Search PubMed⌕ Search

Biomedical subjects

M B Youdim

Publications and source records attributed to M B Youdim.

At least 217 records · Page 12Linked to original sources
PubMed1985

A new rapid and sensitive bioluminescence assay for monoamine oxidase activity.

The in vivo luminescence of an aldehyde-requiring mutant of the luminous bacteria Vibrio harveyi (M42) increases dramatically upon the addition of long-chain aliphatic aldehydes (C8-C16). The intensity of this luminescence is linearly related to aldehyde concentration. This property was utilized for the determination of monoamine oxidase activity using n-octylamine and n-decylamine as substrates, which are converted by monoamine oxidase to n-octylaldehyde and n-decylaldehyde, respectively. The addition of the amine to a suspension containing rat liver mitochondria and M42 cells initiated a luminescence that was directly proportional to monoamine oxidase activity according to two parameters: (1) the rate of the initial increase in luminescence and (2) the final "steady-state" level of luminescence. The new assay has advantages of high sensitivity, rapidity, the possibility to perform discontinuous as well as continuous monitoring of monoamine oxidase activity, and applicability to turbid preparations.

Aldehydes↗
PubMed1985

Modification of blood pressure and nictitating membrane response to sympathetic amines by selective monoamine oxidase inhibitors, types A and B, in the cat.

The selective monoamine oxidase (MAO) inhibitors clorgyline, selegiline and AGN 1135 did not cause a change in responses of the cat nictitating membrane to preganglionic sympathetic nerve stimulation at 5 Hz. Both selective MAO-A and MAO-B inhibitors markedly potentiated nictitating membrane contractions in response to beta-phenylethylamine (PEA). However, the responses to tyramine were unchanged. The pressor responses to tyramine were potentiated by the selective MAO-A inhibitor clorgyline (2 mg kg-1) but not by selegiline (1.0 mg kg-1) and AGN 1135 (1.5 mg kg-1), selective MAO-B inhibitors. At the doses used selegiline and AGN 1135 caused a near total selective inhibition of liver and brain MAO-B, while clorgyline inhibited MAO-A only in the brain. AGN 1135, like selegiline, could be a useful drug in potentiating the action of L-DOPA in Parkinson's disease.

Amines↗
PubMed1985

Prevention of dopaminergic toxicity of MPTP in mice by phenylethylamine, a specific substrate of type B monoamine oxidase.

N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is toxic to dopaminergic neurones in several mammalian species including mice. Combined treatment with phenylethylamine prevented in mice the long-term (30 days post-treatment) dopamine depletions in striatum induced by MPTP. Phenylethylamine, a naturally-occurring specific substrate of monoamine oxidase (MAO) type B, probably protects against effects of MPTP by competitively inhibiting the oxidative conversion of MPTP to its toxic metabolite N-methyl-4-phenylpyridinium ion catalysed by MAO-B.

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

Monoaminergic involvement in the pharmacological actions of buspirone.

Buspirone, MJ-13805 and MJ-13653 did not produce a '5-hydroxytryptamine (5-HT) syndrome' in rats at doses up to 20 mg kg-1. These drugs were very weak 5-HT uptake blockers (IC50 much greater than 10 microM) compared to drugs such as chlorimipramine. These drugs did not inhibit either monoamine oxidase (MAO)-A or MAO-B. The Ki values for these agents as inhibitors of [3H]-5-HT and [3H]-ketanserin binding to rat frontal cortex or hippocampal membranes were in the microM range, well above the brain concentrations achieved after an oral dose of 25 mg kg-1. Parenterally administered buspirone blocked apomorphine-induced stereotypy, inhibited the 5-HT syndrome elicited by 5-methoxy-N,N-dimethyltryptamine, and delayed the onset of p-chloroamphetamine induced behaviours.

Animals↗
PubMed1985

5-Hydroxytryptamine release in vivo from a cytoplasmic pool: studies on the 5-HT behavioural syndrome in reserpinized rats.

Treatment of rats with reserpine in order to disrupt vesicular amine storage reduces 5-hydroxytryptamine (5-HT) levels throughout brain by 90-95%. Despite the drastic reduction in brain 5-HT content by reserpine, the 5-HT releasing drug p-chloramphetamine (PCA) produces a behavioural syndrome in reserpine-treated rats which is not different from that observed in normal animals given PCA. Prior treatment of reserpinized rats with p-chlorophenylalanine (PCPA), the irreversible tryptophan hydroxylase inhibitor which inhibits the synthesis of new 5-HT, prevents the PCA-induced behavioural syndrome. The 5-HT receptor antagonist methergoline, blocks the PCA effect in reserpine-treated rats. Treatment of reserpinized rats with pargyline, a non-selective inhibitor of monoamine oxidase, in order to increase cerebral 5-HT levels, shifts the PCA dose-response curve for inducing the 5-HT behavioural syndrome to the left. The specific 5-HT uptake blocker, fluoxetine, protects normal and reserpine-treated rats from the 5-HT depleting effects of PCA but does not always prevent the PCA-induced 5-HT behavioural syndrome. These results indicate that PCA releases 5-HT into the synapse from a small cytoplasmic pool which is resistant to reserpine and suggest that this newly synthesized compartment of 5-HT represents the 'functional' transmitter pool.

Animals↗
PubMed1984

The increased opiate action of beta-endorphin in iron-deficient rats: the possible involvement of dopamine.

Rats made nutritionally iron-deficient (ID) have been shown to have a lower brain non-haem. A selective diminution of the binding capacity of the D2-dopaminergic receptors alone was found among nutritionally iron-deficient rats. Peripherally administered beta-endorphin significantly elevated the pain threshold only in the iron-deficient rats. Naloxone blocked the beta-endorphin effect in ID rats. Morphine, as well as haloperidol, elevated the pain threshold in both the iron-deficient and the control rats but significantly more in the former group. No additive effects of combined treatment with beta-endorphin and haloperidol on pain threshold were found. Other neuroleptics also elevated the pain threshold. A possible hypothesis is that dopamine (via beta-endorphin) may play a role in modifying the pain threshold.

Animals↗
PubMed1984

Isolated chromaffin cells from adrenal medulla contain primarily monoamine oxidase B.

Cultured chromaffin cells from bovine adrenal medulla were found to contain primarily the B form of monoamine oxidase. This monoamine oxidase B enzyme was somewhat distinct from B enzymes from other sources, in that noradrenaline was a much poorer substrate than serotonin. Nonetheless, studies with selective inhibitors of the A form (clorgyline) and the B form [(-)-deprenyl] confirmed that chromaffin cell monoamine oxidase was the B form. The observation that chromaffin cell monoamine oxidase has poor affinity for catecholamines is consistent with physiological needs that require the cell to synthesize and store large amounts of catecholamines.

Adrenal Medulla↗
PubMed1984

Induction of prolactin (PRL) receptors by PRL in the rat lung and liver. Demonstration and characterization of a soluble receptor.

A soluble PRL receptor has been identified in the 100,000 X g supernatant from homogenates of lungs and livers of male and female rats treated with either estradiol (E2; 2 mg kg-1 day-1 for 7 days, sc) or ovine PRL (oPRL; 0.1 mg kg-1 day-1 for 14 days, sc). Fifty percent of the total PRL-binding activity in the liver homogenate of E2-treated male rats was found in the supernatant fraction, and only 12% in intact female rats. The soluble PRL receptor has the same specificity, protein dependence, and binding affinity (Ka = 2.8 X 10(9) M-1) characteristics as the membrane-bound receptor. A sheep anti-PRL-receptor antiserum specifically inhibited the binding of [125I]iodo-oPRL to the soluble PRL receptor. Column chromatography on Sepharose 6B revealed a single peak of [125I]iodo-oPRL-receptor complex from liver of E2-treated rats, having a mol wt of 340,000, whereas the 100,000 X g supernatant from lungs and livers of oPRL-treated rats revealed two specific peaks of [125I]iodo-oPRL complex with mol wts of 340,000 (A) and 165,000 (B), respectively. Peak A represented 25% and 27% and peak B, 35% and 49% of the total column radioactivity for liver and lung 100,000 X g supernatant fraction, respectively. Peak B coeluted with a rabbit anti-oPRL antiserum, suggesting that it is a PRL antibody. Anti-PRL-receptor antibody reduced the radioactivity associated with peak A but not peak B. Heat inactivation at 60 C (30 min) resulted in a complete loss of binding in peak A without affecting peak B. The results indicate that the soluble PRL-binding sites, increased in rat lung and liver after treatment with oPRL or E2, may represent an intermediate step in new receptor synthesis before incorporation into the membrane.

Animals↗
PubMed1984

A new selective suicide inhibitor of peripheral DOPA decarboxylase.

Although the present study is based on a small number of patients, our clinical data clearly show that DFMD is as effective as other peripheral decarboxylase inhibitors in potentiating the action of L-DOPA. In 3 patients, we observed an improvement above that with previous therapy. This may suggest that in some patients DFMD is either more effective than other decarboxylase inhibitors or that it has its own effect. Subjective complaints with DFMD were frequent and 9 of the 10 patients preferred their previous therapy. In 5 patients, we observed an increase in blood pressure while on DFMD plus L-DOPA and 2 had EEG changes. These effects appear to be drug-related. Because of its side effects, DFMD cannot be considered in this form as a useful adjuvant in Parkinson therapy. However, further studies are necessary for the development of selective inhibitors.

Aged↗
PubMed1984

Modulation of dopamine receptor in the striatum by iron: behavioral and biochemical correlates.

The present study has shown that in the rat brain iron is unevenly distributed and may be associated with the dopaminergic neuron. The function of the large amounts of iron in certain brain areas, such as the pallidum, caudate nucleus, substantia nigra, nucleus accumbens, and olfactory tubercule, is not known. But it is obvious that by reduction of brain iron, as in the case of nutritional iron deficiency, certain dopamine-mediated behavioral phenomena and biochemical reactions are altered. These changes have been attributed to the selective reduction in dopamine D2 receptors and function in brain areas rich in dopamine neurons and iron. If iron is especially important to dopaminergic modulatory systems in the brain, its deficit might explain the increasing number of reports on behavioral disturbances, EEG, and event-related potentials (ERPs) associated with nutritional iron deficiency in children.

Animals↗
PubMed1983

Effects of forskolin in rat vas deferens--evidence for facilitatory beta-adrenoceptors.

Forskolin inhibited the response to electrical field stimulation (0.1 Hz) and antagonised contractile responses to noradrenaline in the isolated rat vas deferens. The inhibition of the response to electrical stimulation (IC50 0.1 microM) was not affected by either propranolol or yohimbine. Both isoprenaline and forskolin enhanced the total tritium efflux during transmural stimulation of vas deferens which had been prelabelled with [3H]noradrenaline. These data provide evidence that beta-adrenoceptor stimulation enhances noradrenaline release in the vas deferens, although the postsynaptic relaxant effect on smooth muscle predominates in determining the net response. The data are consistent with a stimulation of adenylate cyclase in mediation of both presynaptic and postsynaptic effects of beta-adrenoceptor agonists in the vas deferens.

Adrenergic beta-Agonists↗
PubMed1983

Specific changes in type A and B monoamine oxidase activity in different tissues of hypophysectomized rats.

MAO activity was tested in four organs of young male rats 16 days after hypophysectomy. Five monoamines were used as substrates. In the adrenal glands and the thyroid gland MAO activity towards the substrates preferably deaminated by MAO-A was severely decreased. In the adrenal glands, but not in the thyroid gland, the effect of hypophysectomy could be simulated with dexamethasone, a steroid which inhibits ACTH secretion. A significant rise in MAO activity towards substrates for MAO-A and MAO-B occurred in the heart of hypophysectomized rats. There was little change in the MAO activity of whole brain homogenates after hypophysectomy.

Adrenal Glands↗
PubMed1983

Effect of selective monoamine oxidase inhibition by clorgyline and deprenyl on the norepinephrine receptor-coupled adenylate cyclase system in rat cortex.

The consequences of selective monoamine oxidase (MAO) inhibition on the norepinephrine(NE)-sensitive adenylate cyclase system were determined in slices of rat cerebral cortex. The chronic administration of clorgyline, which selectively inhibited the activity of MAO-A, caused a significant decrease in the responsiveness of the noradrenergic cyclic AMP-generating system. The noradrenergic subsensitivity was accompanied by a significant decrease in the density of beta-adrenoceptors, as measured by 3H-dihydroalprenolol (DHA) binding, without altering the Kd value. However, selective inhibition of MAO-B by deprenyl did not alter the sensitivity of the cyclic AMP-generating system to NE or the specific DHA binding. The basal levels of cyclic AMP in the cortex were unaltered by the drugs. Since inhibition of MAO-A, but not MAO-B, increases the availability of NE, the results support the hypothesis that a persistent NE-receptor interaction is one of the prerequisites for the in vivo densitization of the NE-sensitive adenylate cyclase and the concomitant down-regulation of the number of beta-adrenoceptors in brain.

Adenylyl Cyclases↗
PubMed1983

Selective MAO A and B inhibitors: their mechanism of action and pharmacology.

The 14C-selective irreversible "suicide" MAO A (clorgyline, Lilly 51641; M & B 9303) and MAO B inhibitors (deprenyl, AGN 1135 and pargyline) bind to the enzyme active site stoichiometrically mol/mol of enzyme. In the case of the acetylenic inhibitors (clorgyline, deprenyl and pargyline) this binding occurs at the N (5) of the FAD isoalloxazine moiety, the enzyme co-factor. Since the inhibitor binding sites of both enzyme forms are identical, it would appear that enzyme inhibitor selectivity must be related to the presence of different recognition sites near their active sites. Studies of structure-MAO inhibitory relationship have shown that the MAO B recognition site is smaller than the enzyme A site. Considering that MAO A for most part is intraneuronal and its substrates noradrenaline (NA) and serotonin (5-HT) have been implicated in the pathogenesis of depressive illness, it would appear that selective A inhibitors would be more effective as antidepressants. Data presented shows that MAO A inhibitors rather that the B inhibitors potentiate pharmacological and behavioural actions mediated by NA and 5-HT. Furthermore, if down-regulation of beta-adrenergic receptors is involved in the mechanism of action of antidepressants it is interesting that chronic treatment with a selective MAO A (clorgyline) but not MAO B (deprenyl) inhibitor resulted in the reduction of [3H]dihydroalprenolol binding and cyclic AMP response to NA in the rat cortex. Recently similar changes were found in peripheral adrenergic systems. These data support the theory that neuronal MAO A inhibition results in elevation of cytoplasmic and synaptic NA and 5-HT, which mediates pre- and post-synaptic receptor changes.

Animals↗
PubMed1983

Effect of prolactin, testosterone and estrogen on prolactin binding in the rat testis, prostate, seminal vesicle and liver.

We have studied the hormonal control of prolactin (PRL) binding in the male rat sex glands and liver, subsequent to the recent demonstration and characterization of specific PRL binding sites in rat testis, prostate and seminal vesicle. Ovine PRL (200 micrograms/rat/day, 7 days) caused a time-dependent reduction in testicular binding of 125I-labelled PRL (measured 2 days after last injection) to 58% of control. Testosterone alone (1 mg/rat/day, 7 days) or PRL caused similar reductions in binding, while their coadministration further lowered PRL binding to 10% of control. The synergism of PRL and testosterone suggests that either these doses are submaximal, or that they are acting on different systems. Estradiol was administered as a single dose of 2 mg/rat and the PRL binding determined on day 10 and day 19 was reduced to 37% of control, as after testosterone. Addition of PRL whether from day 1 to day 7 or from day 11 to day 17 of estradiol injection had no effect, suggesting that the EB site of action is closer to the PRL receptor than that for PRL or testosterone. Estradiol resulted in a 72% reduction of PRL binding in the prostate, after 10 days, which subsequent PRL completely restored. PRL also partially restored the estradiol-induced time-dependent weight reduction of the prostate, but PRL coadministered from day 1 of estradiol did not inhibit the estradiol effects, suggesting a competitive mechanism for the two. While testosterone more than doubled PRL binding in the seminal vesicle, estradiol reduced it by 32% and organ weight by 21%. PRL given after estradiol restored the weight loss, but not the binding, suggesting that two different mechanisms of action are involved. In the liver, coadministration of testosterone with PRL could not inhibit the induction by PRL of its own hepatic sites, in keeping with a more direct site of action for PRL than for testosterone. These results demonstrate the profound effects of PRL, and of the sex steroids testosterone and estrogen, on PRL binding in the male sex glands and liver. The physiological implication of these findings on the role of PRL in male sexual function is currently being investigated.

Animals↗