Neurotoxicity of some MAO inhibitors in adult rat hypothalamic cell culture

Monoamine oxidase-A (MAO-A) (amiflamine (AMF) and 4-methylthioamphetamine (MTA)) and MAO-B (l-deprenyl) inhibitors were found to be cytotoxic in a concentration-dependent manner for RCHT cells derived from adult rat hypothalamus. The cytotoxic effects were increased when the inhibitors were co-incubated with dicoumarol and especially with 25 μM AMF+100 μM dicoumarol (2.5-fold; P<0.001). The treatment of RCHT cells solely with AMF induced a marked decrease in the expression of DT-diaphorase mRNA.     

MAO inhibitors and depressive disorders today

MAO inhibitors are now only exceptionnally used in France. These medications are efficient to improve depressive states resistent to tricyclic antidepressants. Some authors suggest that we have to control the efficacy of the MAOI by evaluation of the part of inhibition of the activity of the enzyme MAO. This possibility of biological control, the apparition of specific medications inhibiting MAO A or MAO B, the efficacy of some associations (MAOI + tricyclic antidepressants or MAOI + tryptophane precursors) should lead us to reconsider our opinion about these medications.     

Possible melatonin involvement in the hypotensive effect of MAO inhibitors

Summary Effect of selective inhibitors of MAO-A and B isoenzymes on pineal melatonin (and related indoles), arterial blood pressure and brain MAO-A and B activities has been evaluated in intact, pinealectomized and shamoperated rats.Selective inhibition of MAO-A but not MAO-B activity stimulated pineal melatonin synthesis and decreased arterial blood pressure in intact and sham-operated animals. Pinealectomy attenuated the hypotensive effect of MAO-A inhibition.The possible melatonin contribution to both antidepressive and hypotensive effects of MAO inhibitors is discussed.     

Modification of L-DOPA pharmacological activity by MAO inhibitors

Summary Dopamine behaves mainly as a MAO-A substrate in rodent brain, but selective inhibition of MAO-B results in an increased turning activity following L-DOPA administration in hemi-Parkinsonian rodents. Unilateral substantia nigra dopaminergic denervation results in serotonergic hyper-innervation which may increase the contribution of MAO-A in the denervated striatum. Possibly as a result of this, there was no change in striatal MAO-A activity when 95% of dopaminergic innervation was reduced by 6-hydroxydopamine, as assessed by apomorphine-induced turning activity. MAO-B as well as MAO-A may contribute to deamination of dopamine produced from L-DOPA.     

An open trial of MAO inhibitors in bulimia

Twelve bulimic women with prominent depression and anxiety were treated with monoamine oxidase inhibitors (MAOIs). A dramatic response was seen in 10 cases. The implications of this open clinical trial for the understanding and treatment of bulimia are discussed.     

On the binding of monoamine oxidase inhibitors to some sites distinct from the MAO active site, and effects thereby elicited

Many inhibitors of monoamine oxidase, particularly those developed during the past three decades, are often referred to as being "selective" for one or other isoform of the enzyme. However true this may be, selectivity within the EC 1.4.3.4 family does not preclude the possibility of interactions of these drugs with other proteins unrelated to monoamine oxidase. Indeed, evidence exists which either suggests or demonstrates directly that many of these inhibitors do interact with, and affect the behaviour of, other enzymes, receptor systems and uptake pumps, with potentially interesting consequences, desirable or otherwise, for the patient or the pharmacologist. An overview of many such interactions, and speculation upon some of the possible consequences, are provided in this review.     

Clinical pharmacology of MAO inhibitors: safety and future

In this article, we review the clinical pharmacology of monoamine oxidase inhibitors (MAOIs). Now, MAOIs are used for the treatment of depressive disorders, anxiety disorders, Parkinson's disease, and Alzheimer's disease. The selective monoamine oxidase-B inhibitor selegiline and the selective and reversible inhibitor of monoamine oxidase-A (RIMA) moclobemide are free from the hypertensive crisis, the so-called "cheese effect." Therefore, selective MAO-B inhibitors and RIMAs hold promise as safer alternatives to classical MAOIs. It is clear that much remains to be investigated with regard to the clinical pharmacology of MAOIs. It seems obvious that a greater understanding of the pharmacodynamics and pharmacokinetics of MAOIs could result in improved treatment of the patients in the future.     

Studies on the nötropic potential of some angiotensin converting enzyme inhibitors in the mouse

1. 1. The effects of captopril, epicaptopril and fosenopril were compared with codergine mesylate in a number of tests which may be predicative of potential nöotropic activity. None of the drugs tested protected against KCN induced hypoxic seizures. However, in the acute atropine sulphate induced hyperactivity test, in which the behaviour of the mice in the ‘open field’ apparatus was assessed, both captopril and codergine mesylate were found to reverse the atropine induced hyper-motility. The effect of captopril would not appear to be a direct reflection of its angiotensin converting enzyme (ACE) inhibitory activity as fosenopril is also a potent ACE inhibitor.

2. 2. Only codergine mesylate was found to reverse the atropine sulphate induced amnesia in a one trial avoidance task, captopril and its analogues being inactive in such a test.

3. 3. Chronically administered codergine mesylate, captopril and its analogues reversed the hypermobility in the ‘open field’ apparatus that occurred following the injection of a single dose of the neurotoxin trimethyltin.

4. 4. None of the changes in locomotor activity would appear to be due to adverse effect of the drugs on motor coordination.

5. 5. It is concluded that captopril may be worthy of more detailed studies as a potential nöotropic agent.

Effect of MAO inhibitors on the high-affinity reuptake of biogenic amines in rat subcortical regions

The noradrenaline (NA), dopamine (DA) and serotonin (5HT) reuptake inhibitory potency of deprenyl, the highly selective and irreversible inhibitor of MAO-B, methamphetamine enantiomers, and some other MAO inhibitors (clorgyline, J-508, J-511, J-512, J-516, LK-63, U-1424, 2-HxMP) was compared. In vitro hypothalamic NA reuptake was inhibited by (+)-, and (-)-methamphetamine, (+)- J-508 and (+)-deprenyl (IC50: 0.35, 3.5, 17.0 and 17.8 mumol/l, respectively), and U-1424, J-512, J-516, LK-63 and 2-Hx-MP showed IC50 > 1000 mumol/l. Striatal DA reuptake was inhibited by (+)-, and (-)-methamphetamine, (+)-, and (-)-deprenyl and clorgyline with IC50 of 0.6, 42.0, 24.0, 98.6 and 27.0 mumol/l, respectively, however the other compounds were ineffective. Hippocampal 5HT reuptake was slightly inhibited by clorgyline (IC50 205.0 mumol/l), while the other MAO-inhibitors were devoid of potency. Data suggest that potency and selectivity of MAO inhibition and reuptake inhibition are independent features of the compounds, and metabolism of deprenyl results in increased noradrenaline and dopamine reuptake inhibition.     

The effects of lifelong treatment with MAO inhibitors on amino acid levels in rat brain

Summary In a previous paper a possible relationship had been suggested to exist between age-induced changes in total MAO activity and amino acid levels in some rat brain areas.To further investigate the possible involvement of MAO activity in changes of brain amino acid levels with aging, moclobemide and Ro 19-6327, short acting MAO-A and MAO-B inhibitors, respectively, were administered to female Wistar rats for their whole life-span. Brain amino acid levels in animals treated with MAO inhibitors were compared to those of young and old nontreated rats. The age-induced changes in brain amino acid concentrations found in the present study were in good agreement with those previously reported. Treatment with both moclobemide and Ro 19-6327 was found to restore taurine and serine concentrations in cortex and glutamine concentrations in cerebellum, to the same values as in young rats, to decrease cerebellum concentrations of serine and to increase taurine concentrations in hypothalamus. Administration of moclobemide brought aspartate concentrations in accumbens and cortex back to the same values as in young rats. A similar effect was observed on hypothalamus glutamate concentrations in rats treated with Ro 19-6327. Some possible causes and consequences of the correction of age-induced brain amino acid levels by chronic administration of MAO inhibitors are discussed.     

Evaluation of selective human MAO inhibitory activities of some novel pyrazoline derivatives

A series of 1-[2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetyl]-3,5-diaryl-4,5-dihydro-1H-pyrazole derivatives were prepared by reacting 2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetylhydrazine with appropriate chalcones. The chemical structures of all compounds were confirmed by elemental analyses, IR, ¹H NMR and ESI–MS. All the compounds were investigated for their ability to selectively inhibit monoamine oxidase (MAO) by in vitro tests. MAO activities of the compounds were compared with moclobemide and selegiline and all the compounds were found to inhibit human MAO-A selectively. The inhibition profile was found to be competitive and reversible for all compounds by in vitro tests. Among the compounds examined, compounds 5ae, 5af and 5ag were more selective than moclobemide, with respect to the K _i values experimentally found. In addition, the compound 5bg showed MAO-A inhibitor activity as well as moclobemide. A series of experimentally tested compounds (5ae–5ch) were docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The AUTODOCK 4.01 program was employed to perform automated molecular docking.     

Insights into the mechanisms of action of the MAO inhibitors phenelzine and tranylcypromine: a review.

Although the non-selective monoamine oxidase inhibitors phenelzine and tranylcypromine have been used for many years, much still remains to be understood about their mechanisms of action. Other factors, in addition to the inhibition of monoamine oxidase and the subsequent elevation of brain levels of the catecholamines and 5-hydroxytryptamine, may contribute to the overall pharmacological profiles of these drugs. This review also considers the effects on brain levels of amino acids and trace amines, uptake and release of neurotransmitter amines at nerve terminals, receptors for amino acids and amines, and enzymes other than monoamine oxidase, including enzymes involved in metabolism of other drugs. The possible contributions of metabolism and stereochemistry to the actions of these monoamine oxidase inhibitors are discussed.     

Studies on vascular permeability in peripheral nerves

Summary Permeability changes of vasa nervorum and exudation of serum albumin in a nutritional peripheral neuropathy induced by isonicotinic acid hydrazide (INH) in rats were studied by menas of fluorescence microscopic tracing of intravenously injected albumin tagged with Evans blue or with fluorescein isothiocyanate.All rats given INH for fourteen days which developed histologically demonstrable neuropathy also showed abnormal vascular permeability and exudation of the albumin conjugate into the endoneurium. Once outside the blood vessels the conjugate had a predilection for spreading in the endoneurial interstices along the nerves.Thus, like traumatic peripheral neuropathies, this nutritional neuropathy is associated with permeability changes of vasa nervorum and exudation of serum albumin in the endoneurium. The simultaneous occurrence of nerve fibre lesions and permeability changes of vasa nervorum indicates that these two phenomena are in some way related to each other.Supported by grants from the Swedish Multiple Sclerosis Society and from the Swedish Medical Research Council, Project B 68-12X-82-04.