Inhibition of monoamine oxidase type A, but not type B, is an effective means of inducing anticonvulsant activity in the kindling model of epilepsy.
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The anticonvulsant activity of inhibitors of monoamine oxidase (MAO) was reported early after the development of irreversible MAO inhibitors such as tranylcypromine, but was never clinically used because of the adverse effects of these compounds. The more recently developed reversible MAO inhibitors with selectivity for either the MAO-A or MAO-B isoenzyme forms have not been studied extensively in animal models of epilepsy, so it is not known which type of MAO inhibitor is particularly effective in this respect. We compared the following drugs in the kindling model of epilepsy: 1) L-deprenyl (selegiline), i.e., an irreversible inhibitor of MAO-B, which, however, also inhibits MAO-A at higher doses, 2) the novel reversible MAO-B inhibitor LU 53439 (3,4-dimethyl-7-(2-isopropyl-1,3, 4-thiadiazol-5-yl)-methoxy-coumarin), which is much more selective for MAO-B than L-deprenyl, 3) the novel reversible and highly selective MAO-A inhibitor LU 43839 (esuprone; 7-hydroxy-3, 4-dimethylcoumarin ethanesulfonate), and 4) the irreversible nonselective MAO inhibitor tranylcypromine. Esuprone proved to be an effective anticonvulsant in the kindling model with a similar potency as L-deprenyl. In contrast to esuprone and L-deprenyl, the selective MAO-B inhibitor LU 53439 was not effective in the kindling model; this substantiates the previous notion that the anticonvulsant activity of L-deprenyl is not related to MAO-B inhibition, but to other effects of this drug, such as inhibition of MAO-A. Drugs inhibiting both MAO-A and MAO-B to a similar extent (tranylcypromine) or combinations of selective MAO-A and MAO-B inhibitors (esuprone plus LU 53439) had no advantage over MAO-A inhibition alone, but were less well tolerated. The data thus suggest that selective MAO-A inhibitors such as esuprone may be an interesting new approach for the treatment of epilepsy. (+info)
Effect of low-dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine-induced dopamine release in vivo.
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1. Chronic treatment with low doses of the selective monoamine oxidase (MAO) type B inhibitors selegiline [(-)-deprenyl] and rasagiline, causes elevation in extracellular level of 3,4-dihydroxyphenylethylamine (dopamine) in the rat striatum in vivo (Lamensdorf et al., 1996). The present study was carried out to determine whether this effect of selegiline could be the result of an inhibition of the high-affinity dopamine neuronal transport process. 2. Changes in activity of the dopamine transporter (DAT) in vivo following selegiline treatment were evaluated indirectly by microdialysis technique in the rat, from the change in striatal dopamine extracellular concentration following systemic amphetamine administration (4 mg kg(-1), i.p.). Striatal levels of the DAT molecule were determined by immunoblotting. Uptake of [3H]-dopamine was determined in synaptosomes from selegiline-treated animals. 3. Amphetamine-induced increase in striatal extracellular dopamine level was attenuated by one day and by chronic (21 days) treatment with selegiline (0.25 mg kg(-1), s.c.). 4. Striatal levels of DAT were elevated after 1 and 21 days treatment with selegiline, but were not affected by clorgyline, rasagiline, nomifensine or amphetamine. 5. The increase in DAT expression, and attenuation of amphetamine-induced dopamine release, were not accompanied by a change in [3H]-dopamine uptake in synaptosomes of selegiline-treated animals. 6. The results suggest that a reversible inhibition of dopamine uptake occurs following chronic low dose selegiline treatment in vivo which may be mediated by an increase in endogenous MAO-B substrates such as 2-phenylethylamine, rather than by the inhibitor molecule or its metabolites. Increased DAT expression appears to be a special property of the selegiline molecule, since it occurs after one low dose of selegiline, and is not seen with other inhibitors of MAO-A or MAO-B. The new DAT molecules formed following selegiline treatment appear not to be functionally active. (+info)
Dose linearity study of selegiline pharmacokinetics after oral administration: evidence for strong drug interaction with female sex steroids.
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AIMS: The purpose of this study was to characterize the dose relationship of selegline and desmethylselegiline pharmacokinetics within the selegiline dose range from 5 to 40 mg. METHODS: Eight female subjects, of whom four were using oral contraceptives, ingested a single dose of 5 mg, 10 mg, 20 mg or 40 mg of selegiline HCl in an open four-period randomized study. Concentrations of selegiline and desmethlylselegiline in serum were measured by gas chromatography for 5 h. As it became evident that the use of oral steroids had a drastic effect on selegiline concentrations, the pharmacokinetic analyses were performed separately for oral contraceptive users and those not receiving any concomitant medication. RESULTS: The total AUC and Cmax of selegiline were 10-to 20-fold higher in those subjects taking oral steroids compared with subjects with no concomitant medication; this finding was consistent and statistically significant at all the four dose levels. The dose linearity of selegiline pharmacokinetics failed to be demonstrated in both groups. The AUC and Cmax of desmethylselegiline were only moderately higher (about 1.5-fold; P=NS at each dose level) in the subjects taking oral steroids than in those not receiving concomitant medication. The AUC values of desmethylselegiline increased in a dose linear manner in subjects with no concomitant medication, but not in the oral steroid group. The metabolic ratio (AUC(desmethylselegiline)/AUC(selegiline)) was several-fold lower in the group receiving oral steroids compared with the no-concomitant-medication group (P<0.005 at all the four dose levels). CONCLUSIONS: Concomitant use of oral contraceptives caused a drastic (20-fold) increase in the oral bioavailability of selegiline. The highly significant difference in the metabolic ratio between the groups provides evidence that the mechanism of the interaction between selegiline and female sex steroids involves reduced T-demethylation of selegiline. The present results suggest that concomitant use of selegiline with exogenous female sex steroids should be avoided or the dosage of selegiline should be reduced in order to minimize the risks of selegiline related adverse drug reactions. (+info)
Selegiline effects on cocaine-induced changes in medial temporal lobe metabolism and subjective ratings of euphoria.
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To test the effect of selegiline, a specific monoamine oxidase B (MAO-B) inhibitor, on the cerebral metabolic and euphorigenic effects of cocaine in experienced users, eight cocaine-dependent (CD) subjects were evaluated using a within-subjects design. Each subject participated in two pairs of [F-18]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans (baseline scan followed 24 h later by a second scan obtained in conjunction with a 40-mg cocaine infusion) performed before and after a 1-week period of daily treatment with 10 mg selegiline administered orally. The hippocampus and amygdala were evaluated because of their hypothesized involvement in the addiction process, and the thalamus was evaluated as a comparison region. Following 7 days of selegiline treatment, the magnitude of the subjective euphoria ("high") produced by cocaine infusion was reduced by 40% (cocaine by selegiline interaction F = 7.15, df = 1.21, p = .014). Selegiline treatment also altered glucose utilization (normalized against whole brain counts) in the two limbic regions, but not the thalamus. In the amygdala, the effects of cocaine differed, depending upon whether or not patients were being treated with selegiline (cocaine by selegiline interaction F = 4.67, df = 1,19.8, p = .043). A different effect was observed in the hippocampus, where selegiline treatment decreased metabolic activity irrespective of whether cocaine was given (main effect F = 7.70, df = 1.20, p = .012). The concomitant changes in both the subjective experience of the "high" and normalized amygdala glucose utilization after selegiline treatment, suggest that a relationship exists between cocaine-induced euphoria and limbic metabolism. The data suggest that selegiline may be a useful adjunct in the treatment of cocaine dependence. (+info)
Selegiline in the treatment of Alzheimer's disease: a long-term randomized placebo-controlled trial. Czech and Slovak Senile Dementia of Alzheimer Type Study Group.
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OBJECTIVE: To evaluate the efficacy and adverse effects of the type B monoamine oxidase inhibitor selegiline (also known as I-deprenyl) in the treatment of Alzheimer's disease. DESIGN: Long-term, double-blind, placebo-controlled trial. SETTING: Seven cities (1 or 2 nursing homes in each city) in the Czech and Slovak Republics. PATIENTS: A total of 173 nursing-home residents fulfilling the DSM-III criteria for mild to moderate Alzheimer's disease. INTERVENTIONS: Selegiline (10 mg per day) or placebo (both including 50 mg ascorbic acid) administered for 24 weeks. OUTCOME MEASURES: Clinical Global Impressions scale and Nurses Observation Scale for Inpatient Evaluation at baseline and at weeks 6, 12 and 24; Clock Drawing Test at baseline and 24 weeks, results of which were evaluated as normal or pathologic, and quantitatively on a modified 6-point scale; Sternberg's Memory Scanning test at baseline and at weeks 6, 12 and 24; Mini Mental State Examination, and electroencephalogram at baseline and 24 weeks; Structured Adverse Effects Rating Scale; physical, laboratory, hematological and electrocardiographic examinations at baseline and weeks 12 and 24. RESULTS: A total of 143 subjects completed enough of the trial to be entered in the analysis. Subjects were analyzed by 2 subgroups depending on whether they had a normal or pathologic result of the Clock Drawing Test. Analysis of variance showed significant improvement with selegiline versus placebo among those with a normal result of the Clock Drawing Test on the Mini Mental Status Examination (total score and orientation-place subscale) and among those with a pathologic result of the Clock Drawing Test of Sternberg's Memory Scanning test (for both speed and accuracy), on the Clinical Global Impressions scale as well as in terms of the dominant frequency on electroencephalograms. CONCLUSION: Selegiline has a long-term beneficial effect in Alzheimer's disease on memory modalities that reflect the function of the prefrontal areas of the brain, which are rich in dopamine receptors. The delayed appearance of differences between selegiline and placebo supports the notion that the mechanism of action is through neuronal rescue or neuroprotection. The differential response of patients with normal and pathologic results of the Clock Drawing Test may reflect the fact that the evaluation methods' sensitivity to change depends on the severity of dementia. (+info)
Neuroprotective rather than neurorescue or neurorestorative effect of selegiline against MPTP-induced dopaminergic toxicity.
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AIM: To study the neuroprotective, neurorescue, neurorestorative effects of selegiline (Sel) on nigrostriatal dopaminergic neuronal system and its inhibition of brain monoamine oxidase B (MAO-B). METHODS: The striatal levels of dopamine and its metabolites were measured using HPLC with electrochemical detection (HPLC-EC). The inhibition of MAO-B was tested by an improved fluorimetric assay. RESULTS: 1-Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) (30 mg.kg-1 i.p.) reduced the striatal dopamine level by 73% in mice. Selegiline (Sel, 10 mg.kg-1 i.p.) before, but not after, MPTP treatment protected against MPTP-induced nigrostriatal dopaminergic neurotoxicity. There were no differential effects between Sel and saline treatments on the recovery of striatal dopamine levels, which were partially restored during 2 wk. 1-Methyl-4-phenylpyridinium (MPP+) (5 mg.kg-1 i.p.) produced no dopaminergic neurotoxicity. Furthermore, Sel selectively and irreversibly inhibited mouse brain MAO-B in vitro (IC50 = 17 nmol.L-1, 95% confidence limits = 14-20 nmol.L-1). CONCLUSION: Selegiline has neuroprotective rather than neurorescue or neurorestorative effects on MPTP-induced nigrostriatal dopaminergic neuronal degeneration, which is directly pertinent to its selective and irreversible inhibition of brain MAO-B activity. (+info)
Species-dependent differences in monoamine oxidase A and B-catalyzed oxidation of various C4 substituted 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridinyl derivatives.
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In an attempt to provide a better understanding of the scope and limitations of animal models used in some drug development programs and to further our understanding of potential metabolic bioactivation reactions, we have undertaken studies to profile the monoamine oxidase A and B (MAO-A and -B, respectively) activities in liver and brain mitochondrial preparations obtained from a variety of species using a series of 1-methyl-4-aryl-1,2,3, 6-tetrahydropyridinyl substrates. Mitochondrial preparations were incubated with substrates at 37 degrees C in the presence or absence of clorgyline, (R)-deprenyl, or a mixture of these two propargylamines to inhibit MAO-A, MAO-B, or both enzymes. The rates of formation of the corresponding dihydropyridinium metabolites were estimated spectrophotometrically. MAO-B was found to be the principal enzyme present in all tissues. Human liver displayed more MAO-A activity than the liver of any other species studied; subhuman primates displayed little or no detectable MAO-A activity. The properties of the preparations from rat liver were most similar to those from human liver with respect to the MAO-A/MAO-B ratios and the kinetic parameters of the four substrates used to profile enzymatic activity. The kinetic properties of mitochondrial preparations from bovine liver, a commonly used source of purified MAO-B preparations, were consistently different from all of the other species studied. The mitochondrial preparations from rabbit brain and liver also were unusual in that they displayed relatively low MAO activities. Additionally, these enzyme activities were considerably less susceptible to inhibition by clorgyline and (R)-deprenyl. Finally, an exceptionally low MAO-B liver/brain V(max)/K(m) ratio was observed with the mitochondria obtained from the C57BL/6 mouse, an effect that may contribute to the susceptibility of this strain to the toxic effects of the parkinsonian-inducing neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine. (+info)
Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl.
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1. There are differences between the excitotoxic actions of quinolinic acid and N-methyl-D-aspartate (NMDA) which suggest that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors. The present study was designed to examine the effect of a potent antioxidant, melatonin, and the potential neuroprotectant, deprenyl, as inhibitors of quinolinic acid-induced brain damage. Injections were made into the hippocampus of anaesthetized rats, which were allowed to recover before the brains were taken for histology and the counting of surviving neurones. 2. Quinolinic acid (120 nmols) induced damage to the pyramidal cell layer, which was prevented by the co-administration of melatonin (5 nmols locally plus 2x20 mg kg(-1) i.p.). This protective effect was not prevented by the melatonin receptor blocker luzindole. Neuronal damage produced by NMDA (120 nmols) was not prevented by melatonin. 3. Quinolinic acid increased the formation of lipid peroxidation products from hippocampal tissue and this effect was prevented by melatonin. 4. Deprenyl also prevented quinolinic acid-induced damage at a dose of 50 nmols but not 10 nmols plus 2x1.0 mg kg(-1) i.p. The non-selective monoamine oxidase inhibitor nialamide (10 and 50 nmols plus 2x25 mg kg(-1)) did not afford protection. 5. The results suggest that quinolinic acid-induced neuronal damage can be prevented by a receptor-independent action of melatonin and deprenyl, agents which can act as a potent free radical scavenger and can increase the activity of endogenous antioxidant enzymes respectively. This suggests that free radical formation contributes significantly to quinolinic acid-induced damage in vivo. (+info)