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Biomedical subjects

M B Youdim

Publications and source records attributed to M B Youdim.

At least 199 records · Page 11Linked to original sources
PubMed1986

Modulatory effects of thyroxine treatment on central and peripheral benzodiazepine receptors in the rat.

The effects of 10 days of D-thyroxine (T4) treatment on central benzodiazepine (BZ) receptors in the brain and on peripheral-type BZ binding sites in the heart, kidney, and testis of rats were studied. The experimental hyperthyroidism resulted in an increase in the density of cortical central BZ receptors, without any alteration of the affinity of the receptors to [3H]flunitrazepam. The increase in cortical central BZ receptors was also accompanied by the up-regulation of peripheral BZ binding sites in the heart, kidney, and testis. The affinity of the peripheral BZ binding sites for the ligand [3H]PK 11195 was not affected by T4 treatment in any of these three organs. The increase in the density of brain cortical central BZ receptors was less prominent than the increase in the peripheral BZ binding sites. The modulatory effect of T4 treatment on central and peripheral BZ receptors might be attributed to the direct interaction of the thyroid hormone at these sites or might reflect a physiological compensatory adaptation mechanism to thyrotoxicosis associated with hypermetabolism, anxiety, and stress.

Animals↗
PubMed1986

Monoamine oxidase activity and monoamine metabolism in brains of parkinsonian patients treated with l-deprenyl.

Monoamine oxidase (MAO) type A and type B were measured using kynuramine, 3,4-dihydroxyphenylethylamine (dopamine, DA), and 5-hydroxytryptamine (5-HT, serotonin) in 20 brain areas. The highest activities were found in the striatum (caudate nucleus, putamen, globus pallidus, and substantia nigra), hypothalamus, and c-mammilare. The ratio of DA to 5-HT deamination varied in the different regions, being in favor of DA in the striatum. With kynuramine as the substrate IC50 values of a number of inhibitors indicated that l-deprenyl was far more potent an inhibitor of human brain MAO than clorgyline or harmaline. N-Desmethylpropargylindane hydrochloride (AGN 1135) was also shown to have MAO-B inhibitory selectivity similar to that of l-deprenyl. Brains obtained at autopsy from l-deprenyl-treated Parkinsonian patients showed that, whereas MAO-B was fully inhibited by the therapeutic doses of l-deprenyl, substantial MAO-A activity was still evident. These results are matched by the significant increases of DA noted in caudate nucleus, globus pallidus, putamen, and substantia nigra and the unaltered 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the same regions. These data indicate that the therapeutic actions of l-deprenyl may lie in its selective inhibition of MAO-B resulting in increased brain levels of DA formed from L-dihydroxyphenylacetic acid (L-DOPA).

Aged↗
PubMed1986

Antiidiotypic antibodies raised against anti-prolactin (PRL) antibodies recognize the PRL receptor.

Antiidiotypic antibodies capable of recognizing the PRL receptor have been raised against antibodies to ovine PRL (oPRL) and rat PRL (rPRL). Anti-oPRL or anti-rPRL antibodies were induced in rats or rabbits, respectively, and the immunoglobulin G (IgG) fractions were isolated by affinity chromatography on a Protein A-Sepharose 4B column. Specific anti-oPRL antibodies were purified on an oPRL-Sepharose 4B affinity column. The specific antibodies (0.5 mg/rabbit) in Freund's complete adjuvant were injected into rabbits at 2- to 3-week intervals for 3 months. Antiidiotypic antibodies against rat anti-oPRL specifically inhibited [125I]iodo-oPRL binding to the immunizing anti-oPRL antibody. Membrane binding of the antiidiotypic antibodies was determined by [125I]iodo-Protein A precipitation. It was found to be significantly higher toward membrane preparations rich in PRL receptors, such as liver membranes from pregnant mice or from estradiol-treated male rats or prostate membranes from adult rats. This membrane binding by the antiidiotypic antibody was competitively inhibited by the immunizing anti-oPRL antibody, suggesting that the idiotypic antibody may share common determinants with the PRL receptor. Recognition of the PRL receptor by the antiidiotypic antibodies was also assayed by indirect binding studies. After preincubation of the antiidiotypic antibodies with the membranes, the resulting complex was precipitated and the amount of free antiidiotypic antibody remaining in the supernatant estimated according to its ability to inhibit [125I]iodo-oPRL binding to anti-oPRL IgG. The lowest degree of inhibition of [125I]iodo-oPRL binding was achieved after incubation of the anti-idiotypic IgG with liver membranes from pregnant mice, while the inhibitory capacity was about 5-fold higher subsequent to parallel incubations with the same membranes, which had previously been heated for 30 min at 65 C, or with membranes of male rat liver, demonstrating a direct correlation between the binding of the antiidiotypic antibody to the membranes and the PRL receptor content of the membranes. Furthermore, significant and dose-dependent inhibition of [125I]iodo-oPRL binding to its receptors in various PRL receptor-rich membrane preparations from rats and rabbits was demonstrated with antiserum of rabbits immunized with rabbit anti-rPRL IgG. These results suggest that effective and specific anti-PRL receptor antibodies can be produced using the antiidiotypic antibody procedure, thus avoiding the necessity of isolating and purifying the PRL receptor itself.

Animals↗
PubMed1986

Hydrogen peroxide enhances the activity of monoamine oxidase type-B but not of type-A: a pilot study.

The effect of hydrogen peroxide on monoamine oxidase (MAO) activity has been determined in homogenates of human brain areas taken postmortem. It could be shown that hydrogen peroxide enhances significantly the activity of MAO-B after short-term incubation (2 min), while no changes have been noted after long-term preincubation (60 min) indicating reversibility of this effect. MAO-A activity was not changed or decreased after preincubation with hydrogen peroxide. Freezing and thawing procedures did not change hydrogen peroxide stimulation of MAO in the caudate nucleus, while MAO-A activity dose dependently decreased. Inhibition of hydrogen peroxide stimulated MAO-B activity in human cortex by (-)deprenyl was found to be of similar potency compared to hydrogen peroxide free estimations. Glutathione, ascorbic acid and mannitol did not block MAO stimulation by hydrogen peroxide, while sodium azide led to a complete inhibition of hydrogen peroxide derived MAO activitation. Interorgan comparison showed increase of MAO-B activity in crude mitochondrial fractions of rat liver after preincubation with hydrogen peroxide, while with rat heart a reduction of MAO activity was detectable. As a conclusion these data indicate a possible role of hydrogen peroxide in the age-dependent increase of MAO-B in platelets and brain. Furthermore, increase of cytotoxic hydrogen peroxide via combined L-dopa therapy cannot be excluded to be of importance in the appearance of adverse reactions after long-term treatment with high doses. To reduce hydrogen peroxide production due to MAO activity, a combined treatment of L-dopa plus a selective MAO inhibitor and eventually additional administration of radical scavengers (ascorbic acid, vitamin E etc.) seems to be indicated.

Adult↗
PubMed1986

Pharmacology of MAO B inhibitors: mode of action of (-)deprenyl in Parkinson's disease.

The selective monoamine oxidase (MAO) type B inhibitor has proven to be a useful adjunct to L-dopa therapy of Parkinson's disease. Although not all features of its anti-Parkinson action is known, studies on brains obtained at autopsy from patients on (-)deprenyl show that the selective inhibition of MAO B with a concomitant increase of dopamine, but not of serotonin, in the basal ganglia may be responsible for its mode of action. The increased life expectancy noted in Parkinsonian patients on long term (-)deprenyl therapy (9 years) is another unexpected feature of the drug (Birkmayer et al., 1985). This exciting data, if confirmed in other long term clinical trials, may herald a new approach for the treatment of this degenerative disease, since more recent studies indicate that Parkinson's disease may eventually turn out to be a neurotoxic event (see Snyder and D'Amato, 1986, for review). Thus selective MAO type B inhibitors could represent a unique class of drug, having both therapeutic and preventive actions in one.

Animals↗
PubMed1985

In vivo effect of MPTP on monoamine oxidase activity in mouse striatum.

Striatal monoamine oxidase (MAO)-B, but not MAO-A, activity decreased in mice at 2 and 10 days and was back to control values at 20 and 30 days after systemic administration of N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Striatal dopaminergic (DA) depletions were maximal at 2 days and were only partially reversed at 30 days post-treatment. In rats, unilateral kainic acid lesions increased MAO-B but not MAO-A activity probably due to reactive gliosis, but MPTP did not affect DA levels in control and kainic acid-lesioned striata. Findings support the importance of MAO-B in the toxicity of MPTP and suggest that resistance of rat DA neurons to the neurotoxin is probably not due to species differences in MAO-B activity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Serotonergic involvement in pharmacological action of the anxiolytic-sedatives thalidomide and supidimide.

The anxiolytic-sedative drugs thalidomide and supidimide inhibited spontaneous motor activity in rats. Both compounds inhibited the serotonin (5-HT) behavioural syndrome induced by tranylcypromine (TCP) plus L-tryptophan (TRP) or clorgyline plus the selective 5-HT uptake blocker, LM 5008 (4-[2-(3-indolyl)ethyl]piperidine) and delayed the behavioural effects of p-chloro-amphetamine, a releaser of 5-HT. The behavioural syndrome induced by the 5-HT agonist, 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT) was unaffected by supidimide pretreatment. Thus supidimide does not possess 5-HT receptor antagonistic properties. This was further substantiated by the unaltered 5-HT-induced platelet aggregation in the presence of supidimide (10(-7)-10(-4) M). A decrease of 5-HT release into the synaptic cleft will lead to a diminished behavioural response to drugs that act presynaptically. Supidimide induced a greater increase in accumulation of brain 5-HT in TCP (5 mg/kg) plus TRP (100 mg/kg)-treated animals as compared to that in the corresponding controls. These data indicate that the behavioural and pharmacological actions of supidimide may be related to its inhibition of 5-HT release.

Animals↗
PubMed1985

Prevention of MPTP-induced neurotoxicity by AGN-1133 and AGN-1135, selective inhibitors of monoamine oxidase-B.

Two selective and potent inhibitors of monoamine oxidase (MAO) type B, namely AGN-1133 (N-methyl-N-propynyl-1-indanamine) and AGN-1135 (N-propynyl-1-indanamine), given to mice prior to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) protected against the neurotoxic effects of MPTP. For example, mice treated with these agents prior to MPTP, did not exhibit the decrement in the neostriatal content of dopamine and its metabolites normally seen after MPTP administration. These data lend further support to the concept that the oxidation of MPTP by MAO-B to its corresponding pyridinium analog, 1-methyl-4-phenyl-pyridinium (MPP+) is an important feature of the neurotoxic process.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Modification of pulmonary metabolism of noradrenaline in experimental obstructive jaundice.

The pulmonary metabolism of noradrenaline (NA) was measured in lungs removed from 3 day sham-operated rats and from rats whose bile ducts had been ligated 3 days earlier (BDL). The pulmonary metabolism of NA as measured by a single clearance of the radio-labelled 14C-amine was significantly increased in lungs excised from BDL rats as compared to that measured in the sham-operated rats. The change in metabolism was associated with an alteration in the pulmonary uptake of NA and not with the activities of the enzymes monoamine oxidase types A and B and catechol-O-methyl transferase. Moreover, it was not correlated with rises in the bilirubin or cholesterol concentrations in the serum of the BDL rats and occurred independent of any changes in pulmonary pressure. In a second series of experiments, the evolution of this abnormality over the period of one to six days postoperative was investigated. In the sham-operated rats, there was no significant change in the pulmonary metabolism of NA even by the sixth day. In contrast, there were time-dependent increases from one to six days in these metabolic processes in BDL rats with the highest values being at six days. In contrast, the serum concentrations of bilirubin and cholesterol and activities of the enzymes, alanine transaminase and alkaline phosphatase all rose to their maximum by the fourth day and thereafter declined. Although serum albumin levels fell significantly in BDL rats they were not significantly different from sham-controls. Thus, change in pulmonary metabolism of NA with obstructive jaundice increases with time from one to six days and it not related to the blood chemical changes of biliary obstruction or hepatic synthetic function.

Alanine Transaminase↗
PubMed1985

Oxidation by rat brain of N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) coupled to tetrazolium nitro blue.

The present study shows that the dehydrogenation of N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) can be coupled to tetrazolium nitro blue (TNB), a substance used as electron acceptor in many dehydrogenase reactions. The MPTP-TNB reductase system has an apparent Km value and inhibitor sensitivity similar to those of monoamine oxidase (MAO) type B. MPTP oxidation in the brain may very well be mediated by MAO-B.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Does brain 5-HIAA indicate serotonin release or monoamine oxidase activity?

The question of whether serotonin is deaminated by MAO before it can be released or after release has occurred was investigated by studying the 5-HT behavioral syndrome in acutely reserpinized rats. The release of serotonin from vesicles by reserpine does not produce the serotonin behavioral syndrome which is an in vivo index of serotonin release and receptor activation. However, if rats are first pretreated with a nonselective monoamine oxidase inhibitor (e.g., tranylcypromine), the injection of reserpine is followed by symptoms which are characteristic of the behavioral syndrome including forepaw treading, hindlimb abduction and head weaving. Neither selective MAO-A or -B inhibition with clorgyline or deprenyl, respectively, nor inhibition of serotonin reuptake with fluoxetine prior to reserpine produced the serotonin behavioral syndrome. However, the combination of clorgyline and deprenyl followed by reserpine does so. These behavioral data along with neurochemical analyses of serotonin and 5-hydroxyindoleacetic acid levels lead to the conclusion that serotonin does not have to be released before it is metabolized to 5-hydroxyindoleacetic acid. Consequently, the levels of 5-hydroxyindoleacetic acid in brain reflect MAO activity and not serotonin release or utilization.

Animals↗
PubMed1985

Increased hepatic and reduced prostatic prolactin (PRL) binding in iron deficiency and during neuroleptic treatment: correlation with changes in serum PRL and testosterone.

Iron deficiency (ID) induced in 21 day old male rats for 28 days caused a 7 fold increase in hepatic prolactin (PRL)-specific binding and a parallel 3 fold rise in serum PRL, as expected from both the reported reduction in central dopaminergic (DA) activity and PRL's up-regulating effect on its own liver receptors. Similarly, serum testosterone was increased by 80%. Prostatic PRL binding was slightly reduced (by 27%), possibly because of masking by the raised hormone levels, although more likely by a more generalized reduction in proliferation during ID, as indicated by the 50% prostatic weight loss. Chronic treatment with neuroleptics also increased hepatic PRL binding in accord with their anti DA activity: chlorpromazine (10 mg/kg) or fluphenazine (5 mg/kg) injected daily (i.p.) for 21 days followed by a 3 day drug-free period resulted in 26 and 10 fold increases, respectively. The parallel reductions of serum levels of PRL (by 40%) and of testosterone (by 70%) by both drugs is indicative of the drug withdrawal supersensitivity normally observed in the caudate nucleus DA receptor. A testicular peripheral effect of the neuroleptics probably further accounted for the reduction in testosterone synthesis, reinforcing the induction of liver PRL binding by these drugs and explaining their negative effects on prostate PRL binding and weight. These findings stress the importance of monitoring hormone levels in ID and during treatment with neuroleptics, in order to avoid endocrine side-effects.

Animals↗
PubMed1985

Increased life expectancy resulting from addition of L-deprenyl to Madopar treatment in Parkinson's disease: a longterm study.

In an open, uncontrolled study the longterm (9 years) effect of treatment with Madopar alone (n = 377) or in combination with l-deprenyl (selegiline, selective monoamine oxidase type B inhibitor) (n = 564) have been compared in Parkinsonian patients. In patients who lost their response to conventional Madopar therapy the addition of l-deprenyl resulted in a significant recouping of levodopa effect. The survival analysis revealed a significant increase of life expectancy in Madopar--l-deprenyl group regardless of the fact whether or not the significant demographic differences between the two groups were taken into account. Although the mechanism underlying this action of l-deprenyl is not known, the results are interpreted as indicating l-deprenyl's ability to prevent or retard the degeneration of striatal dopaminergic neurons. l-Deprenyl is the first anti-Parkinson drug having such a property. This hypothesis is not far fetched since l-deprenyl selectively prevents the degeneration of striatal dopaminergic neurons induced in animals by the illicit drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since latter compound is known to cause Parkinsonism in man and primates or Parkinson-like neurochemical and pathological changes in other animals the implications of the present study involving monoamine oxidase activity and l-deprenyl are apparent.

Adult↗
PubMed1985

Induction of prolactin receptors by prolactin in the rat lung and liver: demonstration of separate receptor and antibody entities.

This study examined the role of prolactin (PRL) in inducing its own receptors in rat lung and liver beyond the parallel immunological response evoked. Ovine PRL (oPRL), mixed with polyvinylpyrrolidone (PVP) and injected s.c. daily to male rats for 7, 10 and 14 days, was shown to induce specific binding of [125I]iodo-oPRL in the lung and liver crude membrane fractions. Doses as low as 12.5 ng/kg were effective in inducing PRL-binding sites, which, however, differed qualitatively from those found in livers of 17 beta-estrogen-treated male rats. The oPRL-induced sites were highly specific for oPRL and were relatively stable to heat, suggesting the possible participation of antihormone antibodies in the binding observed. Indeed, anti-oPRL antibodies found in sera of oPRL-treated rats increasingly bound oPRL as a function of the duration of treatment. Water-washing of the membrane fraction succeeded in gradually eliminating the loosely bound antibody and in partially restoring the displacing ability of excess (1 micrograms) rat PRL on oPRL-binding sites in the lung (32.3%) and liver membranes (29.3%). Also restored were the heat lability typical of the receptor site, as well as the inhibitory effect of anti-PRL-receptor antiserum (1:100) on PRL binding (50-65% inhibition of total binding). In keeping with these results, in vitro incubation of liver membranes with rat anti-oPRL antiserum greatly reduced the ability of rat PRL to compete for oPRL binding, supporting the findings after in vivo treatment with oPRL.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Endothelial cells from bovine adrenal medulla develop capillary-like growth patterns in culture.

The endocrine barrier between chromaffin cells and the blood stream in the adrenal medulla is made of capillary endothelial cells. We have now succeeded in isolating endothelial cells from adrenal medullary tissue, which are probably derived from this barrier. These cells grow on plastic surfaces in the absence of special growth factors or collagen overlays and differentiate into organized structures quite similar to true capillaries. The cells contain factor VIII:R, a marker for endothelial cells, and form intercellular junctions characteristic of capillary endothelial cells. They also synthesize and secrete basal lamina structures and engage in transcytosis, a characteristic ultrastructural and functional combination of exocytosis and endocytosis across the thin endothelial cell processes. These endothelial cells can take up and deaminate catecholamines by A-type monoamine oxidase, an enzyme functionally distinct from the B-type monoamine oxidase found in chromaffin cells. These data indicate that the chromaffin cell and its endothelial cell neighbor may constitute the functional unit of catecholamine metabolism in the adrenal medulla.

Adrenal Medulla↗
PubMed1985

Effect of iron chelators on dopamine D2 receptors.

Nutritional iron deficiency induced in rats causes a selective reduction of [3H]spiperone binding in caudate nucleus. This effect can be reversed by iron supplementation in vivo. The possibility that iron may be involved in the dopamine D2 receptor was investigated by examining the effect of various iron and noniron chelators on the binding of [3H]spiperone in rat caudate nucleus. Iron chelators 1,10-phenanthroline, 2,4,6-tripyridyl-s-triazine, alpha, alpha'-dipyridyl, and desferrioxamine mesylate inhibited the binding of [3H]spiperone. The inhibition by 1,10-phenanthroline was noncompetitive and reversible. In the presence of FeCl2 or FeCl3, the inhibitory effect of 1,10-phenanthroline was potentiated. Iron salts or chelators were without effect on the binding of [3H]dihydroalprenolol to beta-adrenoreceptors in caudate nucleus; thus the action of iron chelators on the dopamine D2 receptor tends to be selective. Incubation of caudate nucleus membrane prepared from iron-deficient rats with FeCl2 or FeCl3 did not reverse the diminished binding of [3H]spiperone. The present study indicates that if iron is involved in the physiological regulation of dopamine D2 agonist-antagonist binding sites, it is more complex than hitherto considered.

2,2'-Dipyridyl↗
PubMed1985

Deamination of aliphatic amines by monoamine oxidase A and B studied using a bioluminescence technique.

Deamination of n-octylamine and n-decylamine has been studied in various tissues using a new bioluminescence technique. Selectivity of n-octylamine and n-decylamine as substrates for monoamine oxidase (MAO) A or B has been determined using both clorgyline and (-)-deprenyl inhibition curves and kinetic parameters. Homogenates of rat brain, liver and heart containing predominantly MAO-A or -B were prepared by preincubation for 60 min with (-)-deprenyl or clorgyline (30 nM), respectively. Human placenta (MAO-A) and platelet (MAO-B) were used as reference tissues containing only one MAO form. In tissues (rat liver, brain) containing both MAO forms in equal proportion, inhibition curve studies showed a preference of both substrates for the B form of the enzyme; however, where MAO-A was the major form (rat heart, human placenta), clorgyline was the more effective inhibitor. In the beef brain cortex n-octylamine showed marked preference for MAO-B, whereas n-decylamine was selective toward-MAO-A. Kinetic studies in general supported the picture of greater selectivity of the aliphatic amine substrates for deamination by MAO-B, as reflected by lower Km values for this enzyme type. However, n-octylamine was more selective for MAO-B than n-decylamine in both kinetic and inhibition curve studies. The deamination of these aliphatic amine substrates cannot be explained only by reference to the binary classification of MAO into types A and B.

Amines↗