Inhibition Of Brain Monoamine Oxidase Research Articles

Novel multifunctional neuroprotective iron chelator‐monoamine oxidase inhibitor drugs for neurodegenerative diseases.In vivoselective brain monoamine oxidase inhibition and prevention of MPTP‐induced striatal dopamine depletion

Several multifunctional iron chelators have been synthesized from hydroxyquinoline pharmacophore of the iron chelator, VK-28, possessing the monoamine oxidase (MAO) and neuroprotective N-propargylamine moiety. They have iron chelating potency similar to desferal. M30 is a potent irreversible rat brain mitochondrial MAO-A and -B inhibitor in vitro (IC50, MAO-A, 0.037 +/- 0.02; MAO-B, 0.057 +/- 0.01). Acute (1-5 mg/kg) and chronic [5-10 mg/kg intraperitoneally (i.p.) or orally (p.o.) once daily for 14 days]in vivo studies have shown M30 to be a potent brain selective (striatum, hippocampus and cerebellum) MAO-A and -B inhibitor. It has little effects on the enzyme activities of the liver and small intestine. Its N-desmethylated derivative, M30A is significantly less active. Acute and chronic treatment with M30 results in increased levels of dopamine (DA), serotonin(5-HT), noradrenaline (NA) and decreases in DOPAC (dihydroxyphenylacetic acid), HVA (homovanillic acid) and 5-HIAA (5-hydroxyindole acetic acid) as determined in striatum and hypothalamus. In the mouse MPTP (N-methy-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease (PD) it attenuates the DA depleting action of the neurotoxin and increases striatal levels of DA, 5-HT and NA, while decreasing their metabolites. As DA is equally well metabolized by MAO-A and -B, it is expected that M30 would have a greater DA neurotransmission potentiation in PD than selective MAO-B inhibitors, for which it is being developed, as MAO-B inhibitors do not alter brain dopamine.

Inhibition of brain monoamine oxidase by adducts of 1,2,3,4-tetrahydroisoquinoline with components of cigarette smoke

A series of adducts of 1,2,3,4-tetrahydroisoquinoline (TIQ) and some components of tobacco smoke were investigated for their ability to inhibit rat brain monoamine oxidase. 1-Cyano-TIQ (1CTIQ), N-(1′-cyanoethyl)-TIQ (CETIQ), N-(1′-cyano-propyl)-TIQ (CPTIQ), and N-(1′-cyanobutyl)-TIQ (CBTIQ) were found to act as competitive inhibitors for both MAO-A and MAO-B. K i , values ranged from 16.4 to 37.6 μM. N-(CyanomethyO)-TIQ (CMTIQ) was not found to be an inhibitor ( K i > 100 μM). These findings may help to explain the in vivo inhibitory effects of tobacco smoke on MAO activity and the suggested protective effect of tobacco smoking against Parkinson's disease. They also appear to reinforce the usefulness of reversible MAO inhibitors in smoking cessation and abstinence. However, different results must be expected between Burley and Bright tobacco.

Blood pressure effects of monoamine oxidase inhibitors in response to orally administered tyramine in the rat

The reversible monoamine oxidase-A inhibitors BW 1370U87, BW 616U76, brofaromine, and moclobemide, and the irreversible nonselective monoamine oxidase inhibitor phenelzine were compared for potentiation of the pressor response to oral tyramine. Conscious rats were pretreated with doses of the monoamine oxidase inhibitors sufficient to produce 80% inhibition of brain monoamine oxidase, and then were challenged with orally administered tyramine. Blood pressure was monitored prior to and after tyramine, and peak pressor responses were compared. At a dose of 15 mg/kg tyramine, the pressor response of BW 1370U87 was statistically similar to the vehicle control response. BW 616U76, brofaromine, and moclobemide elicited mild tyramine pressor effects, whereas phenelzine resulted in a marked elevation of blood pressure. Higher doses of tyramine elicited blood pressure elevations from all of the monoamine oxidase inhibitors.

Mercurial induced brain monoamine oxidase inhibition in the teleost Channa punctatus (Bloch).

Neurotoxic effects of mercurials are well established in a variety of animals including man. In mammals, mercury is known to alter brain monamine synthesis, high affinity uptake and central catecholamine development. However, such investigations on the fishes are meager. In the present communication, mercuric chloride (HgCl2) and organic mercurial fungicide Emisan induced changes in the brain monoamine oxidase (MAO) content in the fish C. punctatus are described.

O2E1136) - Inhibition of brain monoamine oxidase A and B form by 1-methyl-4-pheny1-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized metabolite, 1-methyl-4-phenylpyridinium ion (MPP+).

O2E1136) - Inhibition of brain monoamine oxidase A and B form by 1-methyl-4-pheny1-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized metabolite, 1-methyl-4-phenylpyridinium ion (MPP+).

Cadmium-induced inhibition of brain monoamine oxidase in the freshwater catfish

The freshwater catfishClarias batrachus (L.), exposed to 50 ppm of cadmium (Cd) chloride for a period of 135 days exhibited marked inhibition of brain monoamine oxidase (MAO) (p<0.001). The retarded gonadal growth observed in the present study suggests that Cd may be capable of creating imbalance in the aminergic activity of the hypothalamus, which modulates the secretion and release of gonadotropins.

Effect of thiamine deficiency on brain serotonin turnover

Serotonin turnover has been investigated in regional brain areas of rats made thiamine deficient by pyrithiamine (PT). Following intracisternal injection of [14C]5-hydroxytryptamine ([14C]5-HT), a marked increase in the accumulation of [14C]5-hydroxyindoleacetic acid ([14C]5-HIAA) was found in the medulla-pons, hypothalamus and cerebral cortex. [14C]5-HT levels were normal in all of the brain areas except the cerebral cortex which had an increase of 58%. The ratio of [14C]5-HIAA/[14C]5-HT was significantly increased in every brain region of PT-treated rats except the cerebral cortex. Part of this increase in [14C]5-HIAA was shown to be due to impairment of active transport of this 5-HT metabolite out of the brain. However, increased 5-HT synthesis in the cerebellum, hypothalamus, striatum, hippocampus and cerebral cortex was demonstrated by measurement of 5-HT accumulation after inhibition of brain monoamine oxidase. PT-induced increase in endogenous 5-HIAA in the medulla-pons occurred simultaneously with the onset of neurological signs and both parameters were reversible by thiamine administration. These results suggest that acute thiamine deficiency, induced by PT, both increases brain 5-HT synthesis and impairs 5-HIAA efflux from the brain. There is a close correlation between neurological manifestations and changes in brain 5-HT metabolism in acute thiamine deficiency.

Effect of theophylline on monoamine metabolism in the rat brain

The effect of theophylline on brain monoamine metabolism was studied in rats. Single doses of theophylline caused a striking and dose-related increase in the levels of 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MOPEG-SO 4) and 5-hydroxyindoleacetic acid (5-HIAA) in the brain. The level of brain homovanillic acid was only slightly affected. No appreciable change occurred, however, in the levels of brain norepinephrine, serotonin and dopamine. The increased level of brain MOPEG-SO 4 or 5-HIAA after theophylline does not appear to result from its interference with the transport system for the acids in the brain since the rate of decline of the acid levels following pargyline was not affected. Under the conditions of brain monoamine oxidase inhibition, theophylline enhanced the increase in brain normetanephrine level without causing any change in 3-methoxytyramine level. The enhancement of brain normetanephrine level by theophylline became more pronounced when rats were pretreated with imipramine in addition to pargyline. These results suggest that, in the brain, theophylline may cause a release of serotonin leading to its increased turnover. The results also confirm the previous conclusion that the methylxanthine causes a release of norepinephrine and a concomitant increase in its turnover in the brain.

Harmine tremor after brain monoamine oxidase inhibition in the mouse

The TD 50 for harmine in mebanazine-pretreated mice was not significantly different from that in untreated mice. Mebanazine (20 mg/kg s.c.) gave a 99% inhibition of brain monoamine oxidase without tremor. Thus harmine tremor is not related to its effect on brain monoamine oxidase.

Homovanillic and 5-hydroxyindoleacetic acids in cerebrospinal fluid after probenecid: measurement of brain monoamine oxidase inhibition in vivo.

SummaryThe effects of inhibition of monoamine oxidase (MAO) by pargyline on the concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) of dogs are reported. Administration of pargyline reduced control levels of HVA and 5-HIAA and inhibited the probenecid-induced rise of these acid metabolites. The magnitude of this inhibition was related to the dose of pargyline. Pargyline inhibited the probenecid-induced rise in HVA more effectively than the rise in 5-HIAA, suggesting the existence of different monamine oxidases in dog brain. After completion of the pargyline treatment, the probenecid-induced rise of 5-HIAA and HVA returned to normal in about 1 month. Measurement of the acid metabolites in the CSF is a direct index not only of the MAO activity in brain but of the degree to which the metabolism of a specific monoamine is inhibited. Probenecid treatment makes this method sensitive enough that it might be applied for measurement of brain MAO activi...

Inhibition of monoamine oxidase by sodium pentobarbital.

A single intraperitoneal injection of 30, 60, or 90 mg/kg of sodium pentobarbital into male rats produced an appreciable inhibition of monoamine oxidase activity of liver and heart. The brain and kidney activities were practically unaffected. Chronic administration of pentobarbital, 30 mg/kg daily for 20 days, did, however, produce an inhibition of brain monoamine oxidase (MAO) which was maximal 48 h after the last injection. In all other experiments with a single dose of barbiturate the maximal inhibition of MAO appeared 15–30 min after treatment.Sodium pentobarbital inhibited MAO activity in vitro when added to a liver mitochondrial preparation. High concentrations of barbiturate had to be used for the in vitro experiments. The Ki value for sodium pentobarbital was 1.21 × 10−3 M while the Km was 1.6 × 10−5 M. The observed inhibition was of a competitive nature. The inhibition is comparable with that observed for some flavoenzymes following addition of barbiturates.

Selective brain monoamine oxidase inhibition resulting from an interaction between reversible and irreversible inhibitors

Administration of BW 392C60 to rats before treatment with pheniprazine protects liver MAO but not brain MAO from pheniprazine. By proper selection of doses of the two drugs, it is possible to inhibit completely MAO activity in brain while maintaining high MAO activity in liver and certain other peripheral organs. Of the other long acting inhibitors tested, pargyline alone was effectively antagonized by BW 392C60, while tranylcypromine and iproniazid were only slightly affected.

Specific Liver and Brain Monoamine Oxidase Inhibition by Alkyl- and Arylalkylhydrazines.

SummaryAbility of several hydrazine derivatives selectively to inhibit liver or brain monoamine oxidase (MAO) in the intact rat has been compared. Of those studied, the compounds possessing an unsubstituted arylalkylhydrazine structure, such as benzyl hydrazine, β-phenylethylhydrazine, and β-phenylisopropylhydrazine showed greater brain than liver MAO inhibiting properties. Substitution on terminal hydrazine with an isonicotinyl group reversed the brain-liver MAO inhibiting relationship. Compounds lacking the benzene ring as in methyl-, ethyl-, and isopropylhydrazine also showed greater liver than brain MAO inhibiting effects. It is concluded that the benzene ring of the unsubstituted aryl-alkylhydrazines may aid in their passage into the brain.