The discovery of antidepressants: a winding path

Modern treatment of mental depression started with the availability of monoamine oxidase (MAO) inhibitors and tricyclic antidepressants. These drugs also contributed to the early development of psychopharmacology. Attempts to improve the anti-tuberculous action of the hydrazine derivative isoniazid by developing derivatives thereof led to the synthesis of iproniazid. Its introduction as the first modern antidepressant was based on three unexpected actions of the drug: MAO-inhibition, 'reversal' of reserpine-induced sedation, and the presence of psychostimulation as a clinical side effect in man. However, the initial success of iproniazid and other MAO inhibitors, hydrazides and non-hydrazides, was curtailed by the occurrence of undesirable side effects such as potentiation of the blood-pressure elevating action of food amines. The tricyclic antidepressants were a development of the class of antihistamines, one of which, chlorpromazine, showed neuroleptic activity. A congener of this compound, imipramine, was discovered by clinical observation to have unexpected antidepressant effects. The clinical success of this drug (which is still in use) led to the development of a successful series of other tricyclic and non-tricyclic antidepressants. Progress in the elucidation of possible mechanisms of the action of the tricyclic compounds has helped this development. Recent advances in basic research have also induced a revival of MAO-inhibitors since, due to the discovery of MAO-subtypes, inhibitors with higher specificity and fewer undesirable side effects are now available.     

The discovery of antidepressants: A winding path

Summary Modern treatment of mental depression started with the availability of monoamine oxidase (MAO) inhibitors and tricyclic antidepressants. These drugs also contributed to the early development of psychopharmacology. Attempts to improve the anti-tuberculous action of the hydrazine derivative isoniazid by developing derivatives thereof led to the synthesis of iproniazid. Its introduction as the first modern antidepressant was based on three unexpected actions of the drug: MAO-inhibition, reversal of reserpine-induced sedation, and the presence of psychostimulation as a clinical side effect in man. However, the initial success of iproniazid and other MAO inhibitors, hydrazides and non-hydrazides, was curtailed by the occurrence of undesirable side effects such as potentiation of the blood-pressure elevating action of food amines. The tricyclic antidepressants were a development of the class of antihistamines, one of which, chlorpromazine, showed neuroleptic activity. A congener of this compound, imipramine, was discovered by clinical observation to have unexpected antidepressant effects. The clinical success of this drug (which is still in use) led to the development of a successful series of other tricyclic and non-tricyclic antidepressants. Progress in the elucidation of possible mechanisms of the action of the tricyclic compounds has helped this development. Recent advances in basic research have also induced a revival of MAO-inhibitors since, due to the discovery of MAO-subtypes, inhibitors with higher specificity and fewer undesirable side effects are now available.     

Monoamine oxidases in development

Monoamine oxidases (MAOs) are flavoproteins of the outer mitochondrial membrane that catalyze the oxidative deamination of biogenic and xenobiotic amines. In mammals there are two isoforms (MAO-A and MAO-B) that can be distinguished on the basis of their substrate specificity and their sensitivity towards specific inhibitors. Both isoforms are expressed in most tissues, but their expression in the central nervous system and their ability to metabolize monoaminergic neurotransmitters have focused MAO research on the functionality of the mature brain. MAO activities have been related to neurodegenerative diseases as well as to neurological and psychiatric disorders. More recently evidence has been accumulating indicating that MAO isoforms are expressed not only in adult mammals, but also before birth, and that defective MAO expression induces developmental abnormalities in particular of the brain. This review is aimed at summarizing and critically evaluating the new findings on the developmental functions of MAO isoforms during embryogenesis.     

Monoamine oxidase activity in single nerve cell bodies from substantia nigra of rat and man

In single nerve cell bodies isolated from the substantia nigra of man and rat the active forms of MAO A and MAO B were found by the use of the microdiver technique and specific inhibitors.     

Monoamine oxidase activity in single nerve cell bodies from substantia nigra of rat and man

Summary In single nerve cell bodies isolated from the substantia nigra of man and rat the active forms of MAO A and MAO B were found by the use of the microdiver technique and specific inhibitors.     

Beeinflussung der «Adrenalin-Oxydasen» des Blutplasmasin vivo durch biogene Monoamine und Neuropharmaka

Summary In rats adrenaline, noradrenaline, histamine and iproniazid induced in blood plasma a significant increase of the mean of the enzyme activity of adrenaline oxidases (-globulin-factors, different from coeruloplasmin, ferritin and catalase). Reserpine showed initially an increase and later a decrease and ephedrine caused a decrease of the enzymic activity.     

Chlorodimeform and its effect on monoamine oxidase activity in the cattle tick, Boophilus microplus.

The action of the acaricide, chlorodimeform and its metabolite. N-desmethylchlorodimeform, on the activity monoamine oxidase (MAO) from the cattle tick, Boophilus microplus, were studied. Both compounds were found to be potent in vitro and in vivo inhibitors of the enzyme. However the inhibition of MAO does not seem to be related to the toxic action of the acaricide.     

Chlorodimeform and its effect on monoamine oxidase activity in the cattle tickBoophilus microplus

Summary The action of the acaricide, chlorodimeform and its metabolite, N-desmethylchlorodimeform, on the activity monoamine oxidase (MAO) from the cattle tick,Boophilus microplus, were studied, Both compounds were found to be potent in vitro and in vivo inhibitors of the enzyme. However the inhibition of MAO does not seem to be related to the toxic action of the acaricide.     

Sexual steroids and monamine metabolism during gestation.

The experiments show influence of progesterone and estradiol on regulation of enzymes of monamine metabolism, MAO and COMP during pregnancy. Both the hormones inhibit enzymes MAO and COMPT in the adrenals when determined at 0 h parturition. Estradiol has stronger inhibitory effect than progesterone. The results provide evidence for important endocrine implication during pregnancy for processes of monamine regulation.     

Binding of iproniazid to the polymeric forms of iodide peroxidase

Summary ¹⁴C labelled iproniazid binds to iodide peroxidase more effectively in low ionic strength buffer than in high ionic strength buffer, suggesting preferential binding to the monomeric form of iodide peroxidase. During column chromatography, under conditions that separate iodide peroxidase into multiple forms, iproniazid is bound selectively to the monomeric form. Thus, this antithyroid agent appears to bind preferentially to the monomeric enzyme form, or possibly to cause dissociation of the polymeric to the monomeric form.Supported in part by United States Public Health Service Grants AM-13,377 and AM-13,643.     

Sexual steroids and monoamine metabolism during gestation

Summary The experiments show influence of progesterone and estradiol on regulation of enzymes of monoamine metabolism, MAO and COMT during pregnancy. Both the hormones inhibit enzymes MAO and COMT in the adrenals when determined at 0 h parturition. Estradiol has stronger inhibitory effect than progesterone. The results provide evidence for important endocrine implication during pregnancy for processes of monoamine regulation.The generous help of Dr.Raynaud of CEA, France is gratefully acknowledged. A.R.B. is pre-doctoral fellow of Paris University.     

Influence de l'anaérobiose et de différentes tensions d'oxygène sur la libération d'histamine dans la réaction anaphylactiquein vitro

Summary The influence of anaerobiose and of varied oxygen tensions upon respiration and histamine release during anaphylactic reaction in guineapig lung slicesin vitro was studied.No histamine was liberated in the absence of oxygen. With increasing oxygen tensions, increasing histamine quantities were released; these quantities reached the control values when the atmosphere contained 10% oxygen.These results indicate that the mechanism of histamine release in the anaphylactic reaction is linked with the aerobic metabolism of the cell.

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Boursicrs du Consclho Nacional de Pesquisas.     

Monoamine oxidase activity of the brain of Locusta migratoria in normal conditions and after intoxication by two insecticides: chlordimeform and dieldrin]

Our investigations have shown up an MAO activity in locust brain, by the use of a radio-isotopic method, as much at larval as at adult stage. This MAO activity is in a sample of 34,3 dpm/mg of brain tissue (wet weight). Investigations have also been undertaken on effects of dieldrin and chlordimeform poisoning on this MAO activity. Even at sublethal dosages, chlordimeform causes a significant inhibition of MAO activity in vivo. This finding is in accordance with Beeman and Matsumura's work in vitro. Moreover, acute poisoning by dieldrin produces more than 60% of inhibition of MAO, 3 hours after administration of 115 microng of this insecticide by injection in the hoemocelian cavity.     

Platelet monoamine oxidase B: Use and misuse

The human platelet in addition to having serotonin (5-HT) receptors, uptake carriers (receptor) and transmitter storage vesicles, primarily possesses mitochondrial monoamine oxidase (MAO) type B. Similar to the major form of MAO in the human brain, this enzyme actively oxidizes A-B and B substrates (tyramine, dopamine, phenylethylamine) as well as the novel secondary amine anticonvulsant, milacemide and dopaminergic neurotoxin, MPTP. 5-HT oxidation is hardly affected by the platelet enzyme and MAO inhibitors have no net effect on its accumulation. MAO-B is selectively inhibited by 1-deprenyl and thus the platelet enzyme may be useful to monitor the anti-Parkinson activity of such drugs, as related to their ability to inhibit brain MAO-B. The oxidation of the anticonvulsant, milacemide, to glycine in vitro and in vivo by MAO-B, may herald new prospects for the development of inert prodrugs capable of being metabolized to neuroactive substances by MAO-B. The plasma levels of their metabolites may be an index of MAO-B activity found in the platelet and brain.     

Platelet monoamine oxidase B: use and misuse

The human platelet in addition to having serotonin (5-HT) receptors, uptake carriers (receptor) and transmitter storage vesicles, primarily possesses mitochondrial monoamine oxidase (MAO) type B. Similar to the major form of MAO in the human brain, this enzyme actively oxidizes A-B and B substrates (tyramine, dopamine, phenylethylamine) as well as the novel secondary amine anticonvulsant, milacemide and dopaminergic neurotoxin, MPTP. 5-HT oxidation is hardly affected by the platelet enzyme and MAO inhibitors have no net effect on its accumulation. MAO-B is selectively inhibited by 1-deprenyl and thus the platelet enzyme may be useful to monitor the anti-Parkinson activity of such drugs, as related to their ability to inhibit brain MAO-B. The oxidation of the anticonvulsant, milacemide, to glycine in vitro and in vivo by MAO-B, may herald new prospects for the development of inert prodrugs capable of being metabolized to neuroactive substances by MAO-B. The plasma levels of their metabolites may be an index of MAO-B activity found in the platelet and brain.     

Einfluss von Isopropyl-isonikotinsäurehydrazid auf den Katecholamingehalt des Myokards

Summary Iproniazid causes a marked prolonged rise in the catecholaminecontent of the heart of guinea pigs. Isoniazid has a much weaker activity in this respect. This effect of iproniazid on the catecholamines of the heart is less marked in other animal species than in guinea pigs.     

Proliferationen der Fischepidermis nach der Einwirkung von inhibitoren des glykolytischen Energiestoffwechsels

Summary When fluoride-ions or monoiodoacetate is added to the ambient medium, there occur in fish larvae after 12 h, and in eels after 24 h, in some places, solid epidermal proliferations. The effect of glycolysis inhibitors on epidermal mitotic activity might be due to an impairment of energy metabolism as it is nullified by a simultaneous application of inorganic diphosphate or by doubled O₂ partial pressure of 320 mm Hg.     

Interference with histamine and imidazole acetic acid metabolism by salicylates: a possible contribution to salicylate analgesic activity?

In man, rats and mice, the urinary excretion of the histamine and L-histidine metabolite, imidazole acetic acid, is increased and that of the conjugated metabolite, ribosylimidazole acetic acid, decreased by small doses of salicylates. In contrast to salicylates, other non-salicylate anti-inflammatory drugs, indomethacin, phenylbutazone, phenacetin and acetaminophen do not influence the excretion of the urinary metabolites of histamine and L-histidine. Since imidazole acetic acid is reported to have analgesic and narcotic activity, there is the inference that the analgesic properties of salicylate might be due in part to interference in imidazole acetic acid metabolism.     

Stimulation of histamine synthesis in rat mast cells by compound 48/80 in vitro

The histamine content of rat peritoneal fluid cells is doubled within 20 min by 0.5 microgram/ml of compound 48/80. Histamine catabolism inhibitors do not reproduce this effect; cells pre-incubated with alpha-fluoromethylhistidine are unresponsive to compound 48/80 which therefore activates pre-formed histidine decarboxylase rather than 'inducing' it. Non-mast cells showed no change after treatment with compound 48/80.     

Interference with histamine and imidazole acetic acid metabolism by salicylates: A possible contribution to salicylate analgesic activity?

Summary In man, rats and mice, the urinary excretion of the histamine andl-histidine metabolite, imidazole acetic acid, is increased and that of the conjugated metabolite, ribosylimidazole acetic acid, decreased by small doses of salicylates. In contrast to salicylates, other non-salicylate anti-inflammatory drugs, indomethacin, phenylbutazone, phenacetin and acetaminophen do not influence the excretion of the urinary metabolites of histamine andl-histidine. Since imidazole acetic acid is reported to have analgesic and narcotic activity, there is the inference that the analgesic properties of salicylate might be due in part to interference in imidazole acetic acid metabolism.