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P A Wilce

Publications and source records attributed to P A Wilce.

At least 55 records · Page 3Linked to original sources
PubMed1993

Ethanol inhibits NMDA-receptor mediated regulation of immediate early gene expression.

The expression of c-fos mRNA in rat brain was induced by intraperitoneal (ip) administration of N-methyl-D-aspartate (NMDA) and kainic acid, agonists of different classes of glutamate receptors and by caffeine, an antagonist of adenosine receptors. The actions of NMDA but not kainic acid or caffeine were blocked by ethanol. Chronic exposure to ethanol vapour did not increase c-fos expression. However, ethanol-withdrawn rats showed a marked increase in c-fos expression. In situ hybridisation and immunohistochemistry indicated the expression was widely distributed in the brain but particularly in the cortex, hippocampus and the cerebellum. There was no marked change in the sensitivity of the NMDA receptor to inhibition by ethanol after chronic ethanol treatment. The withdrawal-induced expression of c-fos mRNA could be inhibited by prior administration of MK801. These results emphasise the NMDA receptor as an important site of ethanol action and the potential use of immediate early gene expression in neuropharmacology in vivo.

Alcoholism↗
PubMed1993

Chronic ethanol administration sensitizes hippocampal neurons to neurotoxicity of N-methyl-D-aspartic acid.

The hyperexcitability observed following ethanol withdrawal in dependent animals is thought to be related to increased sensitivity of glutamate receptors. This may predispose to 'excitotoxic' neural damage. The aim of this study was to test this hypothesis by intrahippocampal injection of N-methyl-D-aspartic acid (NMDA) in ethanol-dependent rats and to quantify brain damage using enzymic neuronal markers, viz. choline acetyltransferase (ChAT) and glutamate decarboxylase (GAD). Specific activity of GAD but not ChAT was found to be significantly decreased in hippocampi of ethanol-dependent animals following injection of NMDA, suggesting that chronic ethanol administration sensitizes GABAergic neurons to the toxic effects of excitatory amino acid transmitters.

Alcoholism↗
PubMed1992

Involvement of gamma-aminobutyric acid and N-methyl-D-aspartate receptors in the inhibitory effect of ethanol on pentylenetetrazole-induced c-fos expression in rat brain.

The expression of c-fos mRNA in rat brain was induced by intraperitoneal administration of pentylenetetrazole (PTZ) and picrotoxin, which act on the picrotoxin binding site of the gamma-aminobutyric acid-benzodiazepine (GABA-BZ) receptor complex, by N-methyl-D-aspartate (NMDA) and kainic acid, agonists of different classes of glutamate receptors and by caffeine, an antagonist of adenosine receptors. The actions of PTZ and picrotoxin but not that of NMDA were blocked by ethanol and the NMDA-receptor antagonist, MK-801. Ro 15-4513 partially reversed the inhibitory effect of ethanol on PTZ-induced c-fos mRNA synthesis. Acute ethanol administration blocked the actions of PTZ and NMDA without affecting the response to kainic acid or caffeine. Taken together, these data suggest that ethanol blocks c-fos gene activation by noncompetitive antagonists of the GABA-BZ receptor via actions on both the NMDA and GABA receptors.

Animals↗
PubMed1991

Effects of female sex hormones on lipid metabolism in the uterine epithelium of the mouse.

1. The effects of oestrogen and progesterone on synthesis and composition of lipids in the uterine epithelium were studied. 2. Oestrogen treatment for up to 18 hr resulted in an increased incorporation of [14C]acetate into all classes of lipids, but particularly into cholesterol. 3. Progesterone treatment increased incorporation into all classes of lipids except cholesterol and completely inhibited the oestrogen-induced incorporation into cholesterol. We suggest that this may be the mechanism whereby progesterone blocks uterine epithelial cell proliferation. 4. Oestrogen increased incorporation into all classes of phospholipids, and progesterone pretreatment inhibited the marked oestrogen-induced incorporation into phosphatidylinositol. 5. Both oestrogen and progesterone, but particularly progesterone, increased the epithelial cell phospholipid to cholesterol ratio. 6. Oestrogen induced changes in epithelial phospholipid fatty acyl composition: particularly marked was a time related reduction in 20:4 which was inhibited by progesterone pretreatment to only a minor degree.

Acetates↗
PubMed1991

Effect of estradiol and progesterone on phosphatidylinositol metabolism in the uterine epithelium of the mouse.

The effect of estradiol and progesterone on uterine phosphatidylinositol (PtdIns) metabolism was examined in whole uteri and separated uterine luminal epithelium of ovariectomized mice. Incorporation of [3H]myo-inositol in vitro, into inositol-containing phospholipids extracted from whole uteri, increased in mice injected with estradiol, with maximal incorporation at 9-12 h. The breakdown of PtdIns to inositol polyphosphates was also stimulated in whole uteri by estrogen, with an abrupt increase between 6 and 9 h. Comparable increases in both processes occurred in the uterine epithelium after estrogen stimulation and were inhibited by progesterone pretreatment which by itself had little or no effect. These results suggest that PtdIns metabolism is involved in the stimulation of uterine epithelial cell proliferation by estrogens, and its inhibition by progesterone.

Animals↗
PubMed1991

Detection of stable acetaldehyde-modified proteins in the livers of ethanol-fed rats.

Liver cytosolic fractions, obtained from rats pair-fed diets supplemented with either ethanol or an isocaloric amount of sucrose for periods from 3 weeks to 27 months, were tested for the presence of acetaldehyde-modified proteins by immunoblotting, using a partially purified antiserum raised in rabbits against proteins modified by acetaldehyde in vitro. The antiserum reacted with a large number of proteins in cytosolic fractions from ethanol-fed rats but did not react with any proteins in the same fraction from control animals. The duration of the ethanol-containing diet did not appear to influence the number of proteins modified or the total amount of modification within the time range tested. These results indicate that many proteins in rat liver cytosol are targets for modification by acetaldehyde in vivo.

Acetaldehyde↗
PubMed1991

Antibodies against acetaldehyde-modified epitopes: an elevated IgA response in alcoholics.

Several recent reports have shown that antibodies reactive with acetaldehyde (AcH)-modified epitopes are present in alcoholics. However, similar antibodies have also been found in patients with non-alcoholic liver disease and control subjects. In each of these studies total immunoglobulin binding to the AcH-modified proteins was measured, with no attempt being made to identify the classes of immunoglobulin involved. In the present study we employed an enzyme-linked immunosorbent assay (ELISA) to assess the classes of immunoglobulin involved in this response, using plasma samples from 97 alcoholics with varying degrees of liver disease, 35 patients with non-alcoholic liver disease and 33 control subjects. All three groups exhibited a large IgM response and a negligible IgG response. However, the alcoholics exhibited a significantly higher IgA response than either of the other groups. This suggests that the measurement of the IgA response to AcH-modified epitopes may be a specific marker of ethanol abuse.

Acetaldehyde↗
PubMed1991

Acute administration of ethanol suppresses pentylenetetrazole-induced c-fos expression in rat brain.

The effect of acute ethanol administration on pentylenetetrazole-induced c-fos expression in rat brain was studied. Pentylenetetrazole induced the rapid and transient expression of c-fos mRNA in rat brain. Maximal induction at a dose of 30 mg/kg was detected within 30 min and persisted for 60 min. Thereafter c-fos gene expression decreased to control levels by 180 min. No increase in c-fos mRNA was evident at doses of pentylenetetrazole < or = 20 mg/kg, whereas maximal elevation was seen at 30 or 40 mg/kg. This action was inhibited by acute ethanol treatment (blood alcohol level > or = 100 mg/dl). Acute ethanol treatment alone had no effect on c-fos gene expression.

Animals↗
PubMed1991

Acetaldehyde-modified proteins and associated antibodies in ethanol-fed rats.

Rats fed ethanol for periods of 3-27 months were found to produce an immune response to acetaldehyde-modified proteins, whereas treatment for a shorter period (3 weeks) did not lead to such a response. The antibodies from the ethanol-fed animals were shown to be reactive with a series of proteins modified by acetaldehyde in vitro. This suggests that reactivity towards the modified proteins is independent of the carrier protein, with antibodies being raised which interact solely with the acetaldehyde-containing adduct and not the protein itself. We have also been able to demonstrate the presence of modified proteins in the liver cytosol of these ethanol-fed rats. However, unlike previous reports which suggested that only one protein was modified, we found that many cytosolic proteins were modified. This suggests that the modification of proteins by acetaldehyde is less specific than was previously thought.

Acetaldehyde↗
PubMed1991

Alcohol abusers exhibit a higher IgA response to acetaldehyde-modified proteins.

In the present study we have used an enzyme-linked immunosorbent assay to measure the immunoreactivity towards acetaldehyde-modified proteins in plasma from alcoholics, patients with non-alcoholic liver disease and control social drinkers. All three groups showed a response to modified proteins when total immunoglobulin binding was measured. However, when the assay was modified such that class-specific immunoglobulin binding was measured, it was found that the alcoholic response had a significantly greater immunoglobulin A component than patients with non-alcoholic liver disease or controls who were social drinkers. Thus measurement of IgA binding to acetaldehyde-modified proteins may be a marker for alcohol abuse.

Acetaldehyde↗
PubMed1990

Antibodies against acetaldehyde-modified epitopes: presence in alcoholic, non-alcoholic liver disease and control subjects.

Several studies have recently shown the presence of antibodies against acetaldehyde-modifications in the sera of alcoholic patients. To assess the specificity of this immune response, plasma immunoreactivity with proteins modified in vitro by acetaldehyde was measured using an enzyme-linked immunosorbent assay in 97 alcoholic patients with varying degrees of alcoholic liver disease, in 35 patients with non-alcoholic liver diseases and in 33 control subjects who were social drinkers. All three groups showed some response against acetaldehyde-modified epitopes. The highest plasma reactivities were found in alcoholics, especially those with steatosis and alcoholic hepatitis. Plasma from patients with non-alcoholic liver disease and control subjects also reacted with the acetaldehyde conjugates, but to a lesser extent than plasma from alcoholics. The reliability of these antibodies as markers of either alcohol abuse or alcoholic liver disease therefore appears to be low. However, further studies using more precisely modified proteins or elucidation of the classes of immunoglobulin involved in the immune response against the modified proteins may give clearer differences between the three groups.

Acetaldehyde↗
PubMed1990

Interaction of chronic ethanol consumption and aging on brain muscarinic cholinergic receptors.

It has been proposed that ethanol and aging may interact synergistically to impair brain function through effects on central muscarinic receptors. Previous studies have investigated the effect of either chronic ethanol treatment or aging, but not both factors simultaneously, on brain muscarinic receptors. We have studied brain muscarinic receptors in animals treated with ethanol for up to 25 months. Ethanol consumption for 3 and 9 months resulted in increased density of quinuclidinyl benzilate (QNB) binding sites in cortex, coinciding with an increase in high-affinity pirenzepine binding sites and low-affinity carbachol binding sites. Upregulation of QNB binding sites in striatum and hippocampus became obvious after further ethanol treatment (15 and 21 months, respectively). Affinity of QNB binding sites and carbachol binding sites was not altered by ethanol treatment. However, there was an ethanol-related decrease in affinity of low-affinity pirenzepine binding sites in cerebral cortex. Density of QNB binding sites and low-affinity pirenzepine binding sites decreased with age in three brain areas investigated. There were age-related changes in receptor affinity in hippocampus and striatum, but not in cortex. Ethanol-related upregulation of muscarinic receptors was superimposed on age-related loss of receptors. We conclude that acceleration of the aging process associated with ethanol abuse is unlikely to be explained on the basis of alterations in receptor density or affinity.

Aging↗
PubMed1989

Plasticity of brain muscarinic receptors in aging rats: the adaptative response to scopolamine and ethanol treatment.

Young and aged rats were treated chronically with ethanol or scopolamine. Muscarinic receptors were measured in cerebral cortex, hippocampus and striatum. Following scopolamine treatment muscarinic receptor density in cerebral cortex, hippocampus and striatum of young rats increased by 34, 57 and 27%, respectively; in brains of aged rats the increase was 41% in cerebral cortex, 43% in hippocampus and nil in striatum. Affinity of muscarinic receptors was not changed by scopolamine treatment. Following chronic ethanol administration there was a 48% increase in cortical muscarinic receptor density in young, but not aged rats. The density of muscarinic receptors in hippocampus and striatum of both young and aged rats was not affected by ethanol treatment. Affinity of receptors in hippocampus of aged, ethanol-treated rats was increased compared to age-matched controls. Adaptative responses of the muscarinic receptor/transducer system to neurotransmitter availability are present in both young and aged rats, both the ethanol-induced response is present only in young animals. This suggests differences in the mechanism of action of ethanol and receptor agonists and antagonists in modulating receptor plasticity.

Aging↗
PubMed1989

A feeding regime for the study of the interaction of ethanol and aging.

A suitable model for the study of the interaction of the aging process and prolonged treatment with ethanol is described. Animals were given 15% ethanol in the drinking water for up to 25 months. There was little disruption in the growth of the animals. Ethanol treatment resulted in a number of neurological and morphological changes some of which persisted throughout the treatment period. Both young and old animals displayed metabolic tolerance by the criteria of resistance to ethanol-induced hypothermia and increased metabolism of [14C]ethanol. The regime used has proved useful in the study of the interaction of ethanol and aging in the rat.

Aging↗
PubMed1989

Ethanol induces the production of antibodies to acetaldehyde-modified epitopes in rats.

Rats treated with ethanol for periods of 3-27 months were found to produce an immune response to acetaldehyde-modified proteins, whereas treatment for a shorter period (3 weeks) did not lead to such a response. The reactivity towards the modified proteins was shown to be independent of the carrier protein as antibodies were reactive with modified human plasma proteins and modified bovine haemoglobin. The data presented here support the hypothesis that acetaldehyde-modified proteins may act as neoantigens in alcoholics and may play a role in the aetiology of alcoholic liver disease.

Acetaldehyde↗
PubMed1988

Desensitization of adenylate cyclase and cyclic AMP flux during the early stages of liver regeneration.

Liver regeneration is controlled by a complex network of interactions between hormones, growth factors, and a variety of hepatotrophic factors. Transient increases in cAMP in the early stages of liver regeneration that are necessary for DNA synthesis and subsequent mitosis have been reported; however, studies on the mechanisms that control cellular cAMP levels during liver regeneration, namely adenylate cyclase activity, cAMP-dependent phosphodiesterase activity, and cAMP efflux from the cell, have been generally incomplete. In this study we have shown that although there are three peaks in intracellular cAMP levels in the first 24 hours after partial hepatectomy, the adenylate cyclase activity stimulated by glucagon, prostaglandin E2, adrenaline, and fluoride in vitro decreases with time. KD and BMAX of hepatocyte glucagon and beta receptors were similar to the sham controls. Our results are consistent with a mixed homologous/heterologous desensitization of the adenylate cyclase system. There was also a loss of cAMP-dependent phosphodiesterase activity after partial hepatectomy. We speculate that even though the hormone-stimulated adenylate cyclase system has been desensitized, the system retains the ability to respond to the transient pulses of the variety of hormones secreted after partial hepatectomy and thus raise the intracellular concentration of cAMP. The decrease in cAMP-dependent phosphodiesterase may be necessary to prevent rapid breakdown of cAMP.

3',5'-Cyclic-AMP Phosphodiesterases↗