Comparative aspects of monoamine oxidase.
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Although nicotine is generally considered as the main compound responsible for addictive properties of tobacco, some experimental data indicate that nicotine does not exhibit all the characteristics of other substances of misuse such as psychostimulants and opiates. For example, nicotine generally fails to induce locomotor response in mice and self-administration of nicotine is difficult to obtain in rats. We have shown recently that a pretreatment with mixed irreversible monoamine oxidase inhibitors (MAOIs), such as tranylcypromine, triggers a locomotor response to nicotine in mice and induces a robust self-administration of nicotine in rats. We show here that when mice were pretreated with enhancers of extracellular levels of noradrenaline, dopamine or serotonin (D-amphetamine, GBR12783 or para-chloro-amphetamine, respectively) and injected with nicotine (1 mg/kg), only those animals pretreated with para-chloro-amphetamine exhibited a specific locomotor response to nicotine. These data indicate a critical role of serotonin in nicotine-induced locomotor activity in mice. This was further confirmed in microdialysis experiments showing that nicotine induces an increase in extracellular serotonin levels in the ventral striatum in mice pretreated with tranylcypromine. This effect of nicotine on extracellular serotonin levels was absent in mice lacking the beta2-subunit of the nicotinic acetylcholine receptor. Our data suggest that mixed irreversible MAOIs contained in tobacco facilitate the effects of nicotine on serotonin release, thus allowing the locomotor and rewarding effects of nicotine.
We describe a simple method for extracting 3-methoxy-4-hydroxyphenylglycol (MHPG) from plasma. The sample is applied to a 1-mL "Extrelut" column (EM Industries) and eluted 15 min later with ethyl acetate. After mixing the eluate with pentane and back-extraction into water, we inject 25 or 50 microL of the aqueous phase onto a Beckman 15 cm x 4.6 mm (i.d.) column packed with 5-micron ODS particles (Beckman). Peaks are detected with a coulometric detector. The resulting chromatogram is clean, with few extraneous peaks. The extraction recovery of MHPG is 55-60%, which allows for detection of as little as 0.2 microgram of the analyte per liter. The decrease in the concentration of MHPG in plasma of patients treated with phenelzine agrees with the decrease in monoamine oxidase activity in platelets of these patients.
An attempt was made to compare platelet monoamine oxidase (MAO) activity in descriptively based types of nonbipolar depression. Platelet MAO activity was significantly higher in depression secondary to chronic anxiety, compared with primary unipolar depression and depression secondary to borderline personality, and in women compared with men. No significant differences were observed between endogenous-nonendogenous, delusional-nondelusional, psychomotor states, or different age groups.
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Some metabolic consequences of experimental hypertension on rat brain capillaries and kidney glomeruli have been studied in rats made hypertensive by a combination of deoxycorticosterone acetate injection and elevated salt intake (DOCA-salt hypertension) and isoproterenol injection. Enzyme activities were studied in vitro to ascertain directly or indirectly any changes in the metabolism of catecholamines and prostaglandins, and lysosomal integrity under conditions of experimental hypertension. Experimental hypertension was accompanied by an elevation in the activities of aromatic L-aminoacid decarboxylase, dopamine beta-hydroxylase, and malondialdehyde concentration, both in the brain capillaries and kidney glomeruli of rats. On the other hand, monoamine oxidase activity increased in brain capillaries but decreased in kidney glomeruli. Acid phosphatase activity increased marginally in kidney glomeruli but decreased significantly in brain capillaries. The catecholamine-synthesizing potential appears to have been augmented in both the tissue capillaries with a compensatory increase in the degrading enzyme activity in the brain capillaries of hypertensive rats. The absence of such an increase and an actual decrease in the monoamine oxidase activity in the kidney glomeruli may be responsible for the sustained maintenance of the hypertensive state. Increased malondialdehyde concentration may be due to the stimulation of the prostaglandin metabolism by the augmented catecholamine metabolism.
In this study monoamine oxidase (MAO) activity was measured in blood platelets of 21 individuals (age 2 6/12-19 years) who were diagnosed at preschool age as schizophrenics; MAO activity was not significantly different from that found in normals. An insignificant correlation was found between MAO activity in patients and age; a similar correlation for normals was also insignificant. In a sample of 15 families, no significant correlation between MAO activity of patients and their parents was obtained.
Controversy has historically centered on the use of monoamine oxidase inhibitors (MAOI) in the treatment of depression because of safety and efficacy issues. Hypertensive crisis following ingestion of foods containing tyramine is the most feared problem associated with MAOI therapy. The authors conclude that only four tyramine-containing foods clearly warrant absolute prohibition, but indicate situations where moderation should apply. Although MAOI remain second-line agents in the treatment of endogenous depression, it is unclear whether MAOI or tricyclic antidepressants should be the drugs of choice in atypical depression and this question necessitates future research.
Iron has been shown to accumulates at site where neurons degenerate in neurodegenerative diseases of Parkinson's disease, Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis and Friedreich ataxia. Iron is thought to participate or initiate oxidative stress via generation of reactive oxygen species (ROS), such as hydroxyl radical. Iron chelators are neuroprotective and prevent 6-hydroxydoapmine and MPTP dopaminergic neurotoxicity in rats and mice. However, their action on monoamine oxidase (MAO) A and B have not been determined previously since MAO-B inhibitors have been shown to be neuroprotective in cellular and animal models of Parkinson's disease. The chelators 8-hydroxyquinoline, O-phenanthroline, 2,2'-dipyridyl, U74500A and U74600F showed a preference for inhibition of rat brain mitochondrial MAO-A over MAO-B. Their IC(50) ranged from 10(-3) M to 10(-6) M, with 21-amino steroids (U74500A and U74006F) showing a greater selectivity and potency for MAO-A. Desferrioxamine (desferal), a prototype potent iron chelator, exhibited relatively poor MAO inhibitory. The inhibitions of MAO-A and B by 21-amino steroids (Lazaroids) were time dependent and irreversible. Those initiated by 8-hydroxyquinoline, 2,2'-dipyridyl and O-phenanthroline were fully reversible by enzyme dilution experiments. Both Fe(2+) and Fe(3+) reverse the MAO-A and B inhibition induced by the latter chelators, but not those initiated by 21-amino steroids. The data infer that either the inhibition of MAO by 21-amino steroids is either the resultant of their conversion to an irreversible covalently bound ligand or that the iron chelation moiety and MAO inhibitory activity in these compounds are not mutually shared. The results suggest that bifunctional brain penetrable drugs with iron chelating property and MAO inhibitory activity in could be the most feasible approach for neuroprotection in neurodegenerative diseases. Such drug would prevent participation of elevated iron in oxidative stress and formation of reactive hydroxyl radical, via its interaction with H(2)O2 (Fenton chemistry), generated as a consequence MAO and other oxidative enzyme reactions to generative cytotoxic reactive hydroxyl radical. We have now developed several of these compounds with neuroprotective, MAO inhibitory and iron chelating properties from our prototype iron chelators, VK-28 possessing propargylamine moiety of our anti-parkinson drug, rasagiline.
Seminiferous tubules from rats killed 24 hours after injection of pargyline, a monoamine oxidase inhibitor, did not grow well in tissue culture when compared to control tubules. Treated tubules showed severe tubular degeneration and loss of cellular detail after nine days in culture. Animals injected with pargyline for ten days had varying degrees of semi-niferous tubule degeneration with depletion of the spermatogenic elements. It is suggested that pargyline has a detrimental effect on spermatogenesis. Pargyline possibly acts by decreasing MAO levels which, in turn, may increase potentially damaging amines which may be responsible for the testicular damage.
The activation of human platelet monoamine oxidase (MAO) and rat brain mitochondrial MAO ( RBM -MAO) by human plasma were studied. The deamination of two different substrates, tyramine and phenethylamine (PEA) was investigated. The increase in MAO activity in the presence of human plasma can be explained by the observed decrease in the apparent Km for the amine (tyramine, PEA). This activation pattern was the same both for human platelet MAO and RBM -MAO. The activating properties of human plasma were recovered in high molecular weight fractions after gel filtration.
Four (in total) compounds with inhibitory effects on the activity of bovine serum monoamine oxidase were isolated from the methanol-water extracts of Rhei Rhizoma (Daiou) and Sennae Folium (Senna), and identified as sennosides A, B, E and F. Among them, sennosides A and B were obtained from both Rhei Rhizoma and Sennae Folium, while sennosides E and F were detected only in the former. The 50% inhibitory concentrations of the four sennosides were 17, 9, 24 and 13 microM, respectively, and the type of inhibition by seenosides A and B with respect to allylamine as the substrate was non-competitive.
The cardiovascular effects of monoamine oxidase inhibitors (MAOIs) are contrasted with those of the tricyclic antidepressants (TCAs). At therapeutic doses, MAOIs lower supine blood pressure and increase the postural fall in blood pressure, whereas TCAs have only the latter effect. MAOIs have little effect on heart rate and do not prolong cardiac conduction; TCAs increase heart rate and prolong cardiac conduction. Neither class of drugs appears to impair cardiac mechanical functioning. For patients with certain cardiac problems, MAOIs may have an advantage over TCAs.
The charts of 150 inpatients and 51 outpatients treated with a monoamine oxidase inhibitor (MAOI)-tricyclic antidepressant combination were reviewed. The incidence and severity of side effects among the patients on the combined regimen were essentially the same as those seen in the control groups. There were no deaths or strokes resulting from use of this regimen. The most frequent troublesome side effect was orthostatic hypotension. We conclude that the use of a MAOI-tricyclic combination in oral therapeutic doses is safe. However, the efficacy of this combination has not yet been proved, and it may be particularly toxic if taken in an overdose.