PubMed Health⌕ Search

Biomedical subjects

M B Youdim

Publications and source records attributed to M B Youdim.

At least 181 records · Page 10Linked to original sources
PubMed1988

Formation of the neurotransmitter glycine from the anticonvulsant milacemide is mediated by brain monoamine oxidase B.

Milacemide (2-n-pentylaminoacetamide) is a secondary monoamine that in the brain is converted to glycinamide and glycine. This oxidative reaction was suspected to involve the reaction of monoamine oxidase (MAO). Using mitochondrial preparations from tissues that contain MAO-A and -B (rat brain and liver), MAO-A (human placenta), and MAO-B (human platelet and bovine adrenal chromaffin cell), it has been established that mitochondria containing MAO-B rather than MAO-A oxidize (H2O2 production and glycinamide formation) milacemide. The apparent Km (30-90 microM) for milacemide oxidation by mitochondrial MAO-B preparations is significantly lower than that for milacemide oxidation by mitochondrial MAO-A (approximately 1,300 microM). In vitro MAO-B (l-deprenyl and AGN 1135) rather than MAO-A (clorgyline) selectively inhibited the oxidation of milacemide. These in vitro data are matched by ex vivo experiments where milacemide oxidation was compared to oxidation of serotonin (MAO-A) and beta-phenylethylamine (MAO-B) by brain mitochondria prepared from rats pretreated with clorgyline (0.5-10 mg/kg) and l-deprenyl (0.5-10 mg/kg). Furthermore, in vivo experiment demonstrated that l-deprenyl selectively increased the urinary excretion of [14C]milacemide and the total radioactivity with a concomitant decrease of [14C]glycinamide. Such changes were not observed after clorgyline treatment, but were evident only at doses beyond clorgyline selectivity. The present data therefore demonstrate that milacemide is a substrate for brain MAO-B, and its conversion to glycinamide, further transformed to the inhibitory neurotransmitter, glycine, mediated by this enzyme may contribute to its pharmacological activities.

Acetamides↗
PubMed1988

Potentiation of tyramine pressor responses in conscious rats by reversible inhibitors of monoamine oxidase.

Intraperitoneal injection of cimoxatone, moclobemide, amiflamine CGP 11305 A (all 5 mg/kg) increased pressor responses to intravenous tyramine (100 micrograms) in conscious, freely moving rats. Area under mean arterial pressure curve increased by 7.01, 4.28, 5.3 and 3.46 fold respectively. Clorgyline (2 mg/kg) increased area under pressor response curve by 10.4 fold. Tyramine responses returned to normal 24 hours after reversible inhibitors but were still potentiated 24 hours after clorgyline.

Animals↗
PubMed1987

Regulation of central and peripheral benzodiazepine receptors in progesterone-treated rats.

The effects of progesterone treatment to male rats on cortical and hippocampal central benzodiazepine (BZ) receptors and peripheral BZ binding sites (PBS) in kidney, testis and heart were evaluated. Chronic progesterone treatment resulted in a 30% elevation of the density of central BZ receptors in cerebral cortex accompanied by a 24% augmentation of PBS in the kidney. No significant change in the density of central BZ receptors in the hippocampus or of PBS in the testis or heart was observed. No change in the affinity of [3H]flunitrazepam and [3H]PK 11195 binding to central BZ receptors and PBS, respectively, was observed. The increase in PBS in the kidney might be associated with the natriuretic effect of this hormone and the adaptatory increase in aldosterone secretion. The up-regulatory effect of progesterone on cortical central BZ receptors may be involved in the neurobehavioral activities of progesterone.

Animals↗
PubMed1987

Behavioural and biochemical evidence for the release of noradrenaline in mouse brain by TRH and some of its biologically stable analogues.

Small doses of clonidine probably induce hypoactivity (a distinct form of sedation) by stimulating presynaptic alpha 2-adrenoceptors. This was attenuated by injection of 0.1-10 mg/kg of thyrotropin releasing hormone (TRH) or its biologically stable analogues, CG3509, CG3703 and RX77368, when these were given 10 min before clonidine. This effect was dose-dependent in all cases, but the analogues were more potent than TRH. The TRH metabolites, TRH acid and histidyl-proline diketopiperazine (10 mg/kg) were without effect. This response was still attenuated by the analogues, but not TRH, when these were given 1 hr before clonidine. The results, therefore, suggested that it was the basic tripeptide structure which was active and TRH was less potent than its analogues because of rapid metabolism. Attenuation of hypoactivity by TRH and analogues was not due to increased dopaminergic function because apomorphine (5 mg/kg) was ineffective. Thyrotropin releasing hormone (20 mg/kg), CG3509 (10 mg/kg) and CG3703 (1 mg/kg) also induced locomotor activity and produced various other behavioural changes. This was inhibited by prazosin (3 mg/kg) and haloperidol (0.5 mg/kg) but not by yohimbine (1 mg/kg). Apomorphine (5 mg/kg)-induced activity was inhibited by haloperidol and yohimbine but not by prazosin. This indicated that the activity produced by the TRH compounds, but not apomorphine, was partly mediated by alpha 1-adrenoceptors. Both CG3509 (10(-5) and 10(-4) M) and RX77368 (10(-4) M) evoked the release of endogenous noradrenaline from slices of hypothalamus in vitro. The TRH analogues, however, had no affinity for alpha 1- or alpha 2-adrenoceptors in ligand-receptor binding experiments. Viewed overall, the data showed that TRH and its analogues induced the release of noradrenaline in the brain. In addition, a comparison of the behavioural effects of TRH compounds with dopamine and alpha 1-adrenoceptor agonists suggested that in mice these behavioural responses resulted from stimulation of both noradrenergic and dopaminergic function.

Adrenergic alpha-Antagonists↗
PubMed1987

Specific binding sites for prolactin and growth hormone in the adult rabbit lung.

Specific prolactin (PRL) and growth hormone (GH) binding sites were identified and characterized in lung membranes from male and female adult rabbits. The binding of iodinated human GH ([125I]iodo-hGH) and iodinated ovine PRL ([125I]iodo-oPRL) was time, temperature and protein dependent and was found to conform to the requirements defining a physiological receptor, in terms of hormonal and immunological specificities as well as kinetic properties. [125I]Iodo-hGH was displaced from lung membranes by hGH, oPRL, ovine GH and rat GH, while [125I]iodo-oPRL was effectively displaced only by oPRL and hGH. Scatchard plots of the competition curves of [125I]iodo-hGH and [125I]iodo-oPRL were both linear, suggesting, in each case, a single class of binding sites with affinity constants (Ka) of 1.74 +/- 0.64 X 10(9) M-1 and 0.78 +/- 0.28 X 10(9) M-1 and binding capacities of 6.43 +/- 0.53 and 4.16 +/- 0.69 fmol/mg protein, respectively. Anti-PRL-receptor antiserum significantly inhibited the binding of the [125I]iodo-oPRL to rabbit lung membranes, while it was less potent in preventing the binding of [125I]iodo-hGH, which has both lactogenic and somatogenic activity. Removal of endogenous ligand by treating lung membranes with 4 M MgCl2 increased specific binding of hGH about 2.5-fold, exposing additional specific binding sites without significantly changing the binding affinity. The level of binding of hGH and oPRL to rabbit lung did not show a pronounced sex differentiation. In summary, PRL and GH binding sites have been demonstrated for the first time in adult rabbit lung membranes, and they support the possibility of a physiological role for PRL and GH in the lung.

Animals↗
PubMed1987

Normal zinc and iron concentrations in mice after early exposure to phenobarbital.

Zinc and iron levels were studied in mice with early (pre/neonatal) exposure to phenobarbital, as the levels of these trace metals are known to be correlated with specific behaviors shown in our previous and present experiment to be affected by early phenobarbital administration. Mice were exposed to phenobarbital prenatally or neonatally. At adulthood they showed marked reduction from control in all parameters of eight-arm maze performance (P less than 0.001). Since zinc is known to be correlated with this behavior, it was subsequently studied in barbiturate exposed animals. The differences between barbiturate exposed and control offspring for zinc levels in plasma, brain and hippocampus did not reach statistical significance. Our previous studies have shown that the number of dopamine receptors and the resulting apomorphine-induced climbing behavior is altered after early exposure to phenobarbital. The effect of iron level on dopamine receptors is now well established. Subsequently, a group of mice were tested for iron levels in their brain and liver. No significant differences were found. It is suggested that deficits in the hippocampal behaviors, mainly eight-arm maze, after early exposure to phenobarbital are not related to changes in zinc levels. Similarly, early phenobarbital-induced alternation in dopamine receptors and the resulting dopaminergic behaviors are not related to changes in iron levels.

Animals↗
PubMed1987

Localization of MAO-A and MAO-B in human brain: a step in understanding the therapeutic action of L-deprenyl.

The discovery that MAO can be differentiated biochemically and pharmacologically into two forms, types A and B, with different substrate specificities and inhibitor sensitivities has renewed the interest in MAO inhibiting as a therapeutic agent. L-Deprenyl, a selective inhibitor of MAO-B, was introduced by us into clinical use as an adjunct to L-DOPA some years ago. This drug has found therapeutic importance in that it can potentiate the pharmacological action of L-DOPA. The mechanism underlying the action of L-deprenyl is thought to be related to its inhibition of MAO-B and thus increased levels of PEA and DA, as measured in the striatal and limbic region of human brain. Animal studies have indicated the MAO-A is mainly, but not exclusively, located in brain neurons, while MAO-B is preferentially placed in glia and astrocytes. In general human and primate brain studies show similar MAO distribution. The observation that MAO-B activity could not be located in the catecholaminergic neurons of human brain by the use of monoclonal antibody studies seriously questions the validity of this technique. The exact locations of MAO-A and -B in human brain are important to understand the mechanism of L-deprenyl action as an antiparkinson drug. If there is an absence of MAO-B from dopaminergic neurons, one may now consider that MAO-B activity within glia plays a far more important role than hitherto considered. This, however, is questionable.

Animals↗
PubMed1987

Monoamine oxidase B inhibition and the "cheese effect".

The absence of initiation of "cheese effect" (potentiation of sympathomimetic action of tyramine) by 1-deprenyl (selective monoamine oxidase, MAO-B inhibitor) was regarded to be an intrinsic property of this inhibitor. However, availability of other selective MAO-B inhibitors have clearly shown that this is not the case, since the "cheese effect" is associated with the selective inhibition of MAO-A, the enzyme responsible for intraneuronal oxidation of noradrenaline. Following inhibition of neuronal MAO-A, noradrenaline in the cytoplasmic intraneuronal pool can increase to high levels. Since tyramine releases noradrenaline into the cytoplasm and not by exocytosis, its action is potentiated by inhibition of neuronal MAO-A.

Animals↗
PubMed1986

Oxidation and enzyme-activated irreversible inhibition of rat liver monoamine oxidase-B by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces symptoms resembling Parkinson's disease in humans, acts both as a substrate and an enzyme-activated irreversible inhibitor of the B-form of monoamine oxidase from rat liver. Analysis of the inhibitory process showed the compound to be considerably more efficient as a substrate than as an irreversible inhibitor, with about 17000 mol of product being formed per mol of enzyme inactivated. The half-time of the inhibitory process was about 22 min. With the A-form of the enzyme, the compound had a lower Km value and a considerably lower maximum velocity than the corresponding values obtained with the B-form. Under the conditions used in the present work the inhibition of the A-form of the enzyme was largely reversible.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Serotonin metabolism and the nature of monoamine oxidase in squid central nervous system.

Monoamine oxidase activity, using type A and type B substrates and inhibitors, was investigated in the central brain and synaptosomes prepared from the optic lobe of squid. Although substantial MAO activity towards serotonin (5-HT), phenylethylamine and tyramine was present, the enzyme could not be differentiated into the two subtypes previously described in the vertebrate central nervous system. However, this enzyme is functional since 5-HT levels, as identified by immunocytochemical procedures, are low in the squid nervous system and show significant increases in pargyline treated squids.

Animals↗
PubMed1986

Modulation of peripheral benzodiazepine binding sites following chronic estradiol treatment.

A 10 day estradiol treatment of rats resulted in a marked reduction (43%) in peripheral benzodiazepine (BZ) binding sites in the testis and an up-regulation (27%) of these sites in the kidney. No significant alterations in brain central BZ receptors and heart peripheral binding sites were observed. The down-regulation of BZ binding sites in the testis may be related to or accompany estrogen-induced testicular atrophy. The physiological and pharmacological implications of the alterations obtained in the kidney are as yet unclear.

Animals↗
PubMed1986

Characterization of the hepatic prolactin receptors induced by chronic iron deficiency and neuroleptics.

Nutritional iron deficiency (ID), like neuroleptic treatment, results in a reduction in dopaminergic activity and a rise in serum prolactin (PRL). Since PRL has been shown to regulate its own receptors, we studied PRL binding sites during the above treatments. ID induced in 21 day old male rats for 28 days, or treatment with either chlorpromazine (10 mg/kg per day i.p.) or fluphenazine (5 mg/kg per day i.p.) for 21 days or haloperidol (5 mg/kg per day i.p.) for 9 days, caused significant increases (3- to 8-fold) in [125I]oPRL specific binding to the liver membranes. The combined treatment with haloperidol and ID, as above, resulted in an additive effect on hepatic PRL receptors, suggesting that the actions of neuroleptics and ID may be either submaximal or mediated by two different mechanisms. After 7 days or recovery from ID, the induced PRL receptors were completely reduced to the control values. In vitro desaturation of the induced PRL binding sites with MgCl2 caused a further increase (1.57-fold) in PRL binding. Characterization of the hepatic PRL binding sites induced by ID showed properties similar to those reported for the classical PRL receptors, including specificity for the lactogenic hormones, a high affinity constant (2.38 X 10(10) M-1) and inhibition of PRL binding to the induced receptors by an anti-PRL receptor antibody. The results of this study further support the suggested role of endogenous PRL in inducing its own receptors.

Animals↗
PubMed1986

Contrasting monoamine oxidase activity and tyramine induced catecholamine release in PC12 and chromaffin cells.

PC12 (phaeochromocytoma derived) cells possess the catecholamine synthesizing enzymes as well as the ability to store and release the catecholamines in response to K+. However, their monoamine oxidase activity and catecholamine release in response to tyramine has not been examined previously. PC12 cells have monoamine oxidase activity which oxidizes type A (noradrenaline and serotonin) and type A-B (dopamine, tyramine and kynuramine) substrates, and is selectively inhibited by clorgyline (IC50 approximately 10(-6) M). In contrast, PC12 cell monoamine oxidase hardly oxidizes phenylethylamine a type B substrate, and is relatively insensitive to inhibition by the selective monoamine oxidase type B inhibitor, 1-deprenyl (IC50 approximately 10(-6) M). By the above criteria it is apparent that the monoamine oxidase in PC12 is solely type A. The kinetics of the oxidase are similar to those of monoamine oxidase type A reported in other tissues including the adrenergic neuron, having apparent Km values of 400, 280, 170 and 227 microM for noradrenaline, dopamine, serotonin and tyramine. The apparent Km value for phenylethylamine is 235 microM. On the other hand, isolated chromaffin cells have the B form of monoamine oxidase with high affinity (Km approximately 25 microM) for phenylethylamine and low affinities for noradrenaline (Km approximately 1100 microM) and adrenaline (Km approximately 1700 microM). This enzyme form is selectively inactivated by the monoamine oxidase type B inhibitor, 1-deprenyl. In similar fashion to peripheral adrenergic neurons, PC12 cells share the capacity to express a tyramine releasable pool of catecholamines, a property entirely lacking in mature cultured chromaffin cells, even though the latter cells are capable of taking up tyramine by a cocaine sensitive process.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗
PubMed1986

Long-term consequence of early iron-deficiency on dopaminergic neurotransmission in rats.

Nutritional iron-deficiency (ID) induced in rats caused a reduction in peripheral as well as central iron metabolism. This effect was markedly greater in the liver than the brain. Although the decrease in the rate of brain non-haem iron was slower than that of serum and liver, significant diminutions of behavioral response to apomorphine (2 mg/kg) and maximum [3H]spiperone binding (Bmax) in caudate nucleus were noted in these animals. These effects of ID can be reserved by iron supplementation in young (21-day-old) and adult (48-day-old) rats. In contrast, if ID is induced in new born (10-day-old) animals, the diminished brain non-haem iron, behavioral response to apomorphine and [3H]-spiperone binding in caudate nucleus will not recover even after 6 weeks of iron supplementation. However, these animals have normal serum iron, haemoglobin and liver iron. These data point to the profound effect early ID can have on the development of dopaminergic neurotransmission, since brain iron concentration increases its maximum in the 4-5 weeks after birth. The implications of the present finding is that the prevalence of ID in children occurs in the first decade of life, when brain iron accumulation reaches values observed in adults. The profound cognitive changes associated with ID in children is thought to be dopamine-dependent and is not always reversible with iron therapy.

Aging↗
PubMed1986

Iron deficiency alters discrete proteins in rat caudate nucleus and nucleus accumbens.

Young rats (21 days old) made nutritionally iron deficient, by feeding them a semisynthetic diet containing skimmed milk for 5 weeks, had significantly lowered hemoglobin levels (5.2 +/- 4 g/100 ml). The nonheme iron content in caudate nucleus was decreased by 47%. The behavioral response of iron-deficient rats to apomorphine (2 mg/kg) and the density of 3,4-dihydroxyphenylethylamine (dopamine) D2 receptors, as measured by [3H]spiperone binding in caudate nucleus, were significantly reduced by 70 and 53%, respectively. The possibility that nutritional iron deficiency may affect protein content in brain was investigated by measuring the apparent concentration of proteins in caudate nucleus and nucleus accumbens from iron-deficient and control animals using two-dimensional gel electrophoresis. The data indicate that iron deficiency can affect content in these two brain regions. Significant changes in the content of 10 proteins were noted in the caudate nucleus and nucleus accumbens in iron-deficient rats. The albumin level was significantly increased in both regions studied, whereas the neuron-specific enolase level was increased in the nucleus accumbens and the glial fibrillary acidic protein level was reduced in the caudate nucleus. The significance of these protein content changes, as well as a reduction in content of a 94-kilodalton protein (a molecular size similar to that of the D2 dopamine receptor), remains to be established.

Albumins↗