The possible mechanisms of action of (-)deprenyl in Parkinson's disease

Summary (-)Deprenyl, a selective inhibitor of MAO-B, was found to be 60 times less potent in inhibiting intestinal MAO in the rat than clorgyline, the selective inhibitor of MAO-A. This is one of the reasons why (-)deprenyl is safe with respect to the hazards involved in combination with a variety of foods and drugs and its administration is not contraindicated in parkinsonian patients.(-)Deprenyl is a potent inhibitor of the uptake of amines into the nerve endings of catecholaminergic neurons. By the aid of N-methyl-N-propargyl-/l-indenyl/-ammonium. HCl (J-508), a newly developed highly potent MAO inhibitor, devoid of uptake-inhibitory and releasing effects, a tyramine-uptake model for testing the effects of MAO inhibitors on uptake, using different isolated noradrenergic organs (cat nictitating membrane, perfused ear artery and strip of pulmonal artery of the rabbit, rat vas deferens), was introduced. In contrast to the nonselective and A-selective MAO inhibitors, as well as to the newly developed selective MAO-B inhibitors (J-508, U-1424), (-)deprenyl was unique in inhibiting tyramine-uptake in all the tests.(-)Deprenyl was found to inhibit the release of acetylcholine in isolated striatal slices of the rat, owing to its blocking effect on the uptake of dopamine. N-methyl-N-propargyl-/2-furyl-1-methyl/-ethylammonium (U-1424), a new selective inhibitor of MAO-B devoid of uptake-inhibitory effect did not significantly influence the ouabain induced striatal acetylcholine release.The release of dopamine from the synaptosomes of the rat striatum was found to be enhanced by clorgyline and tyramine and only slightly influenced by (-)deprenyl.The advantage of the combination of levodopa and (-)deprenyl in the treatment of Parkinson's disease was summarized as follows. Levodopa exerts its therapeutic effect by stimulating the postsynaptic dopaminergic receptors of the caudate interneurons, thereby it suppresses, by stimulating also the presynaptic autoreceptors, the activity of nigrostriatal dopaminergic neurons. (-)Deprenyl acts as an activator of the nigrostriatal dopaminergic neurons. As these neurons contain MAO-B in man, (-)deprenyl increases the dopamine content of the nerve terminals and as a potent inhibitor of the re-uptake of dopamine it intensifies the physiological control on the cholinergic caudate neurons.     

Clinical evaluation of deprenyl (selegiline) in the treatment of Parkinson's disease

ABSTRACT — The experiences of a seven-year study on deprenyl in the treatment of Parkinson's disease are summarized. It was found that the main advantage of deprenyl was that it permitted the reduction of die dose of levodopa in optimally treated patients. In the initial stage of Parkinson's disease deprenyl is only partially sufficient as monotherapy. Deprenyl can administered successfully for correcting the "wearing off" effect.     

Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson's disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial

Deprenyl (selegiline) delays the need for levodopa therapy in patients with early Parkinson's disease, but the long-term benefits of this treatment remain unclear. During 1987 to 1988, 800 patients with early Parkinson's disease were randomized in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism trial to receive deprenyl, tocopherol, combined treatments, or a placebo and were then placed on active deprenyl (10mg/day). A second, independent randomization was carried out in early 1993 for 368 subjects who by that time had required levodopa and who had consented to continuing the deprenyl treatment (D subjects) or changing to a matching placebo (P subjects) under double-blind conditions. The first development of wearing off, dyskinesias, or on-off motor fluctuations was the prespecified primary outcome measure. During the average 2-year follow-up, there were no differences between the treatment groups with respect to the primary outcome measure (hazard ratio, 0.87; 95% confidence interval, 0.63, 1.19; p = 0.38), withdrawal from the study, death, or adverse events. Although 34% of D subjects developed dyskinesias and only 19% of P subjects did (p = 0.006), only 16% of D subjects developed freezing of gait but 29% of P subjects did (p = 0.0003). Decline in motor performance was less in D subjects than P subjects. Levodopa-treated Parkinson's disease patients who had been treated with deprenyl for up to 7 years, compared with patients who were changed to a placebo after about 5 years, experienced slower motor decline and were more likely to develop dyskinesias but less likely to develop freezing of gait.     

Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson's disease. A randomized multicenter study

Objectives: levodopa improves the quality of life in parkinsonian patients, however long term response is compromised by the emergence of motor fluctuations and dyskinesias. The aim of this study was to compare the occurrence of motor fluctuations and dyskinesias in previously untreated patients assigned to receive levodopa, a dopamine agonist or deprenyl.Thirty-five neurological departments in Italian hospitals participated in this randomized open trial. Patients with Parkinson's disease, who required the initiation of an effective antiparkinsonian treatment, were randomly assigned to receive levodopa, dopamine agonists or deprenyl. The end-points were motor dyskinesias and motor fluctuations occurring in a median follow-up period of about 3years.After a median follow-up of 34months, motor fluctuations and dyskinesias were less frequent in patients assigned to a dopamine agonist or deprenyl than in patients assigned to levodopa (relative risk [RR] 0.5, 95% confidence interval [95% CI] 0.3-0.8, and RR=0.6, 95% CI 0.3-0.9, respectively), but dopamine agonists were less effective and less well tolerated than levodopa. The lower frequency of motor fluctuations in patients assigned to deprenyl was no longer statistically significant when prognostic predictors were considered in a multivariable analysis. Long-term mortality did not differ in the three arms of the study. Dopamine agonists and deprenyl can be considered as an alternative to levodopa for starting treatment in Parkinson's disease patients. However, on clinical grounds, only small advantages are expected over the traditional therapy initiation with levodopa.     

Deprenyl (selegiline) in the treatment of Parkinson''s disease

ABSTRACT — The effects of deprenyl were investigated in 45 parkinsonian patients suffering from fluctuations in disability under long-term levodopa treatment. During a 1 to 3 month period of treatment, 5–10 mg of deprenyl caused a significant reduction in response fluctuations in 26 out of 45 patients (58 %). This improvement was only moderate (58 %) or minimal (42 %). Of 11 parkinsonian patients taking deprenyl with levodopa and benserazide for up to 4 years, 6 patients (55 %) showed moderate and 5 patients (45 %) minimal improvement initially. The improvement in response fluctuations was maintained during the follow-up period, although there was a clear decline in the degree of improvement. The addition of deprenyl to levodopa treatment also caused a further improvement in parkinsonian disability, which, however, decreased during the treatment period. Deprenyl appears to be a useful adjuvant to levodopa in patients with daily fluctuations in disability.     

Amphetamine and 2-phenylethylamine in post-mortem Parkinsonian brain after (-)deprenyl administration

Summary Deprenyl is an inhibitor of monoamine oxidase type B, the enzyme responsible for 2-phenylethylamine oxidation, and is used in conjunction with L-Dopa therapy in Parkinson's disease. Post-mortem studies in human brain tissue have shown that after (-)deprenyl administration to parkinsonian patients amphetamine is present in concentrations up to 56 ng/g. It also could be shown that phenylethylamine concentrations are substantially increased in such patients.Phenylethylamine and amphetamine have been investigated using a gas chromatographie technique.     

Deprenyl and tocopherol antioxidative therapy of parkinsonism (DATATOP)

Abstract– DATATOP is a double-blind, multi-center, placebo-controlled clinical trial aimed at slowing the decline of patients who are in the early stages of Parkinson's disease (PD). The specific aim is to determine whether or not chronic administration of deprenyl 10 mg per day and/or tocopherol 2000 IU per day to early, otherwise untreated PD patients will prolong the time until levodopa therapy is required to treat emerging disability. Deprenyl and tocopherol exert antioxidative effects through separate but complementary mechanisms of action. A 2 X 2 factorial design allocates eligible subjects to one of four treatment groups: 1) deprenyl alone, 2) tocopherol alone, 3) deprenyl plus tocopherol, or 4) placebo. Eligible subjects include early PD patients (illness duration less than 5 years and in stages I and II), aged 30 to 79, who are not taking or requiring any anti-PD medications. The major response variable is the time period from randomization until the blinded investigator judges levodopa necessary to treat emerging parkinsonian disability. Randomization is stratified to ensure that treatment assignments are balanced for each blinded investigator. Cerebrospinal fluid is sampled just prior to randomization and one month after washout of experimental medications in order to help distinguish between symptomatic and protective effects of interventions. Based on pilot studies it is estimated that approximately 85 % of untreated PD patients will require levodopa within two years and a total sample size of 800 subjects will provide a 95 % likelihood for detecting a 10 % "survival'difference between experimental medications and placebo. Between September 1987 and November 1988, 800 eligible subjects were enrolled in DATATOP by 34 investigators of the Parkinson Study Group, representing research centers in the United States and Canada. Primary analyses of DATATOP should be completed in 1991.     

Modification of levodopa responses by deprenyl (selegiline): An electrophysiological and behavioral study in the rat relevant to Parkinson's disease

From using in vitro intracellular recordings from mesencephalic neurons and monoamine-depleted rats, we report that the functions of levodopa in the brain are greatly enhanced and prolonged by high does of the monoamine oxidase (MAO) inhibitor deprenyl. Dopaminergic neurons were hyperpolarized and inhibited by levodopa application. These effects of levodopa were largely potentiated by pretreatment with nonselective does of deprenyl. Furthermore, when locomotor activity induced by levodopa was examined on a rodent model of parkinson's disease, pretreatment of the animals with nonselective doses of deprenyl caused an enhancement of the antiparkinsonian action of levodopa. The great increase in levodopa responses by deprenyl suggests a likely therapeutic use of this dopamine precursor with a higher dosage of the MAO inhibitor, to reduce effectively the daily levodopa requirements in Parkinson's disease patients.     

Treatment strategies for extension of levodopa effect.

The initial benefits of levodopa decline for as many as half of all patients with Parkinson's disease treated for 2 years or more. Although levodopa is the most effective means for symptom relief, many parkinsonian patients lose the consistency of optimal symptom control. The variability experienced by such patients may arise from several alternative mechanisms at the level of the central nervous system (e.g., a narrowed therapeutic window for receptor-mediated effects or the loss of storage capability for dopamine in the parkinsonian brain). Whatever the cause, several practical methods have been developed. Dopaminergic agonists have played a major role in improving such problem. There are also several strategies for enhancing levodopa's dose by dose effectiveness, including sustained-release levodopa preparations and enteral infusions of levodopa. Another approach is the use of selegiline (deprenyl), MAO-B inhibitor slowing the breakdown of dopamine and thereby extending the duration of levodopa effect. Although selegiline can lessen the abruptness of levodopa wearing off, it can also exacerbate undesired peak effects of the drug. Clinical trials are planned with levodopa pro-drugs and inhibitors of catechol-O-methyltransferase to learn if these approaches can improve problems of long-term levodopa therapy.     

Deprenyl reduces the death of motoneurons caused by axotomy.

Deprenyl, a monoamine oxidase B inhibitor, appears to slow the progression of neurological deficits in Parkinson's disease and cognitive decline in Alzheimer's disease. The mechanisms for the slowing of the diseases are unknown. Deprenyl can reduce the death of murine substantia nigra neurons when administered after the neurons are damaged in MPTP parkinsonism by increasing the neurons' survival after they are damaged, rather than by just protecting the neurons against damage by blocking the conversion of MPTP to its active form as was previously thought. The death of immature motoneurons after separation from their muscle targets by axotomy provides a model for assessing trophically dependent neuronal survival. To determine whether deprenyl can alter the survival of neurons other than those in the substantia nigra, we examined the survival of rat facial motoneurons after axotomy at 14 days of age. Using a combination of immunocytochemistry for choline acetyl transferase and Nissl staining, we found that deprenyl treatment (10 mg/kg every second day) increased by 2.2 times the number of motoneurons surviving 21 days after the axotomy. This finding showed that deprenyl treatment can rescue neurons other than those in the substantia nigra and can compensate in part for the loss of target-derived trophic support caused by axotomy.     

L-deprenyl, levodopa pharmacokinetics, and response fluctuations in Parkinson's disease

Six patients with Parkinson's disease (PD) and therapeutic response fluctuations (RF) on levodopa treatment participated in an open-label trial of L-deprenyl (Eldepryl) in conjunction with Sinemet. Deprenyl (10 mg/day) allowed a slight but not statistically significant 22% reduction of total daily levodopa intake after 4 weeks of treatment, with a significant but unsustained reduction in the number of daily "off" periods and an increase in the portion of waking day spent "on." Pharmacokinetic studies revealed no effect of deprenyl on the plasma levodopa concentration vs. time curve, or the coefficient of variation (C.V.) of plasma levodopa levels measured over an 8-h period. Plasma DOPAC levels were unaffected, suggesting that the majority of peripheral DOPAC is generated by action of MAO-A. For most patients, benefit was not maintained. Two patients have continued taking the drug, and both have enjoyed significant reductions in total levodopa dose. Both have mild end-of-dose failure and little dyskinesia. Since no changes in peripheral pharmacokinetics of levodopa could be demonstrated, any therapeutic action of deprenyl in PD would appear to be due to prolongation of dopaminergic activity within the CNS.     

Deprenyl in the management of response fluctuations in patients with Parkinson's disease on levodopa.

Fluctuations in response to levodopa are a common and serious complication of long-term levodopa therapy. It may be possible to prolong the effect of each dose of levodopa by retarding the breakdown of dopamine. The selective monoamine oxidase type B inhibitor deprenyl, which is extensively metabolised to amphetamine and methamphetamine, has this effect as well as possible actions on dopamine release and re-uptake. In a double-blind crossover trial against placebo, deprenyl prolonged the action of levodopa and produced an objective improvement in mobility in five of 10 patients with dose-related response swings, and a subjective improvement in a further four patients. In another group of seven patients with random fluctuations in symptoms, only two noted subjective improvement, and there was an apparent increase in the severity of response swings in five patients. Deprenyl exacerbated dyskinesias, but had no serious side-effects. We conclude that deprenyl is unlikely to benefit patients with random response swings, and may cause deterioration in such cases. However, it may be a useful adjuvant in the management of dose-related response fluctuations in patients already on optional levodopa therapy.     

Deprenyl (selegiline) combined with levodopa and a decarboxylase inhibitor in the treatment of Parkinson's disease

ABSTRACT — The purpose of this double-blind placebo controlled study was to estimate how much the levodopa dosage can be reduced, when deprenyl is used, without worsening the disease and to see whether deprenyl can reduce the "off-periods". The trial included 40 patients of both sexes with at least 3 years history of Parkinson's disease who were undergoing stabilized levodopa therapy. The deprenyl dosage was 5 mg daily in the first 4 weeks. The levodopa dosage was reduced until there was demonstrable impairment.
The trial demonstrates that with deprenyl the levodopa dosage can be reduced considerably without prejudicing the therapeutic outcome. Some patients showed improvement, and the "off-periods" were reduced in many cases.     

Involvement of endogenous N-methyl(R)salsolinol in Parkinson's disease: induction of apoptosis and protection by (-)deprenyl

An endogenous dopamine-derived N-methyl(R)salsolinol has been suggested to be involved in the pathogenesis of Parkinson's disease. In Parkinson's disease, the level of N-methyl(R)salsolinol increased in cerebrospinal fluid and the high activity of a synthesizing enzyme, (R)salsolinol N-methyltransferase, was detected in lymphocytes. This isoquinoline induced apoptotic DNA damage in human dopaminergic neuroblastoma SH-SY5Y cells. Among catechol isoquinolines, only N-methylsalsolinol induced apoptosis in the cells, and the scavengers of hydroxyl radicals and antioxidants suppressed DNA damage, suggesting that reactive oxygen species initiate apoptosis. The isoquinoline activated caspase-3 like proteases and a caspase-3 inhibitor protected the cells from DNA damage. (-)Deprenyl, but neither clorgyline nor pargyline, prevented apoptotic cell death. The mechanism of the protection was due to stabilization of mitochondrial membrane potential reduced by the toxin. In Parkinson's disease apoptosis may be induced in dopamine neurons by this endogenous neurotoxin, and (-)deprenyl may protect them from apoptotic death process.     

Anti-apoptotic function of L-(-)deprenyl (Selegiline) and related compounds

(-)Deprenyl has been proposed to be neuroprotective to dopamine neurons in the parkinsonian brains. To clarify the mechanism, the effects of (-)deprenyl and structurally related compounds on apoptosis induced by a neurotoxin, N-methyl(R)-salsolinol, and reactive oxygen species, nitric oxide and peroxynitrite, were examined in dopaminergic SH-SY5Y cells. DNA damage was quantified by the single cell gel electrophoresis (comet) assay. (-)-Deprenyl protected the cells from apoptosis in a dose-dependent way, which required pre-treatment at least for 20 min. The effect was confirmed even after washing out of (-)deprenyl, indicating that (-)-deprenyl initiates the intracellular process to antagonize the apoptotic death program. The studies on the structure-activity relationship reveal that N-propargyl residue with hydrophobic structure is essential for the anti-apoptotic function. These results suggest that (-)deprenyl and related compounds may be applicable as neuroprotective agents in neurodegenerative diseases.     

Deprenyl (selegiline) in combination treatment of Parkinson's disease

ABSTRACT — Long-term treatment of parkinsonian patients with levodopa (plus decarboxylase inhibitor) leads to decreasing levodopa efficacy and increasing side-effects. Then main therapeutic problems are on-off phenomena, end-of-dose akinesia and levodopa-induced dyskinesias. Deprenyl, a selective MAO-B inhibitor, has produced good therapeutic effects in combination either with levodopa alone or with levodopa plus decarboxylase inhibitor in the treatment of end-of-dose akinesia and on-off phenomena.
In an open trial with 48 parkinsonian patients deprenyl was added to previous levodopa plus decarboxylase-inhibitor therapy. Good effects were achieved in respect of mild on-off phenomena and end-of-dose akinesia, minor success in the alleviation of dyskinesia and depression. In four further patients with a post-traumatic parkinsonian syndrome, no improvement of rigidospasticity and vigilance was demonstrable.     

Progress in monoamine oxidase (MAO) research in relation to genetic engineering

Monoamine oxidase (MAO) is an enzyme that oxidizes various physiologically and pathologically important monoamine neurotransmitters and hormones such as dopamine, noradrenaline, adrenaline, and serotonin. Two types of MAO, i.e. type A (MAO-A) and type B (MAO-B), were first discovered pharmacologically. MAO-A is inhibited by clorgyline; and MAO-B, by deprenyl. cDNAs MAO-A and MAO-B were cloned and their structures determined. MAO-A and MAO-B are made of similar but different polypeptides and encoded by different nuclear genes located on the X chromosome (Xp11.23). MAO-A and MAO-B genes consist of 15 exons with identical intron-exon organization, suggesting that they were derived from a common ancestral gene. Both enzymes require a flavin cofactor, flavin adenine dinucleotide (FAD), which binds to the cysteine residue of a pentapeptide sequence (Ser-Gly-Gly-Cys-Tyr). Both enzymes exist on the outer membrane of mitochondria of various types of cells in various tissues including the brain. In humans, MAO-A is abundant in the brain and liver, whereas the liver, lungs and intestine are rich in MAO-B. MAO-A oxidizes noradrenaline and serotonin; and MAO-B, mainly beta-phenylethylamine. In the human brain, MAO-A exists in catecholaminergic neurons, but MAO-B is found in serotonergic neurons and glial cells. MAO-A knockout mice exhibit increased serotonin levels and aggressive behavior, whereas MAO-B knockout mice show little behavioral change. The gene knockout mice of MAO-A or MAO-B, together with the observation that some humans lack MAO-A, MAO-B, or both have contributed to our understanding of the function of MAO-A and MAO-B in health and disease. MAO-A and MAO-B may be closely related to various neuropsychiatric disorders such as depression and Parkinson's disease, and inhibitors of them are the subject of drug development for such diseases.     

Neural mechanisms underlying peak-dose dyskinesia induced by levodopa and apomorphine are distinct: evidence from the effects of the alpha(2) adrenoceptor antagonist idazoxan.

Dyskinesia, secondary to dopamine replacement therapy, is the major complication of currently available therapies for Parkinson's disease. Alpha(2) adrenoceptor antagonists, such as idazoxan, can significantly reduce levodopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, nonhuman primate model of Parkinson's disease and in human. This action of adrenoceptor antagonists may involve blockade of the actions of noradrenaline synthesised from levodopa. We hypothesise that, because dopamine receptor agonists, such as apomorphine, cannot be metabolised to produce noradrenaline, activation of adrenoceptors may not be involved in dyskinesia produced by such agents. If this were the case, idazoxan would not be expected to reduce apomorphine-induced dyskinesia. MPTP-lesioned marmosets with stable dyskinesia induced by prolonged levodopa therapy were given an acute challenge with apomorphine (0.3 mg/kg subcutaneously) or levodopa (8.0 mg/kg orally), these doses produced equivalent peak-dose dyskinesia. Idazoxan (2.5 mg/kg p.o.), or vehicle, was then administered with either apomorphine or levodopa. Idazoxan abolished levodopa-induced dyskinesia but did not affect apomorphine-induced dyskinesia (P < 0.05 and P > 0.05, respectively, Wilcoxon matched pairs test). Idazoxan also extended the anti-parkinsonian actions of levodopa but did not affect those of apomorphine. The pharmacological characteristics of the neural mechanisms underlying levodopa-induced dyskinesia and apomorphine-induced dyskinesia in parkinsonism thus appear to be distinct, at least with respect to the involvement of alpha(2) adrenoceptors. Specifically, levodopa, but not apomorphine-induced dyskinesia, involves activation of adrenoceptors. This finding may have major implications for understanding dyskinesia and should be borne in mind when designing clinical studies in which levodopa or dopamine receptor agonist challenges are employed to assess potential anti-dyskinetic properties of drugs.     

Recent observations on the clinical pharmacology of (-)deprenyl

Summary Serial tyramine challenges were given to 4 patients with Parkinson's disease who had taken 10 mg of a selective monoamine oxidase B inhibitor, (-)deprenyl, for up to eighteen months. In doses sufficient for complete inhibition of the platelet enzyme, no clinically significant adverse pressor reactions (cheese effects) occurred nor were any significant tyramine responses seen when higher doses of deprenyl (40–60 mg daily) were given for three weeks.A balanced crossover study in six healthy young male adults showed that (-)deprenyl was associated with a significant increase in the frequency of periods of wakefulness and stage 2 sleep and a significant decrease in REM sleep and sleep stages 3 and 4.In 85 patients with Parkinson's disease taking 10 mg of (–) deprenyl daily with levodopa and carbidopa for up to eighteen months, a mean dosage reduction of 200 mg levodopa daily was possible; 19 of the 39 patients who had end-of-dose akinesia responded favourably and only one of the 10 patients with on-off oscillations improved. On 10 mg (-)deprenyl daily only 4 patients showed an amphetamine response, but this was more frequent when 40 mg deprenyl was given daily. In 5 patients taking 40 mg (-)deprenyl daily without other medications a mild antiparkinsonian response occurred comparable to that seen with amphetamine.