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At least 19 recordsLinked to original sources

PubMed1987

N-propargylbenzylamine, a major metabolite of pargyline, is a potent inhibitor of monoamine oxidase type B in rats in vivo: a comparison with deprenyl.

In an effort to explore the contribution of the metabolites of pargyline towards the in vivo inhibition of monoamine oxidase (MAO), the effects of pargyline and its major metabolites on the production and metabolism of a number of biogenic amines were studied in rats. The administration of pargyline gave rise to three major ethyl acetate extractable metabolites: benzylamine, N-methylbenzylamine and N-propargylbenzylamine (NPB). Only NPB demonstrated in vivo monoamine oxidase inhibitory properties at an acute dose of 30 mg kg-1. The acute effects of pargyline, NPB, and deprenyl on urine and brain concentrations of a number of biogenic amines (phenylethylamine (PEA), m- and p-tyramine, noradrenaline (NA), dopamine, and 5-hydroxytryptamine (5-HT) and their metabolites were evaluated. Increased urine and brain concentrations of PEA were considered to represent in vivo inhibition of type B MAO while decreased concentrations of NA and 5-HT metabolites were regarded as indicators of an in vivo inhibition of MAO type A. NPB, like deprenyl and pargyline, significantly increased urine and brain PEA while only pargyline reduced 5-HT metabolism, suggesting that the metabolism of pargyline to NPB may contribute towards the MAO type B inhibitory effects of pargyline in vivo. Since the therapeutic benefits of MAO inhibitors in clinical practice usually require some period of chronic treatment, the chronic effects of repeated 14 daily doses of the above MAO inhibitors on central and peripheral biogenic amines were evaluated at the following times: during treatment, one day and five days after termination of treatment. The biochemical changes observed during the course of chronic NPB, pargyline and deprenyl treatments generally follow the expected in vitro characteristics of these drugs, but the detailed changes observed suggest clear differences. For example, the in vivo effect of pargyline on urine 5-hydroxyindoleacetic acid excretion was considerably weaker than its effect on the excretion of NA and dopamine metabolites. These changes are opposite to the in vitro effects of pargyline on 5-HT, dopamine and NA oxidative deamination. Inhibitions of the metabolism of all the amines studied were clearly observed during chronic MAOI treatments, but these effects were less evident five days after the end of treatment, suggesting an almost normal metabolism of biogenic amines. It is concluded that while MAO inhibitors may be the primary compound responsible for MAO inhibition, the effects of their metabolites in some cases may also play equally important roles in the regulation of monoamines both in the periphery and the brain. Thus, as demonstrated here, NPB was found to be as potent as pargyline and deprenyl with regard to its in vivo MAO type B inhibitory properties.

Animals↗

PubMed1976

Comparison of short and long-lasting effects of pargyline on cerebral dopamine metabolism.

Behavioural and somatic responses to L-DOPA in rats are potentiated by short-term pretreatment with pargyline. It was therefore of interest to study the influence of the delay between pargyline pretreatment and L-DOPA-injection on the fate of the latter in rat brain. In rats treated with pargyline (50 mg/kg s.c.), the half-lives of recovery of striatal MAO activity and normal endogenous contents of homovanillic and 3,4-dihydroxyphenylacetic acids in striatum ranged from 9 to 14 days. The same treatment led to a marked increase (50-100-fold) in the accumulation of 3H-methoxytyramine in whole brain and, though less so, in 3H-dopamine formed from i.v. 3H-DOPA. Recovery from this effect of pargyline, however, was more rapid with a half-life of 15-19 h. Similar changes were observed when 3H-DOPA or 3H-dopamine was injected intracisternally, indicating that the phenomenon did not take place in the cerebral blood capillary walls, which are known to contain DOPA decarboxylase and MAO activities. The only labelled deaminated metabolite of dopamine in the brain after 3H-DOPA i.v. was 3H-homovanillic acid, which was strongly reduced 2 h after pargyline, but normalized after 24 h of pretreatment with the MAO inhibitor. When 3H-alpha-methyldopa instead of 3H-DOPA was injected, no increase in 3H-alpha-methyldopamine and its O-methylated derivative was produced by pargyline pretreatment. Moreover, in an experiment in which the animals were pretreated with pargyline at various times up to 21 days, a second injection of the MAO inhibitor 1.5 h before 3H-DOPA restored the increase in 3H-DA + 3H-MT observed with a single treatment with pargyline 1.5 h before the labelled amino acid. These results suggest that this short-lasting effect of the MAO inhibitor is related to the MAO inhibitory properties of the drug. The threshold dose of pargyline for producing the short-term effect was about 10 times higher than that for an overall MAO (DA deaminating) inhibition. However, it seems unlikely that this was due to near maximal inhibition of overall MAO activity, i.e. that it occurred only when MAO was inhibited by more than, say, 90%. The data reported suggest the existence of a small portion of an additional form of MAO with a rapid turnover and with a marked capacity to deaminate dopamine or methoxytyramine, and a greater resistance to inhibition by pargyline than cerebral MAO in general.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1977

Pargyline-induced increases in sensitivity to the effects of drugs on operant behavior in pigeons.

Pigeons responded under a multiple fixed-interval 5-min, 30-response fixed-ratio schedule of food reinforcement. Acute pargyline doses between 10.0 and 50.0 mg/kg (i.m.); given immediately prior to the session, decreased responding. Daily administration of 50 mg/kg pargyline (24 mg/kg, every 12 hr) initially decreased responding. Tolerance developed so that after 4 days of daily pargyline, responding had returned to control values. Chronic pargyline resulted in an enhanced sensitivity to the effects of d-amphetamine, ephedrine, tyramine, and morphine on schedule-controlled responding. Both d-amphetamine and pentobarbital increased fixed-interval responding at relatively low doses, while higher doses decreased responding. Daily pargyline resulted in an increased sensitivity to both the increases and decreases in response rates produced by d-amphetamine. In contrast, sensitivity to pentobarbital was not changed after daily pargyline, Ephedrine, tyramine, and morphine only decreased fixed-interval responding. Chronic pargyline resulted in an increased sensitivity to the response-rate decreasing effects of ephedrine, tyramine, and morphine. In addition to the increased sensitivity of fixed-interval responding to the effects of tyramine, the dose-effect curve for fixed-ratio responding was also a shifted to the left. Daily pargyline did not result in changes in sensitivity of fixed-ratio responding to the effects of the other drugs tested.

Animals↗

PubMed1976

Effect of pargyline on morphine tolerance and physical dependence development in mice.

The effects of single and repeated pargyline administration on morphine antinociception in both naive and morphine-tolerant mice and on naloxone-precipitated withdrawal in morphine tolerant-dependent animals were investigated. Adult, male Swiss-Webster mice were rendered tolerant to and dependent on morphine by the s.c. pellet implantion technique. Morphine analgesia, as assessed by the tail-flick antinociceptive test, was potentiated in tolerant animals by acute adminstration of pargyline but antagonized by repeated pargyline administration; pargyline produced similar effects in non-tolerant mice and to the same relative degree. Repeated pargyline treatment during morphine pellet implantation enhanced the withdrawal jumping response precipitated by naloxone in dependent mice. Pargyline also, after a single injection, exacerbated jumping in mice undergoing abrupt withdrawal. Neither acute nor chronic pargyline administration altered the brain distribution of injected morphine in non-tolerant mice. It was concluded that pargyline may modify acute morphine actions and withdrawal without materially altering the process(es) involved in the development of tolerance and physical dependence.

Animals↗

PubMed1976

Precipitation of abstinence-like syndrome in morphine-dependent mice by pargyline.

In mice rendered morphine-dependent by pellet implantation for 3 days, the administration of pargyline 6 hours after pellet removal intensified narcotic abstinence behavior, particularly the narcotic withdrawal jumping response. Pargyline, 75 mg/kg i.p., caused a 6- to 9-fold increase in the incidence of jumping in mice withdrawing from morphine 6 hours after removal of the pellet, whereas this effect was not observed: 1) 1 hour after the injection of pargyline or 2) in animals still implanted with the morphine pellet. The median effective dose (ED50) of pargyline required to elicit withdrawal jumping in mice implanted with morphine decreased with increasing physical dependence. The ED50 for 72 hours was about one-sixth that after 24 hours of implantation. Additionally, pargyline potentiated naloxone-precipitated withdrawal jumping as evidenced by a reduction of the naloxone ED50 by approximately one-half. Administration of other monoamine oxidase inhibitors such as pheniprazine, iproiazid or tranylcypromine failed to alter the indicence of jumping in dependent mice undergoind abrupt morphine with drawal. Further, dopamine receptor stimulation by amphetamine, pheniprazine or amantadine antagonized the pargyline-induced jumping response. These data suggest that the increased incidence of withdrawal jumping observed after pargyline in morphine-dependent mice is not related to monoamine oxidase inhibition but rather to a possible pargyline-induced decrease in dopaminergic activity.

Amantadine↗

PubMed1979

Further characterization of the inhibition of aldehyde dehydrogenase activity by pargyline.

The in vivo inhibition of low Km mitochondrial aldehyde dehydrogenase (AlDH) activity by pargyline was not maximal until more than 30 minutes after i.p. injection. Enzyme activity returned to control levels within 36 hours of drug injection but the return of activity was slowed by cycloheximide pretreatment. Female rats and higher basal total and low Km mitochondrial AlDH activities than did males. Injection of pargyline inhibited low Km mitochondrial AlDH activity more in males than in females. Incubation of rat liver microsomes with an NADPH-generating system and pargyline produced an in vitro inhibitor of low Km mitochondrial AlDH activity. Pretreatment of rats with phenobarbital increased the AlDH inhibitor produced by incubation of their microsomes with pargyline. Injection with benzylpropargylamine, N-demethylated pargyline, also preferentially inhibited the low Km form of mitochondrial AlDH activity. Neither pargyline nor benzylpropargylamine injections affected microsomal AlDH activity. Total AlDH activity, measured with 5mM propionaldehyde, in rat liver 100,000g supernatant was not changed by administration of either drug. Supernatant activity assayed with 50 microM propionaldehyde was inhibited by both pargyline and benzylpropargylamine treatment.

Aldehyde Oxidoreductases↗

PubMed1986

In vivo labelling and axonal transport of monoamine oxidase in the rat basal ganglia using radioactive pargyline.

The enzyme monoamine oxidase was labelled in the rat striatum or substantia nigra with locally injected radioactive pargyline. The binding was prevented by a pretreatment with non-radioactive pargyline, or with a combination of clorgyline and deprenyl. Most of the MAO labelled with 3H-pargyline was of the B-type, but also some MAO-A was labelled, as shown in rats pretreated with clorgyline or deprenyl separately. Seven days after the injection of (3H)-pargyline into the striatum a significant labelling was observed in the substantia nigra. This labelling was clorgyline sensitive, indicating type A MAO, and was not present when striatal neurons were destroyed with kainic acid. Labelling of the striatum following 3H-pargyline injection into the substantia nigra was also less in kainate intoxicated striata. Damage of nigral dopamine neurons with 6-hydroxydopamine did not influence the distribution of the label. Thus by using 3H-pargyline, specific labelling and axonal transport of type A MAO in striatal neurons projecting to the substantia nigra was demonstrated.

Animals↗

PubMed1991

Effects of daily afternoon melatonin administration on monoamine accumulation in median eminence and striatum of ovariectomized hamsters receiving pargyline.

The effects of daily afternoon melatonin injections on the accumulation of monoamines were studied in extracts of median eminence, and of caudate nucleus, of intact and ovariectomized Syrian hamsters which were administered pargyline 2 h prior to sacrifice. Although no significant effect of melatonin administration on the serotonin (5HT) accumulation after pargyline could be detected, significantly increased amounts of 5HT and of the 5HT metabolite, 5-hydroxyindole acetic acid, were detected in median eminence and in caudate nucleus of melatonin-injected hamsters not treated with pargyline. In both median eminence and in posterior pituitary, dopamine (DA) concentrations were significantly reduced by melatonin administration. In the median eminence of intact hamsters, the accumulation of DA after pargyline was reduced to 22% of controls by melatonin injections; in ovariectomized hamsters, the accumulation of DA was reduced to 9% of controls by melatonin injections. The accumulation of norepinephrine after pargyline was significantly reduced by melatonin administration only in ovariectomized hamsters. No significant inhibitory effects of melatonin injections could be detected on DA accumulation in caudate nucleus. These data suggest that melatonin injections result in substantial inhibition of daytime DA synthesis in median eminence independently of its effects on gonadal steroids. Paradoxically, melatonin-induced inhibition of median eminence DA activity occurred concomitantly with suppression of pituitary and plasma prolactin (PRL). We conclude that daily afternoon melatonin injections inhibit PRL secretion and interfere with cycles of LH in spite of decreased DA activity in the median eminence.

Animals↗

PubMed1978

Inhibition of aldehyde dehydrogenase by propiolaldehyde, a possible metabolite of pargyline.

Pargyline (Eutonyl) inhibited aldehyde dehydrogenase (AlDH) in vivo in rats as adduced by the elevation of ethanol-derived blood acetaldehyde (AcH), but had no effect in vitro on the enzyme in intact mitochondria. SKF-525A, an inhibitor of the hepatic microsomal P-450 enzyme system, completely prevented the pargyline-induced elevation of blood AcH in vivo, further implicating a metabolite of pargyline as the active inhibitor of AlDH. Of the potential pargyline metabolites tested, N-benzylpropargylamine and propargyl alcohol--like pargyline itself--readily inhibited AlDH in vivo but were without effect on the enzyme in vitro. These data implicated propiolaldehyde, a theoretically possible product of metabolism of all three of the above compounds, as the active metabolite responsible for AlDH inhibition. Indeed, propiolaldehyde at a concentration of 200 micron essentially completely inhibited the low Km AlDH of intact rat liver mitochondria.

Acetylcholine↗

PubMed1976

The effect of pargyline and other monoamine oxidase inhibitors on blood acetaldehyde levels in ethanol-intoxicated mice.

Pargyline (100 mg/kg i.p.) administered to Swiss-Webster mice prior to the injection of ethanol (4 g/kg i.p.) elevated blood acetaldehyde levels to a mean of 20 mug/ml, compared to less than 1 mug/ml in control mice treated with ethanol alone. Elevated blood acetaldehyde was observed when ethanol was given at 15 minutes, 2 or 5 hours after pargyline; the action of pargyline had largely disappeared after 18 hours. The magnitude of the increase in blood acetaldehyde levels was dependent upon the dose of pargyline between 20 and 100 mg/kg; however, the elevation was relatively independent of the ethanol dose between 1 and 6 g/kg. Of the other monoamine oxidase inhibitors tested, Lilly 51641 showed a strong elevation in acetaldehyde (mean 13.3 mug/ml), whereas deprenyl and clorgyline gave modest elevations (2.9 and 2.6 mug/ml, respectively), and nialamide and tranylcypromine were only weakly active (1.4 and 1.2 mug/ml, respectively). Blood acetaldehyde levels in mice treated with pargyline and ethanol were strongly depressed (85%) by pyrazole, an inhibitor of alcohol dehydrogenase, and moderately to strongly depressed (49-71%) by pretreatment with phenobarbital, an inducer of liver aldehyde dehydrogenase.

Acetaldehyde↗

PubMed1987

Pargyline reduces/prevents neuroleptic-induced acute dystonia in monkeys.

The neuropharmacologic mechanisms underlying neuroleptic-induced extrapyramidal syndromes (EPS) were studied using a nonhuman primate model. Twenty-six Cebus albifrons monkeys were given weekly challenges of haloperidol (0.025 mg/kg IM), and half of the animals received the monoamine oxidase (MAO) inhibitor pargyline (5 mg/kg PO) daily for 17 consecutive days during the protocol. Pargyline caused no changes in baseline behaviors, but significantly reduced haloperidol-induced acute dystonia (AD) (-67%, P less than 0.002) and parkinsonism (-56%, P less than 0.005). The majority (8 of 13) of the experimental group had complete prevention of neuroleptic-induced EPS during cotreatment with pargyline. Behavioral scores returned to baseline levels after stopping pargyline, and did not show the further sensitization to haloperidol-induced AD that occurred in the control group. The possible mechanisms by which an MAO inhibitor might influence neuroleptic-induced AD were considered. The most likely explanation would appear to involve facilitation of striatal dopamine (DA) neurotransmission by inhibition of intra- and extraneuronal MAO, thus supporting the hypothesis that AD is due to decreased striatal DA function with secondary cholinergic hyperfunction.

Animals↗

PubMed1979

Sex differences in behavioral and thermal responses to pargyline and tryptophan.

The effects of parenterally injected pargyline and tryptophan on rectal temperature and behavior have been studied in male and female rats. Pargyline alone (50 mg/kg) produced hypothermia in both sexes. Pargyline (50 mg/kg) followed by low doses (20--50 mg/kg) of tryptophan caused a behavioral syndrome consisting of tremor, hindlimb abduction, forepaw treading, and straub tail. In females, but not in males, hypothermia was potentiated. The same dose of pargyline followed by higher doses (60--150 mg/kg) of tryptophan produced a short hypothermia followed by a dose-dependent behavioral syndrome, hyperthermia, and mortality. On all of these measures, females responded following shorter latencies and lower doses of tryptophan. Both hypothermia and hyperthermia were observed in treated animals following pretreatment with a peripheral decarboxylase inhibitor. The results suggest a complex role for serotonin in thermoregulation. The sex differences observed suggest higher activity of serotonin in female rat brains following the drug treatment, which may be accounted for by a higher utilization rate of tryptophan.

Animals↗

PubMed1979

Comparative behavioral effects of clorgyline and pargyline in man: a preliminary evaluation.

The antidepressant and other behavioral effects of clorgyline, a preferential inhibitor of monoamine oxidase (MAO) type A, were compared with those of pargyline, a preferential inhibitor of MAO type B, in 16 depressed patients. In a subgroup of more severely depressed patients, clorgyline treatment for 4 weeks resulted in significant improvement on both observer-rated and self-rated scales, while minimal changes occurred during pargyline treatment. Similarly, in a crossover study that included 8 patients examined with multiple scales, clorgyline had generally greater antidepressant and antianxiety effects than did pargyline, although pargyline had some activating effects and also tended to produce more side effects. MAO type A inhibition may be more important than MAO type B inhibition for antidepressant efficacy.

Clinical Trials as Topic↗

PubMed1990

Pargyline increases 6-hydroxydopamine levels in the neostriatum of methamphetamine-treated rats.

Neostriatal 6-hydroxydopamine (6-OHDA) was detected in 6 of 13 rats pretreated 2 or 4 hr earlier with methamphetamine (MA; 100 mg/kg, SC) and pargyline (25 mg/kg, IP, 30 min before MA injection). Neostriatal 6-OHDA was detected in 2 of 16 rats treated 2 or 4 hr earlier with MA. These results suggest that pargyline pretreatment may enhance formation of 6-OHDA from endogenous stores of dopamine (DA) following MA administration. Alternatively, these results suggest that pargyline pretreatment may protect endogenously formed 6-OHDA from oxidative deamination by monoamine oxidase. Enhancement of MA-induced neostriatal 6-OHDA levels may be the mechanism by which pargyline enhances the long-term neurotoxic effects of MA upon dopaminergic nerve terminals. These observations support the hypothesis that MA toxicity to DA-containing fibers is caused by the conversion of released DA into 6-OHDA.

Animals↗

PubMed1979

The effect of pargyline and desmethylimipramine on monoamine concentrations and amphetamine-induced glycogenolysis in the mouse brain.

1. Pargyline (100 mg/kg) increased the concentration of cerebral noradrenaline dopamine and 5-hydroxytryptamine in the mouse. Amphetamine (5 mg/kg) reduced the concentration of noradrenaline and increased the concentrations of 5-hydroxytryptamine and dopamine. 2. When amphetamine was administered 4 h after an injection of pargyline, the effect of the sympathomimetic drug on the concentrations of noradrenaline and 5-hydroxytryptamine was not altered. The effect on the dopamine content was reversed, amphetamine causing a decrease instead of an increase. 3. Pargyline increased the concentration of cerebral glycogen, whereas amphetamine caused a decrease. 4. The administration of amphetamine 4 h after pargyline resulted in a decrease in brain glycogen similar to that seen after amphetamine alone. 5. These results suggest that the potentiation of the effect of amphetamine on animal behaviour by pretreatment with an inhibitor of monoamine oxidase is not mediated through a central action on noradrenaline release. 6. Amphetamine-induced glycogenolysis was antagonized by 71% by desmethylimipramine (10 mg/kg). 7. The change in glycogen concentration as a function of time after an injection of amphetamine was not modified when 2 consecutive doses of amphetamine were given with an interval between doses of 30 minutes.

Animals↗

PubMed1976

Dose-response effects of beta-phenylethylamine on stereotyped behavior in pargyline-pretreated rats.

We studied the dose-response and the time-course effect of beta-phenylethylamine (4.0-64.0 mg/kg, ip) on stereotyped behavior and motor activity in male Sprague-Dawley rats pretreated 2 hr eariler with pargyline (0.25-8.0 mg/kg, iv). Stereotyped behavior, defined as repetitive, nongoal-directed head movements and sniffing, and changes in motor activity were observed immediately after injection of beta-phenylethylamine for a 1 hr period. With increasing doses of pargyline pretreatment, beta-phenylethylamine produced, in a dose-response relationship, progressively more stereotyped behavior accompanied by increased motor activity. Without pargyline pretreatment, only 64.0 mg/kg beta-phenylethylamine induced behavioral changes. Stereotyped behavior and increased motor activity had an onset at 4-6 min after the injection of beta-phenylethylamine, peak at 10-30 min, and gradual decline in the next 10-20 min. These results are discussed in terms of a possible relationship with the degree of inhibition of Type a and Type B monoamine oxidase acused by the different doses of pargyline.

Animals↗

PubMed1979

Selectivity of clorgyline and pargyline as inhibitors of monoamine oxidases A and B in vivo in man.

During 4 weeks of treatment with clorgyline, a selective MAO-A inhibitor, platelet monoamine oxidase (MAO) activity was unchanged. During a similar 4-week crossover treatment period with pargyline, a selective MAO-B inhibitor, platelet MAO activity was essentially completely inhibited in the same individuals. The differential effects of the two drugs on platelet MAO, which consists exclusively of the MAO-B form, suggests that the in vitro selectivity of clorgyline, and possibly of pargyline, on MAO-A and MAO-B may be maintained in vivo during long-term administration in man. Reductions in blood pressure, heart rate, and plasma amine oxidase activity were generally similar in magnitude during treatment with both drugs, however, suggesting that either these effects are nonspecific consequences of both MAO-A and MAO-B inhibition, or that pargyline also inhibited MAO-A activity.

Blood Platelets↗

PubMed1988

Effect of antibiotics on the binding of pargyline to monoamine oxidase in cultured hepatocytes.

The laser dye rhodamine 123 has been used to establish that the binding of [3H]pargyline to monoamine oxidase is a more sensitive indicator of mitochondrial perturbation than measurements of protein synthesis, secretion, or degradation. The amount of monoamine oxidase labelled depends on the antibiotic used. The labelling was considerably lower in the presence of gentamycin than in the presence of either chloramphenicol or of penicillin and streptomycin. The accumulation of gentamycin within the cells was the cause of the reduced labelling of monoamine oxidase which was not accompanied by an alteration in the metabolism of pargyline. The gentamycin effect can be prevented by incubating the cells in medium supplemented with methylamine prior to adding the monoamine oxidase inhibitor. Long term culture of cells with gentamycin can result in the cell culture medium becoming dark brown. Under these conditions the monoamine oxidase labelling is increased due to an inhibition of pargyline metabolism. The results indicate that the choice of antibiotic is important in patients being treated with both antibiotics and monoamine oxidase inhibitors.

Anti-Bacterial Agents↗