating hormone were measured by radioimmunoassay in three areas of human brain at necropsy in seven subjects with Wernicke-Korsakoff syndrome and in 52 controls. Thiamin concentration in six brain areas was also measured. Mamillary body beta-endorphin concentrations were significantly increased in those with the syndrome compared with controls, and those controls with high alcohol intake showed increased mamillary body beta-endorphin compared with controls with low alcohol intake. Brain thiamin concentration was similar in both groups, with the exception of the brainstem, where it was reduced in subjects with Wernicke-Korsakoff syndrome. Thalamic beta-endorphin in controls was inversely correlated with thiamin in frontal white matter, frontal cortex, parietal white matter and parietal cortex, while beta-endorphin in the hypothalamus of patients was inversely correlated with thiamin in frontal cortex, parietal white matter, thalamus and brainstem. These results suggest that there is a disturbance of the endorphinergic system in Wernicke-Korsakoff syndrome which may be related to alcohol intake.

The Korsakoff syndrome: a neurochemical perspective.

Korsakoff's disease is an amnesic syndrome associated with midline diencephalic and brain stem pathology. A number of neurochemical systems course through or near the loci of brain lesions found postmortem in Korsakoff patients, which has stimulated studies to learn whether these systems are implicated in amnesia. Data suggest that the loss of brain catecholamine function contributes to this amnesic syndrome and may also be a factor in the memory impairments associated with normal aging. At present, data are insufficient to determine whether cholinergic systems are disturbed in Korsakoff's patients; however, it is likely that multiple neurochemical abnormalities underlie this disorder.

Effects of thiamine deficiency on brain metabolism: implications for the pathogenesis of the Wernicke-Korsakoff syndrome.

Chronic alcoholism results in thiamine deficiency as a consequence of inadequate dietary intake and of impaired absorption of the vitamin. In addition, there is evidence to suggest that alcohol reduces thiamine phosphorylation to thiamine pyrophosphate (TPP) in brain. TPP is a cofactor for the pyruvate dehydrogenase complex (PDHC), alpha-ketoglutarate dehydrogenase (alpha KGDH) and transketolase (TK), three enzymes involved in cerebral glucose and energy metabolism. Pyrithiamine-induced thiamine deficiency in the rat results in early, selective, reversible reductions of alpha KGDH in brain; PDHC activities are unaffected. Reductions of alpha KGDH are accompanied by decreased aspartate, glutamate and GABA and by concomitantly increased alanine in the brain of thiamine-deficient animals. It is suggested that decreased alpha KGDH, rather than decreased PDHC constitutes 'the biochemical lesion' in thiamine deficiency encephalopathy first enunciated by Peters in the 1930s. If sufficiently prolonged and severe, thiamine deficiency results in brain cell death. Possible mechanisms involved include compromised cerebral energy metabolism and focal accumulation of lactate, both of which could result from decreased activities of alpha KGDH. In addition, it is proposed that brain cell death in severe thiamine deficiency may result from excessive release of excitotoxic amino acids. Comparable mechanisms could be involved in the cell death and in the pathogenesis of the thiamine-unresponsive symptoms of the Wernicke-Korsakoff Syndrome in humans.

Alcoholic organic brain disease: nosology and pathophysiologic mechanisms.

Study of alcoholic chronic organic brain syndrome may have applicability to the large population of alcoholics with less severe cerebral dysfunction. Brain impairment in alcoholics may be conceptualized as two clinically and neuropathologically distinguishable organic brain syndromes: alcohol amnestic disorder or Korsakoff's psychosis (KP) and alcoholic dementia. Alcoholic organic brain disease may result from two interacting pathophysiological processes: nutritional (thiamine) deficiency and ethanol neurotoxicity. Subcortical periventricular lesions associated with KP result primarily from thiamine deficiency, whereas ethanol neurotoxicity and various secondary effects of alcoholism may contribute to the cortical neuropathological changes associated with alcoholic dementia. These two patterns of brain damage may be differentiable in individual alcoholics using cognitive tests and other measures of CNS function and, therefore, allow selection of a treatment strategy based on pathophysiological considerations. Studies in animals and humans suggest that a genetic predisposition to thiamine deficiency may contribute to alcoholism-associated dysfunction of brain and other organ systems and possibly have a causative role in the development of alcoholism.

Trace elements in brains of patients with alcohol abuse, endogeneous psychosis and schizophrenia.

The concentrations of Co, Fe, Rb, Se and Zn were analysed, by means of neutron activation analysis, in the brains of three patients with alcohol abuse, of one patient with endogeneous psychosis and of one patient with schizophrenia. The patients with alcohol abuse suffered from the Wernicke-Korsakoff syndrome. The data were compared with results from brains which were not diseased ("normals"). Patients with alcohol abuse had diminished values of rubidium in nearly all analysed samples of cerebral nuclei (greater than 30% compared to normals), whereas the Rb values were normal or diminished in cortical regions. The cobalt values were reduced (greater than 20%) in eight out of 14 nuclei and in five out of nine cortical regions. Differences in the Fe and Se values were mainly located in the cerebral nuclei. In the caudate nucleus the patient with endogeneous psychosis had highly significant elevated values of all analysed elements. The element concentrations of the patient with schizophrenia did not significantly differ from those of normal controls. The loss of nearly all elements was conspicuous in those regions which show neuro-pathological cell degeneration or atrophy in the case of Wernicke-Korsakoff syndrome. This loss of element concentrations in patients with alcohol abuse is interpreted as a loss of cellular vitality.