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Biomedical subjects

V Glover

Publications and source records attributed to V Glover.

At least 127 records · Page 7Linked to original sources
PubMed1987

Analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as monoamine oxidase substrates: a second ring is not necessary.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is oxidised to a neurotoxic metabolite by monoamine oxidase B (MAO B). Using two colorimetric assays, we have examined a range of its structural analogues as possible further substrates of this enzyme in order to identify the types of environmental or endogenous compounds that might also be neurotoxic. Compounds with fully saturated or unsaturated pyridine rings were not substrates; nor were a range of tetrahydro-beta-carbolines or isoquinolines. Four substrates for MAO were found, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-Me-MPTP), 4-phenyl-1,2,3,6-tetrahydropyridine (PTP), 4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine (Cl-PTP) and ethyl-1-methyl-1,2,3,6-tetrahydro-4-pyridine-carboxylate (ethyl-MTP-carboxylate). Ethyl-MTP-carboxylate is of particular interest as it shows that a tetrahydropyridine without a phenyl ring can also be a substrate. Cl-PTP, PTP and ethyl-MTP-carboxylate appeared to be partially metabolised by MAO A. The inhibitor sensitivity of 2'-Me-MPTP oxidation was more complex.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Psychiatric morbidity and platelet monoamine oxidase activity in cancer patients.

Psychometric ratings for both anxiety and depression in 30 cancer patients were significantly elevated compared with values in 16 controls. The scores were especially high in the 14 patients who did not have breast cancer. This group also had significantly greater platelet monoamine oxidase activity than either the breast cancer patients or controls. Platelet monoamine oxidase activity values correlated significantly with both depression and anxiety scores in the whole cancer group.

Adult↗
PubMed1987

Selegiline and the prophylaxis of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration causes a Parkinson's disease like syndrome in man and primates, with selective degeneration of the substantia nigra. This discovery has raised the possibility that some environmental or endogenous toxin causes idiopathic Parkinson's disease. MPTP is oxidised to its neurotoxic metabolite, 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase B (MAO B). MPTP toxicity is prevented by pretreatment with the MAO B inhibitor selegiline ((-)-deprenyl). We have screened a range of structural analogues of MPTP as possible alternative substrates for the enzyme. All compounds which were found to be substrates for MAO B were tetrahydropyridines, some with substituents on the phenyl ring. The most interesting substrate, ethyl-MTP-carboxylate, did not have a phenyl ring. The precise histochemical localisation of MAO B within the rat and marmoset brain has been established. There was substantial activity within the nigrostriatal pathway of the marmoset; in comparison, the rat had only a low background MAO B level. These results may partially explain why the marmoset is more susceptible to the action of MPTP than the rat.

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

Distribution of endogenous benzodiazepine receptor ligand-monoamine oxidase inhibitory activity (tribulin) in tissues.

The distribution of monoamine oxidase inhibitor-benzodiazepine receptor binding inhibitor, extractable into ethyl acetate at pH 1, was examined in a range of rat tissues. Great variation in the activity of both inhibitors was found in the different tissues, the highest being present in superior cervical ganglion, and lowest in adrenal gland. There was a highly significant correlation between the distribution of the two activities in different tissues, supporting the concept that they both derive from the same molecule (tribulin). The level of inhibitory activity in some of the tissues was such that variations might conceivably play a significant role in vivo.

Animals↗
PubMed1986

Monoamine oxidase B(MAO-B) is the major catalyst for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) oxidation in human brain and other tissues.

A new in vitro radiometric method has been developed for the direct assay of the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine (MPTP) to its main neurotoxic metabolite 1-methyl-4-phenylpyridinium. This assay has been used to show that the rate of oxidation of MPTP parallels that of phenylethylamine in a range of human and rodent tissues, providing strong evidence that this reaction is predominantly catalysed by monoamine oxidase B (MAO-B). In human brain the reaction was inhibited by selective doses of the MAO-B inhibitor (-)-deprenyl. When dopamine was added to the incubation mixture, products of MPTP oxidation appeared to form a complex with it.

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

Purification and characterization of tribulin, and endogenous inhibitor of monoamine oxidase and of benzodiazepine receptor binding.

A low molecular weight fraction of human urine (less than 500 daltons) which both inhibits monoamine oxidase and benzodiazepine binding to central and peripheral receptors has been purified by ethyl acetate extractions, HPLC and thin layer chromatography. This material extracted equally well at acid and basic pH and was insoluble in heptane. It competitively inhibited binding of 3H-clonazepam, a central benzodiazepine receptor agonist and, in addition, displaced 3H-Ro 5-4864, a specific peripheral benzodiazepine receptor ligand, from its binding sites. It showed no GABA shift with the benzodiazepine receptor antagonist, Ro-15 1788. MAO A and B were inhibited approximately equipotently and the material competitively inhibited tyramine oxidation by rat liver. It was stable on boiling and is unlikely to be a peptide.

Animals↗
PubMed1986

Equol and other compounds from bovine urine as monoamine oxidase inhibitors.

Equol, its methylated derivative, and a carbazole, all isolated from bovine urine, are relatively potent inhibitors of monoamine oxidase with IC50 values of 158, 28, and 16 microM respectively (using 83 microM tyramine as substrate). The probable dietary origin of these compounds suggests that "natural" monoamine oxidase inhibitors may be more widespread than had previously been suspected.

Animals↗
PubMed1986

The role of MAO in MPTP toxicity--a review.

MPTP is oxidized to its toxic metabolite MPP+ by MAO B in both primate and rodent brains and this reaction can be inhibited by (-)-deprenyl. MPTP can also act as an inhibitor of both MAO A and B. There is some evidence that MAO B is localized predominantly in glia, and this would explain why dopamine uptake blockers also can prevent MPTP toxicity. The possibility that molecules with a similar action to MPTP cause idiopathic Parkinson's disease is discussed.

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

Attempts to attenuate the 'cheese effect'. Combined drug therapy in depressive illness.

Although earlier results, employing intravenous tyramine challenge, had indicated that a tricyclic antidepressant plus monoamine oxidase inhibitor drug combination might be free from the 'cheese effect', the experiments reported here, involving oral tyramine challenge during the combined therapy, showed that relaxation of a tyramine-free diet during such a drug regimen might be unsafe. Preliminary observations indicated that combined (-)-deprenyl plus nonselective monoamine oxidase inhibitor therapy might lead to an unacceptable degree of orthostatic hypotension without reduction in tyramine sensitivity.

Adult↗
PubMed1985

Red wine contains a potent inhibitor of phenolsulphotransferase.

Many ethanolic drinks, especially red wine, contain potent inhibitors of phenolsulphotransferase. At a dilution of 1/75 from the original beverage, extracts from six types of red wine inhibited human platelet phenolsulphotransferase P by a mean of 99% and human platelet phenolsulphotransferase M by 12%. Such extracts had no significant effect on rat liver monoamine oxidase A or human platelet monoamine oxidase B. The inhibitors, which have not yet been identified, can be extracted into ethyl acetate at acid or neutral pH. Thus, they are not monoamines. Flavonoid phenols are plausible candidates. As phenolsulphotransferase M and P are involved in the metabolism of many phenols, including drugs, the inhibition of these enzymes could result in the enhancement of pharmacological potency and have important clinical consequences.

Alcoholic Beverages↗
PubMed1985

Triazolam, an anomalous benzodiazepine receptor ligand: in vitro characterization of alprazolam and triazolam binding.

Both alprazolam and triazolam displaced clonazepam (but not Ro 5-4864) from rat brain membranes with high affinity, showing them to act at central but not peripheral benzodiazepine receptors. At 0 degrees C, 10 microM gamma-aminobutyric acid (GABA) increased the ability of alprazolam, but not of triazolam, to displace ethyl-beta-carboline-3-carboxylate (beta-CCE) and Ro 15-1788 from these receptors. At 37 degrees C, GABA increased the affinity of the receptors for both drugs, with a +GABA/-GABA ratio of 1.5 for each in promoting Ro 15-1788 binding displacement. As both triazolam and alprazolam act as anxiolytics in vivo, the results at 37 degrees C would be compatible with the hypothesis that GABA causes an increase in affinity of drugs that act in this way, but the results at 0 degrees C would not be compatible. At 37 degrees C, alprazolam had a higher IC50 for the benzodiazepine receptor than at 0 degrees C, whereas triazolam showed the reverse effect. The relative IC50 values in vitro at 37 degrees C correlated better with the potency in vivo than those obtained at 0 degrees C. At 0 degrees C, both drugs showed Hill plots with slopes of 0.9-1 with beta-CCE and Ro 15-1788. At 37 degrees C, the slopes with triazolam were much reduced, indicating that the drug may have a selective action on a subclass of central benzodiazepine receptors. In the studies reported here, alprazolam behaved like other benzodiazepines, whereas triazolam showed several anomalous properties. It would be of interest if these properties could be related either to the drug's use as a hypnotic or to the side effects it sometimes induces.

Alprazolam↗
PubMed1985

Tribulin: an endogenous monoamine oxidase inhibitor/benzodiazepine receptor ligand.

Tribulin is a low molecular weight inhibitor both of monoamine oxidase and of benzodiazepine receptor binding. It has been highly purified from human urine and has also been isolated from human plasma and animal brain. Its structure is still unknown but its properties do not appear to correspond with any known monoamine or benzodiazepine receptor binding inhibitor. Tribulin output has been found to be increased in a variety of states associated with stress and anxiety, including lactate-induced panic attacks, alcohol or benzodiazepine withdrawal and generalized anxiety disorder.

Animals↗
PubMed1984

Platelet monoamine oxidase and phenolsulphotransferase M and P in cancer.

Phenolsulphotransferase and monoamine oxidase inactivate a wide range of dietary and endogenous phenols/monoamines by sulphoconjugation and oxidative deamination respectively. In this study, both enzymes were measured in platelets from cancer patients and controls. Of the two variants of phenolsulphotransferase, activity of the P form was normal in all groups. Activity of the M form was, however, significantly less than control values in patients with cancer of the rectum and bowel but not in other cancer patient groups. If this finding reflects enzyme activity elsewhere in the body and is not merely a manifestation of an abnormal platelet population, the deficit could expose affected subjects to the action of potentially carcinogenic dietary phenols. Platelet monoamine oxidase activity was significantly raised in the cancer group as a whole, and in all sub-types investigated apart from breast cancer. The increase in the cancer group as a whole was independent of sex, age, drugs, radiotherapy, smoking or platelet count. Its mechanism and significance are unknown but there may be links with the patients' psychiatric state.

Adult↗