Showing papers on "Monoamine oxidase B published in 1981"

Is the failure of (-)deprenyl, a selective monoamine oxidase B inhibitor, to alleviate depression related to freedom from the cheese effect?

Abstract: The selective monoamine oxidase (MAO) B inhibitor (-)deprenyl failed to produce any greater benefit than placebo in a limited double-blind trial conducted in depressive patients. Its relative freedom from the so-called cheese effect was confirmed, however, in drug-treated patients challenged IV with tyramine. There is evidence to suggest that this cheese effect, a facilitated tyramine-induced hypertensive response, is pharmacologically distinct from MAO inhibition proper. Thus, it is conceivable that its central counterpart, an enhanced noradrenaline release due to the access of traces of tyramine to the CNS, is a prerequisite for any therapeutic benifit obtainable with the MAO-inhibitory drugs in general.

Differences in the structure of A and B forms of human monoamine oxidase.

Abstract: [3H]Pargyline-labeled polypeptides associated with the A and B types of monoamine oxidase (MAO) activity in human tissues were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) [3H]Pargyline was bound to MAO A in a crude mitochondrial fraction from the placental trophoblast of a male newborn and to MAO B in blood platelets from the umbilical vein of the same newborn [3H]Pargyline was also bound to MAO A and B in a crude mitochondrial fraction from cultured skin fibroblasts of a male adult and to MAO B in blood platelets from the same individual Specific labeling of proteins associated with type A or type B activity in fibroblast cells was achieved by preincubation with selective B or A inhibitors, respectively For all tissues, SDS-PAGE of [3H]pargyline-bound samples revealed a labeled protein band of apparent molecular weight 63,000 for MAO A and 60,000 for MAO B When SDS-solubilized, [3H]pargyline-labeled MAO A and B proteins from the same male newborn were subjected to limited proteolysis and one-dimensional peptide mapping in SDS gels, different patterns of [3H]pargyline-labeled peptides were obtained These findings indicate that distinct enzyme molecules are associated with the A and B types of human MAO activity

Specificity of Endogenous Substrates for Types A and B Monoamine Oxidase in Rat Striatum

Abstract: Studies were designed to evaluate specificity of the transmitter amines serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA), as well as the trace amines p-tyramine (p-TA) and beta-phenylethylamine (PEA) for types A and B monoamine oxidase (MAO) in rat striatum. 5-HT was found to be a specific substrate for the type A enzyme. However, the specificity of PEA for the type B enzyme was found to be concentration-dependent. When low concentrations of PEA and 5-HT were used to measure type B and type A activities, respectively, both clorgyline and deprenyl were highly selective for the sensitive form of MAO in vivo. However, as the concentration of PEA was increased, the type B inhibitor deprenyl became less effective in preventing deamination of PEA. Conversely, the type A inhibitor clorgyline became more effective in this regard. Kinetic analysis following selective in vivo inhibition showed PEA deamination by both forms of MAO with a 13-fold greater affinity for the type B enzyme. In vivo dose-response curves obtained with the common substrates DA and p-TA showed approximately 20% deamination by the B enzyme. Kinetic values for DA and p-TA deamination in in vivo-treated tissue possessing only type A or type B MAO activity, revealed a 2.5-fold greater affinity for the type A enzyme. These studies show the importance of concentration on substrate specificity in striatal tissue. The results obtained characterize the common substrate properties of DA and p-TA as well as of PEA in rat striatum. In addition, the presence of regional specificity for 5-HT deamination by only type A MAO is demonstrated.

Modulation of affinity of postsynaptic serotonin receptors by antidepressant drugs

Abstract: Antidepressant drugs are generally thought to act by changing aminergic neurotransmission. Thus, according to the indoleamine hypothesis1, antidepressant drugs increase the amount of serotonin (5-HT) available at the receptor level by inhibition either of 5-HT uptake or of its degradative enzyme (monoamine oxidase)2. Various experimental observations have, however, suggested that the effects of antidepressant drugs may be located at the postsynaptic receptor level3–7. We report here that antidepressant drugs alter the structural conformation of the postsynaptic serotoninergic receptor in synaptosomal membranes isolated from rat and horse brains in such a way as to inactivate them.

Monoamine oxidase inhibitors in bipolar endogenous depressives.

Abstract: Clinical lore suggests that monoamine oxidase inhibitors (MAOIs) are not effective in endogenous depression. A review of previous placebo-controlled trials of MAOI in patients with endogenous depression neither refutes nor confirms their utility in this patient group. We present patients in the depr

Type A monoamine oxidase catalyzes the intraneuronal deamination of dopamine within nigrostriatal, mesolimbic, tuberoinfundibular and tuberohypophyseal neurons in the rat.

Abstract: Clorgyline (0.3–10mg/kg, i.p.) inhibited type A monoamine oxidase (5-hydroxytryptamine as substrate) but not type B monoamine oxidase (phenylethylamine as substrate) in homogenates of rat striatum and olfactory tubercle; deprenyl (0.3–3 mg/kg, i.p.) inhibited type B but not type A monoamine oxidase in these homogenates. The same doses of clorgyline increased concentrations of dopamine in striatum, and dopamine and norepinephrine in the olfactory tubercle, median eminence and posterior pituitary; they also reduced the concentrations of dihydroxyphenylacetic acid and the rate of synthesis of dopamine (DOPA accumulation after a decarboxylase inhibitor) in the same brain regions. On the other hand, the administration of deprenyl at doses that markedly inhibited type B monoamine oxidase did not alter the concentrations of dopamine, norepinephrine and dihydroxyphenylacetic acid or the rate of accumulation of DOPA in these brain regions. In addition, only clorgyline significantly lowered serum concentrations of prolactin. These results suggest that type A monoamine oxidase catalyzes the intraneuronal deamination of dopamine within terminals of nigrostriatal, mesolimbic, tuberoinfundibular and tuberohypophyseal dopamine neurons.

Monoamine oxidase inhibitor efficacy in depression and the "cheese effect".

Abstract: It is widely agreed that the monoamine oxidase (MAO) inhibiting group of drugs have a useful role to play in the treatment of depressive illness. However, there is no generally accepted set of criteria to distinguish patients likely to respond from those who are therapy-resistant, and any precise division can only be made in retrospect (Pare & Sandier, 1959). MAO inhibitors employed in clinical practice are, without exception, 'suicide' inhibitors, compounds which are themselves metabolized to form a product which combines irreversibly and lethally with the active centre of the enzyme (for recent review, see Singer et al. 1979). Although a number of competitive, reversible inhibitors, synthesized by several different drug companies, are now undergoing evaluation, their clinical effectiveness has yet to be proved. Since the early days, it has been tacitly or explicitly (Pare & Sandier, 1959) assumed that these drugs produce their therapeutic benefit by allowing a build-up within the brain of a particular monoamine substrate of the enzyme. Indeed, such an assumption has been one of the main props of the monoamine hypothesis of depressive illness (Schildkraut, 1965). Recently, this interpretation of MAO inhibitor action has been further refined. MAO can be subdivided pharmacologically by its sensitivity to the inhibitor, clorgyline, into two forms (Johnston, 1968): MAO A which prefers the 'classical' neurotransmitters, noradrenaline and 5-hydroxytryptamine as substrates, and MAO B which preferentially oxidizes certain less well-studied monoamines (see Singer et al. 1979). Lipper et al. (1979) have now suggested that inhibition of the A form of the enzyme, in their case with clorgyline itself, is a necessary prerequisite for therapeutic benefit in depressive illness. They indicated that the relatively selective MAO B inhibitor, pargyline, only possesses antidepressant activity in a dose large enough to bring about some degree of MAO A inhibition in addition. On the surface of it, this hypothesis received support from the recent double-blind trial of Mendis et al. (1981) which failed to demonstrate any therapeutic benefit deriving from the selective MAO B inhibiting drug, ( —)-deprenyl, in patients with primary depressive illness. Even leaving to one side the counterevidence of certain, admittedly open, studies where improvement was reported in response to deprenyl (Varga & Tringer, 1967; Tringer et al. 1971; Mann & Gershon, 1980) and the fact that the trial of Mendis et al. (1981) was a limited one, because the drug was and is in short supply, deprenyl is sufficiently atypical an MAO inhibitor to make it inadvisable for us to take for granted any straightforward explanation of its mechanism of action. MAO inhibitors have enjoyed a modest success which would have been considerably greater but for one important adverse reaction, the 'cheese effect', the profound and sometimes disastrous rise in blood pressure which generally follows the administration of tyramine-containing foods to subjects under treatment. And yet there is little doubt that deprenyl, otherwise another powerful 'suicide' MAO inhibitor, is quite free from the 'cheese effect' at the 10-20 mg per day dosage schedule commonly employed in clinical practice (Elsworth et al. 1978). Indeed, only during a 50 mg per day dosage schedule and then with intravenous tyramine challenge, has any flicker of a hypertensive response been observed (Mendis et al. 1981). At first sight, such virtual absence of the 'cheese effect' is puzzling, for selective inhibition of MAO B with deprenyl, although real enough, probably represents an acute pharmacological response within a particular dosage range (Glover et al. 1980; Murphy et al. 1981): prolonged administration of the drug in clinically useful dosage seems likely to inhibit both forms of the enzyme in the human brain within a period of weeks although, for

Monoamine oxidase activity in platelets as related to monoamine oxidase activity and monoaminergic function in the brain

Abstract: In this review the evidence for a correlation between platelet monoamine oxidase and brain monoaminergic function is discussed. It is suggested that platelet monoamine oxidase is genetically determined by the same set of genes that regulate the levels of serotonin turnover in the central nervous system. As a consequence the estimation of platelet monoamine oxidase provides a simple and effective method for the identification of patients at risk for vulnerability to psychiatric illness.

Elevation of epinephrine concentration in rat brain by LY51641, a selective inhibitor of type A monoamine oxidase.

Abstract: LY51641, N-[2-(o-chlorophenoxy)ethyl]cyclopropylamine hydrochloride, selectively inhibited type A monoamine oxidase (MAO) (measured with 10 microM 14C-serotonin as substrate) without inhibiting type B MAO (measured with 12.5 microM 14C-phenylethylamine as substrate) in rat brain. The inhibition of type A MAO was accompanied by an increase in epinephrine concentration in hypothalamus. Although the absolute concentration of epinephrine in rat hypothalamus is low relative to norepinephrine and dopamine, the percentage increase in epinephrine after LY51641 was greater than the percentage increase in dopamine or norepinephrine. The inhibition of type A MAO activity and increase in hypothalamic epinephrine concentration following a single 30 mg/kg dose of LY51641 persisted for at least 10 days. Both effects were seen at doses as low as 0.03 mg/kg of LY51641. A 0.2 mg/kg dose of LY51641 given daily for 5 days retained selectivity in inhibiting type A MAO and increased epinephrine concentration. Two analogs of LY51641 of differing selectivity elevated epinephrine concentration to a degree related to percentage inhibition of type A MAO, and the effect of LY51641 was antagonized by pretreatment with harmaline, a short-acting reversible inhibitor of type A MAO. These findings support earlier evidence that in rat hypothalamus, epinephrine oxidation occurs by type A not type B MAO.

Aliphaticamines asMAOsubstrates intherat: the effectof selective inhibitorson the deamination ofn-pentylamine

Abstract: Monoamine oxidase (MAO, EC 1.4.3.4.) is an enzyme widely distributed in mammalian tissues and especially in the brain. Two major forms, MAO A and MAO B seem to exist on the basis of substrate specificity and existence of reversible and irreversible inhibitors. MAO A preferentially deaminates biogenic amines such as 5-hydroxy-tryptamine (5-HT), adrenaline and noradrenaline and is selectively inhibited by clorgyline, whereas MAO B oxidises the microamine phenylethylamine (PEA) and is inhibited by deprenyl (Neff et al., 1976; Fowler et al., 1978; Gerardy, 1980; Houslay et al., 1976).

Decreased cerebral catabolism of [3H]histamine in vivo after S-adenosylmethionine administration.

Abstract: Administration of S-adenosyl-L-methionine (SAM) (200 mg/kg) to adult mice significantly elevated its cerebral levels while the steady-state levels of histamine (HA) and S-adenosyl-L-homocysteine remained unaltered. [3H]HA (1 microCi/10 microliters) was injected intraventricularly (i.vt.) 20 sec, 2, 5, 10 or 20 min prior to sacrifice (1 hr after SAM) and brains were analyzed for [3H]HA, [3H]methylhistamine (MeHA) and [3H]methylimidazoleacetic acid. Brains of SAM-treated mice contained more [3H]HA than vehicle-treated controls at 20 sec, 2, 5 and 10 min (22, 35, 52 and 25%, respectively). [3H]MeHA levels were lower than controls at 20 sec, but higher at 2 and 5 min. Fifteen minutes after i.vt. [3H]histidine, brains of SAM-treated mice contained 47% more [3H]HA and 39% more [3H]MeHA (compared to controls) while [3H]histidine and [3H]methylimidazoleacetic acid levels remained unchanged. SAM treatment had no effect on the activity of cerebral histamine-N-methyltransferase, S-adenosyl-L-homocysteine hydrolase and monoamine oxidase type A (substrate 5-hydroxytryptamine) when tested in vitro, while monoamine oxidase B (substrate phenylethylamine) activity was significantly decreased. In vitro, SAM had no effect on monoamine oxidase A or B. The findings demonstrate that, unexpectedly, the rate of catabolism of HA to MeHA is significantly decelerated in brains containing elevated levels of SAM.

Brain monoamine oxidase and replacement of its coenzyme flavin in rats.

Abstract: The influence of 7-ethyl-8-methylflavin and 7-methyl-8-ethylflavin, vitamin-like homologues of riboflavin, on rat brain mitochondrial monoamine oxidase (MAO) was studied using tyramine as substrate. While riboflavin deficiency caused the enzyme activity to fall to 80% of norma, when 7-ethyl-8-methylflavin replaced riboflavin as the precursor of its coenzyme, it caused essentially complete loss of the enzyme activity. We showed that while 7-ethyl-8-methylflavin can serve as a coenzyme for MAO, 7-methyl-8-ethylflavin cannot serve as coenzyme for this enzyme.

Topology and lipid protein association of MAO-A and MAO-B

Abstract: Oxidative deamination of biogenic monoamines is believed to be accomplished by at least two principal functionally different forms of monoamine oxidase (MAO, EC 1.4.3.4) (Tipton, et al., 1976). In rat brain, serotonin is deaminated by MAO-A whereas phenylethyl amine is deaminated by MAO-B (Jain, 1977). The multiple MAO enzymes which have been localized in the outer mitochondrial membrane are intrinsic membrane-bound flavoproteins (Greenawalt and Schnaitman, 1970). Vigorous procedures involving sonication, organic solvent extraction, and/or detergent treatment are required to solubilize the enzyme with concomitant preferential loss of the MAO-A characteristics (Tipton, 1975). Treatment of the solubilized MAO active fractions with chaotropic agents to remove the lipid moiety results in the disappearance of the apparent multiplicity both in terms of electrophoretic mobility and substrate-inhibitor specificity (Houslay and Tipton, 1973). These results favor the model that the MAO-A and B activities reside with the same enzymic protein. However, immunochemical studies (Dennick and Mayer, 1977; McCauley and Racker, 1973) show equivocal results.

Multiple forms of human brain monoamine oxidase

Abstract: Treatment of normal human brain mitochondria with a mixture containing Triton X-100 and urea resulted in solubilization of monoamine oxidase (MAO) exhibiting tyramine-, serotonine-, phenylethylamine- and dopamine deaminase activities at ratios similar to those characteristic for the initial mitochondria. A purified preparation of the enzyme was obtained after AH-Sepharose chromatography; it was shown that in the brain there were present four isoenzymes of MAO possessing different substrate specificity. Investigation of some properties of MAO (activity, solubilization and isozyme composition) from brain regions showed absence of asymmetry and higher enzymatic activity in the subcortical brain region as compared with right and left brain cortex.

Identification of type A monoamine oxidase in mouse and rabbit liver mitochondria.

Abstract: Type A monoamine oxidase was identified in liver mitochondria of mouse and rabbit 5-Hydroxytryptamine was a common substrate for type A and type B monoamine oxidase in these enzyme preparations where its concentration was 10 mM

Selective inhibition of type A monoamine oxidase by pyrazidol

Abstract: Effect of a new antidepressant pyrazidol (1,10-trimethylene-8-methyl-1,2,3,4-tetrahydropyrazino /1,2-/ indole) on the liver and brain MAO activity of rats was studied in experiments in vivo and in vitro. Pyrazidol selectively blocks type A MAO (the substrates serotonin and noradrenaline) and does not virtually affect or has a far less action on type B MAO (the substrate 2-phenylethylamine).

Synthesis of 14C-labeled inhibitors of monoamine oxidase

Abstract: The monoamine oxidase inhibitors pargyline and clorgyline have been synthesized by methylation of the appropriate secondary propargylamines, using [14C]dimethyl sulphate. This simple method should be generally applicable to other compounds of this class.

Synthesis and study of α-piperidinoacetanilides as monoamine oxidase inhibitors

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