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Biomedical subjects

R Nordmann

Publications and source records attributed to R Nordmann.

At least 37 records · Page 2Linked to original sources
PubMed1990

Ethanol-induced lipid peroxidation and oxidative stress in extrahepatic tissues.

An ethanol-induced oxidative stress is not restricted to the liver, where ethanol is actively oxidized, but can affect various extrahepatic tissues as shown by experimental data obtained in the rat during acute or chronic ethanol intoxication. Most of these data concern the central nervous system, the heart and the testes. An acute ethanol load has been reported to enhance lipid peroxidation in the cerebellum. This is accompanied by an increase in the cytosolic concentration of low-molecular-weight iron derivatives which may contribute to the generation of aggressive free radicals. The ethanol-induced decrease in the main antioxidant systems (superoxide dismutase, alpha-tocopherol, ascorbate and selenium) is a likely contributor to the cerebellar oxidative stress. Most of these disturbances can be prevented by allopurinol administration. Some experimental data support also the occurrence of pro- and anti-oxidant disturbances in the cerebellum and in other regions of the central nervous system after chronic ethanol administration. Chronic ethanol administration enhances lipid peroxidation in the heart. The increased conversion of xanthine dehydrogenase into xanthine oxidase as well as the activation of peroxisomal acyl CoA-oxidase linked to ethanol administration could contribute to the oxidative stress. Chronic ethanol administration elicits in the testes an enhancement in mitochondrial lipid peroxidation and a decrease in the glutathione level, which appear to be correlated to the gross testicular atrophy observed. Vitamin A supplementation attenuates the changes in lipid peroxidation, glutathione and testicular morphology. Whether the reported disturbances are involved in the pathogenesis of the tissue disorders observed in alcoholic patients remains unanswered.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism↗
PubMed1990

Iron chelation by deferoxamine inhibits lipid peroxidation during cardiopulmonary bypass in humans.

Iron catalysis is involved in oxygen-derived free radical generation and subsequent lipid peroxidation, which have been reported to occur during cardiopulmonary bypass in humans. We assessed the effects of the iron chelator deferoxamine on the susceptibility of circulating low density lipoproteins (LDLs) to induced peroxidation in 20 adult patients (10 controls and 10 treated) undergoing cardiopulmonary bypass for coronary or valve procedures. Deferoxamine was given both intravenously (30 mg/kg body wt, starting 30 minutes before bypass and extending for the next 4 hours) and as an additive to the cardioplegic solution (250 mg/l). Blood samples were taken from both atria before and immediately after the end of cardiopulmonary bypass. Plasma lipid peroxidation was assessed by measuring spectrophotometrically the thiobarbituric acid reactive substances (TBARS) content of selectively isolated LDLs after their exposure to a peroxidizing agent. Before cardiopulmonary bypass, the right and left atrial blood values of LDL-TBARS were not significantly different between the two groups. Cardiopulmonary bypass resulted in a lipid peroxidation of significantly greater magnitude in control than in treated patients. Postbypass right atrial values for LDL-TBARS (expressed in mumol/mmol LDL-phospholipids) were 45.7 +/- 17.2 (mean +/- SEM) in control patients and 6.9 +/- 2.9 in treated patients (p less than 0.02), whereas in the left atrial blood, LDL-TBARS yielded values of 62.7 +/- 20.5 and 10.3 +/- 3.9, respectively (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiopulmonary Bypass↗
PubMed1990

[Alcohol, iron and oxidative stress].

An oxidative stress has been reported to occur at the hepatic level after ethanol administration. We recently reported that such a stress is also apparent at the cerebellar level during acute ethanol intoxication in rats. Since low molecular weight iron chelates (LMW-Fe) are involved in the biosynthesis of aggressive prooxidant species we presently studied the influence of acute and chronic ethanol administration on hepatic and cerebellar total non-heme iron and LMW-Fe. The results show that an acute ethanol load (50 mmoles/kg b. wt.) administered (i.p.) to male Sprague-Dawley rats elicits altogether a decrease in the non-heme iron content of the serum and a highly significant increase in the hepatic and cerebellar non-heme iron concentration. The LMW-Fe content as well as the percentage of total non-heme iron represented by LMW-Fe are increased at the same time in the cytosolic fraction isolated from hepatic and cerebellar homogenates of the acutely ethanol-treated rats. The ethanol-induced disturbances in the non-heme iron content of liver and cerebellum can be prevented by the administration of allopurinol, which is known to reduce the severity of the oxidative stress observed in these tissues after an acute ethanol load. To study the effects of chronic ethanol administration, rats were given during 4 weeks a 10% (v/v) solution of ethanol in water as sole drinking fluid. The average daily ethanol consumption was 7-9 g. In such alcohol-fed rats the non-heme iron content was decreased by 31% in the serum whereas it was increased by 18% in the liver and by 30% in the cerebellum.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism↗
PubMed1989

Kinetics of interleukin 2 mRNA and protein produced in the human T-cell line Jurkat and effect of cyclosporin A.

The kinetics of interleukin 2 mRNA accumulation in the leukemic T-cell line Jurkat, which can be induced with phytohemagglutinin and phorbol 12-myristate 13-acetate to produce large amounts of interleukin 2, was analyzed by a modified DNA-excess solution hybridization assay using a 5'-32P-labeled oligodeoxyribonucleotide 30 bases long as probe. Cyclosporin A was used as a valuable tool to gain more insight into the quantitative aspects of interleukin 2 production, on the basis of the assumption that transcription of the interleukin 2 gene is completely inhibited shortly after administration of cyclosporin A. The half-life of interleukin 2 mRNA was estimated to be approximately 2 h. With the aid of simple mathematical models, we have been able to relate the concentration of interleukin 2 protein in the supernatant to the interleukin 2 mRNA kinetics. This novel quantitative kinetic analysis revealed that, independent of the absence or presence of cyclosporin A, interleukin 2 protein is synthesized at a rate of approximately 1.3 molecules per molecule of interleukin 2 mRNA per second and secreted within 2 h after it is synthesized and that its half-life in the supernatant is approximately 10 h.

Base Sequence↗
PubMed1989

Gamma and pulse radiolysis investigation of the reaction of desferrioxamine with superoxide anions.

The kinetic scheme of the reaction of desferrioxamine (DFO) with O2-. was studied using pulse and gamma-radiolysis. The rate constant k(O2-. + DFO) is equal to 1.3 +/- 0.1 x 10(6) dm3 mol-1s-1 at pH 7.4. Studying the competition between DFO and ferricytochrome-c for O2-. generated by gamma-radiolysis, we observed that the nitroxide free radical resulting from the reaction of O2-. with DFO and the product(s) resulting from the decay of this nitroxide radical act inversely towards the cytochrome-c-Fe3+/cytochrome-c-Fe2+ redox couple. This explains the discrepancy between our value of k(O2-. + DFO) and the one measured previously using ferricytochrome-c for the detection of O2-. The reported results show that DFO acts as a powerful O2-. scavenger, and that the products resulting from the reaction of DFO with O2-. can initiate oxidative and/or reductive reactions that should be taken into account in interpreting the effects of DFO in vitro and in vivo.

Anions↗
PubMed1989

[Changes in cerebellar iron metabolism and their prevention by allopurinol in oxidative stress related to acute ethanol administration in rats].

An acute ethanol load results in an increased total nonheme iron and cytosolic low molecular weight iron content in rat cerebellum. At the same time the cerebellar susceptibility to lipid peroxidation is enhanced whereas the alpha-tocopherol and ascorbate content is decreased. These changes argue for a cerebellar ethanol-induced oxidative stress, which is prevented by prior allopurinol administration.

Allopurinol↗
PubMed1987

Ethanol alters the adenosine receptor-Ni-mediated adenylate cyclase inhibitory response in rat brain cortex in vitro.

It has been suggested that ethanol stimulates adenylate cyclase in vitro through an increased function of Ns, the activatory component of adenylate cyclase. Because of the interaction of Ns with Ni, the adenylate cyclase inhibitory component, we have studied the effect of ethanol (0.05-0.2 M) on Ni-mediated adenylate cyclase inhibition caused by the adenosine analog N6-phenylisopropyladenosine (N6-PIA) in brain cortical membranes. Ethanol did not alter N6-PIA binding to the adenosine Ri-receptors, stimulated slightly basal adenylate cyclase activity but abolished adenylate cyclase inhibition due to N6-PIA, suggesting an effect of ethanol on the inhibitory coupling pathway. This was further supported by loss of the adenylate cyclase inhibitory response to GTP (greater than 10(-5) M). It thus seems that, besides its effect on the Ns system, ethanol may also impair Ni-mediated adenylate cyclase responses in rat cerebral cortex.

Adenosine↗
PubMed1987

Involvement of iron and iron-catalyzed free radical production in ethanol metabolism and toxicity.

Lipoperoxidation, a degradative process of membranous polyunsaturated fatty acids, has been suggested to represent an important mechanism in the pathogenesis of ethanol toxicity on the liver and possibly also on the brain. Catalysis by transition metals, especially iron, is involved in the biosynthesis of free radicals contributing to lipid peroxidation. Although the exact nature of the redox-active iron implicated in this catalysis is still unknown, it has been well established that lipid peroxidation can be prevented in vitro by iron chelators such as desferrioxamine. Deprivation of redox-active iron through desferrioxamine inhibits by about 50% the microsomal oxidation of ethanol in vitro and reduces very significantly in vivo the overall ethanol elimination rate in rats. Administration of desferrioxamine together with ethanol also reduces the ethanol-induced disturbances in the antioxidant defense mechanisms of the hepatocyte. It also reduces in mice both the severity of physical dependence on ethanol and lethality following the acute administration of a narcotic dose of ethanol. Chronic overloading of rats with iron results, on the opposite, in an increased rate of ethanol elimination, although alcohol dehydrogenase and catalase activities are reduced and cytochrome P-450 depleted in the liver of such iron-overloaded animals. The magnitude of the ethanol-induced increase in lipid peroxidation and decrease in the major membranous antioxidant, alpha-tocopherol, is exacerbated in iron-overloaded rats. Several disturbances of iron metabolism have been reported in human alcoholics. Their contribution to ethanol toxicity appears very likely in the case of hepatic siderosis associated with alcohol abuse. Ethanol could however disturb iron metabolism even in the absence of gross abnormalities of the total iron stores. It is suggested that ethanol intoxication could increase cellular redox-active iron, thus contributing to an enhanced steady-state concentration of reactive-free radicals. This oxidative stress would lead to lipoperoxidative damage and cellular injury.

Alcoholic Intoxication↗
PubMed1987

Mitochondrial generation of superoxide free radicals during acute ethanol intoxication in the rat.

Two hours after an acute ethanol load (50 mmol/kg, i.p.), brain mitochondrial superoxide production was unchanged. This is contrary to our previous findings concerning liver mitochondria. On the other hand, the ethanol treatment caused a marked inhibition of respiration stimulated by phosphate plus ADP (with succinate or pyruvate plus malate as substrates) (state 3) in the brain mitochondria, whereas it did not exert any modification on the hepatic mitochondrial electron transport chain.

Alcoholic Intoxication↗
PubMed1987

Ethanol-induced oxidative stress in the rat cerebellum.

An acute ethanol load (50 mmol/kg, i.p.) produces an increase in lipid peroxidation in the rat cerebellum. The levels of ascorbate and alpha-tocopherol, which represent efficient antioxidants acting synergetically, are decreased. This decrease seems highly indicative of a consumption of the antioxidants in quenching free radicals and suggests that acute ethanol induces an oxidative stress at the cerebellar level. As allopurinol, a xanthine oxidase inhibitor, prevents the decrease in alpha-tocopherol, xanthine oxidase may contribute to this oxidative stress.

Allopurinol↗
PubMed1987

Oxidative stress from alcohol in the brain.

An acute ethanol load administered to rats results in an enhancement in lipid peroxidation in the cerebellum, a brain area which is particularly sensitive to free radical attack. The ethanol load induces also a decrease in the cerebellar concentration of the three main endogenous anti-oxidant small molecules, i.e. alpha-tocopherol, ascorbate and glutathione. These findings are highly suggestive of a cerebellar oxidative stress due to acute ethanol administration. However this administration does not enhance brain mitochondrial superoxide production as well as cerebellar mitochondrial hydrogen peroxide production. An oxidative stress could also play a role in some effects of chronic alcohol intoxication on the brain. This is particularly suggested by the beneficial effects of the administration of desferrioxamine, an iron-chelator and free radical scavenger, on physical dependence on alcohol in rodents. A speculative synthesis of the mechanisms that might be involved in such an oxidative stress on the central nervous system is presented.

Alcoholism↗
PubMed1986

Prolactin as a modulator of lymphocyte responsiveness provides a possible mechanism of action for cyclosporine.

Lymphocyte responsiveness in rats was found to depend on serum prolactin levels. Blocking pituitary prolactin release with bromocriptine severely reduces lymphocyte reactivity in vitro (mixed lymphocyte reaction) as well as in vivo (graft-versus-host reaction). In addition, evidence for a prolactin/growth hormone-related mRNA species produced in mitogen- and antigen-stimulated lymphocytes has been obtained. Prolactin was shown to compete in a dose-dependent fashion with the immunosuppressant cyclosporine (cyclosporin A) for a common binding site on the surface of T lymphocytes. Further, stimulation of prolactin secretion reversed the immunosuppression induced by cyclosporine. We conclude that prolactin is involved in the maintenance of T-cell immunocompetence and that the immunosuppressive effects of cyclosporine may be mediated by the displacement of prolactin from binding sites on lymphocytes.

Animals↗
PubMed1986

Membrane fluidity and alcohol dependence.

Rats were chronically intoxicated with alcohol by exposing them to increasing concentrations of ethanol vapor over a 4-week period. They were tested for alcohol consumption in a free choice situation of water and 10% (v/v) alcohol. On the basis of their intakes they were divided into alcohol-dependent and nondependent groups. Synaptosome membrane fluidity evaluated by fluorescence polarization was compared between the two groups and against nonintoxicated controls. The intoxicated animals had a lower membrane fluidity than controls, mainly because of a highly significant increase of rigidity in the alcohol-dependent group. Furthermore, membrane fluidity was found to be correlated with the degree of behavioral dependence (i.e., alcohol intake during the free choice period).

Alcohol Drinking↗
PubMed1985

[3H]205-501, a non-catechol dopaminergic agonist, labels selectively and with high affinity dopamine D2 receptors.

[3H]205-501, a noncatechol dopaminergic agonist, is presented as a ligand with high affinity (KD approximately 1 nM) and high selectivity for dopamine receptors. pKi values of dopaminergic agonists derived from competition isotherms in the [3H]205-501 binding assay correlate very well with their potency in the acetylcholine release assay, which is controlled by dopamine D2 receptors. There is however no correlation with their potency stimulating adenylate cyclase, a process controlled by dopamine D1 receptors. Thus [3H]205-501 is the first agonist ligand selective for dopamine D2 receptors.

Acetylcholine↗
PubMed1985

Synthesis and pharmacological evaluation of cis-2,3,3a,4,5,6,7,7a-octahydro-3-oxoisoxazolo[5,4-c]pyridine: a structural analogue of the GABA agonist THIP.

The pharmacological activities of the GABA agonist muscimol (1) and its dihydro analogue (2) have been shown to be almost identical. The closely related 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 3), although biologically less active than muscimol, was selected for clinical trials. We report the synthesis of the so far elusive cis-2,3,3a,4,5,6,7,7a-octahydro-3-oxoisoxazolo[5,4-c]pyridine (cis-DH-THIP, cis-4), which--surprisingly--is devoid of any GABAergic activity.

Animals↗