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Modulation of gene expression rather than monoamine oxidase inhibition: (-)-Deprenyl-related compounds in controlling neurodegeneration

Neurology (USA), 1996, 47/6 SUPPL. 3 (S171-S183)

(-)-Deprenyl has been used to irreversibly inhibit monoamine oxidase B (MAO-B) in Parkinson's disease (PD) and Alzheimer's disease (AD) as a possible means of improving dopaminergic neurotransmission or of reducing neuronal necrosis caused by oxidative radical damage. Recent research in tissue culture and animal models has shown that (-)-deprenyl can reduce neuronal apoptosis caused by a variety of agents, in a variety of neuronal subtypes through a mechanism(s) that does not require MAO-B inhibition. Studies using general P450 blockers have shown that one of the principal metabolites of (-)-deprenyl, (-)-desmethyldeprenyl, mediates the antiapoptotic action. Other research has shown that (-)-deprenyl can induce altered expression of a number of genes in preapoptotic neurons both in vitro and in vivo, including the genes for superoxide dismutase (SOD) 1 and 2, BCL- 2 and BCL-x(L), nitric oxide synthase, c-JUN, and nicotinamide adenine dinucleotide dehydrogenase. Antiapoptosis by (-)-deprenyl is associated with a prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons, which has been shown to occur early in apoptosis and is likely an initiating factor. The above changes in gene expression appear to reduce oxidative radical damage to mitochondria and maintain mitochondrial permeability, thereby blocking mitochondrial 'signals' that initiate apoptosis. In situ evidence suggests that apoptosis contributes to neuronal death in a number of neurodegenerative diseases. If apoptosis is critical to the progression of one or more human neurodegenerative diseases, then transcriptionally active agents such as (-)-desmethyldeprenyl may be of value in treating the diseases. The kinetics of (-)-deprenyl metabolism, however, and its biodistribution after oral administration, make it unlikely that the antiapoptotic action has played a major role in benefits found for the drug in PD and AD to date.



L-Deprenyl protects mesencephalic dopamine neurons from glutamate receptor-mediated toxicity in vitro

Journal of Neurochemistry (USA), 1997, 68/1 (33-39)

L-Deprenyl is a relatively selective inhibitor of monoamine oxidase (MAO)-B that delays the emergence of disability and the progression of signs and symptoms of Parkinson's disease. Experimentally, deprenyl has also been shown to prevent neuronal cell death in various models through a mechanism that is independent of MAO-B inhibition. We examined the effect of deprenyl on cultured mesencephalic dopamine neurons subjected to daily changes of feeding medium, an experimental paradigm that causes neuronal death associated with activation of the NMDA subtype of glutamate receptors. Both deprenyl (0.5-50 microM) and the NMDA receptor blocker MK-801 (10 microM) protected dopamine neurons from damage caused by medium changes. The nonselective MAO inhibitor pargyline (0.5-50 microM) was not protective, indicating that protection by deprenyl was not due to MAO inhibition. Deprenyl (50 microM) also protected dopamine neurons from delayed neurotoxicity caused by exposure to NMDA. Because deprenyl had no inhibitory effect on NMDA receptor binding, it is likely that deprenyl protects from events occurring downstream from activation of glutamate receptors. As excitotoxic injury has been implicated in neurodegeneration, it is possible that deprenyl exerts its beneficial effects in Parkinson's disease by suppressing excitotoxic damage.



The natural history of Parkinson's disease

Neurology (USA), 1996, 47/6 SUPPL. 3 (S146-S152)

A large body of evidence indicates that the progression of Parkinson's disease (PD) may be fast in the preclinical stage as well as during the first years of the disease, with a subsequent slowing down of the disease process. As has been shown in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination scores declined at a rate of 8 to 9% per year in untreated patients. A subgroup of levodopa-naive DATATOP patients ('survivors') showed a much slower rate of progression, in the order of 3% per year, suggesting a more benign disease course. A number of clinical factors that may govern the rate of motor decline, such as age at onset, disease duration, gender, and clinical phenotype (akinetic-rigid versus tremulous) have been proposed; however, none of them is proven. In contrast, dopaminergic substitution undoubtedly has had a major impact on the natural history of PD, resulting in a reduction of the mortality ratio from about 3.0 to 1.5. This benefit has been noted particularly in patients in whom levodopa therapy was started early. The positive impact of levodopa is largely derived from its symptomatic action; its influence on the disease process itself remains controversial.



Effect of lazabemide on the progression of disability in early Parkinson's disease

Annals of Neurology (USA), 1996, 40/1 (99-107)

Lazabemide (Ro 19-6327) is a relatively short-acting, reversible, and selective type B monoamine oxidase inhibitor that is not metabolized to amphetamines or other active compounds. We previously found lazabemide to be safe and well tolerated at dosages of up to 400 mg/day during a 6-week study of 201 patients with early untreated Parkinson's disease (PD). We now assess whether or not lazabemide influences the progression of disability in untreated PD. Patients (N = 321) were assigned by randomization to one of five treatment groups (placebo, 25 mg, 50 mg, 100 mg, or 200 mg/day) and followed systematically for up to 1 year. The risk of reaching the primary end point (the onset of disability sufficient to require levodopa therapy) was reduced by 51% for the patients who received lazabemide compared with placebo-treated subjects. This effect was consistent among all dosages. The frequency of adverse experiences did not differ among the treatment groups. At dosages ranging from 25 to 200 mg/day, lazabemide was well tolerated and delayed the need for levodopa in early, otherwise untreated PD. The magnitude and pattern of benefits were similar to those observed after 1 year of deprenyl (selegiline) treatment in the DATATOP clinical trial.



Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP subjects not requiring levodopa

Annals of Neurology (USA), 1996, 39/1 (29-36)

In the controlled trial Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), 310 of the 800 enrolled subjects did not reach the primary end point of disability requiring levodopa therapy during 21 plus or minus 4 (mean plus or minus SD) months of observation or need early initiation of deprenyl (selegiline) during a 2-month withdrawal of experimental treatments. While maintaining the blindness of their original deprenyl and tocopherol treatment assignments, these 310 subjects were administered deprenyl 10 mg/day (open label) and were monitored systematically at 1- to 3-month intervals for up to 18 months (12 plus or minus 5 mo). During this extended trial, the 189 subjects who had been assigned originally to active deprenyl tended to reach the end point of disability faster than the 121 subjects who had not been assigned originally to deprenyl (hazard ratio, 1.43; 95% CI, 0.98, 2.09; p = 0.065). However, the differential rates of reaching the end point may have been due in part to the more severe baseline impairment of deprenyl-assigned subjects, who benefited originally from deprenyl but who were more likely to require levodopa during this extended period of observation. Prior treatment with deprenyl did not lead to superior survival with respect to the end point of disability requiring levodopa, suggesting that the initial advantages of deprenyl were not sustained.



New approaches to drug treatment of Parkinson's disease

Aktuelle Neurologie (Germany), 1995, 22/6 (217-223)

Although the aetiology of Parkinson's disease remains unknown, an improved understanding of the neurobiology of Parkinson's disease has opened up new avenues for pharmacological therapeutic interventions. Some of these new neuropharmacological approaches are still in the experimental preclinical phase, whereas others are currently studied in patients. In addition, experimental neuropharmacological research provides a better understanding of the mechanism of action of conventional antiparkinsonian drugs. Recent experimental evidence suggests that striatal dopamine loss leads to increased glutamatergic transmission in the basal ganglia. In animal experiments, the action of L-dopa and dopamine agonists is potentiated by glutamate antagonists. A number of weak glutamate antagonists with low specificity are available for clinical use. These compounds include amantadine, memantine and budipine. Neurotrophic factors, such as ciliary neurotrophic factor (CNTF) and glial cell line derived neurotrophic factor (GDNF) are promising new approaches for neuroprotection in Parkinson's disease. Problems of bioavailability thus far preclude their use in patients. Catechol-O-methyl-transferase (COMT) inhibitors are a new class of drugs that act on the dopaminergic system. Clinical studies show that COMT inhibitors prolong the action of L-dopa in patients with wearing off phenomenon. In spite of its haematological risk, the atypical neuroleptic clozapine is the treatment of choice for the alleviation of L-dopa-induced psychosis. Clozapine has also beneficial effects on tremor and L-dopa-induced dyskinesias. The monoamine oxidase B (MAO-B) inhibitor deprenyl blocks the oxidative metabolism of dopamine and reduces the formation of free oxygen radicals. On the basis of these properties neuroprotective actions of deprenyl have been postulated. Clinical studies, however, failed to undoubtedly prove a neuroprotective action of deprenyl in patients. New experimental studies show protective actions of deprenyl, which are independent of MAO-B inhibition and which are due to a direct effect on gene transcription.



Novel sites of action for deprenyl in MPTP-parkinsonism: Metabolite-mediated protection against striatal neurotoxicity and suppression of MPTP-induced increase of dopamine turnover in C57BL mice

Progress in Brain Research (Netherlands), 1995, 106 (155-171)

In the present study we provide further evidence for our recent finding that DEP has neuroprotective effects against dopaminergic toxicity of MPTP and its 2'-substituted analogs in mice, which are associated with the ability of its major metabolites, 1-methamphetamine and 1-amphetamine to block the neuronal uptake of the toxic pyridinium metabolites of MPTP and its analogs. Here we demonstrated that protection by a 30-min DEP posttreatment (10 mg/kg) against MPTP (40 mg/kg)-induced decrease of striatal dopamine level is reduced when mice received SKF 525A (25 mg/kg), an inhibitor of the metabolism of DEP 10 min prior to DEP treatment. For the first time, we demonstrated that a 30-min pre- or post-treatment with DEP (10 mg/kg) provided substantial protection against striatal dopamine depletion induced by 2'Et-MPTP (30 mg/kg), which is primarily bioactivated by MAO-A. A 30-min posttreatment with DEP (but not by pargyline or clorgyline), in addition to protection against dopamine depletion, also prevents the decrease in striatal mazindol binding (an indicator of the integrity of dopaminergic terminals) induced by MPTP (40 mg/kg), 2'Me-MPTP (15 mg/kg) or 2'Et-MPTP (30 mg/kg). A subacute DEP treatment of mice with severe injury in the terminal fields of the nigrostriatal dopaminergic system (80-90% loss of dopamine; 2-4-fold increase in dopamine turnover as reflected by higher metabolite/DA ratios) enhanced the recovery of striatal dopamine level and suppressed the MPTP-induced elevation of dopamine turnover. Deprenyl treatment was applied in a wide range of dose (0.01-20 mg/kg, i.p., eight times over 18 days from the 3rd day after the last MPTP injection) to mice that had received MPTP (30 mg/kg; i.p.) for 5 consecutive days. The effect of subacute DEP treatment on the recovery of striatal dopamine level was most pronounced at a cumulative dose of 0.8 mg/kg, indicating that higher dosage of DEP may be less beneficial.



Combined treatment in Parkinson's disease

Neuropsychiatrie (Germany), 1995, 9/SUPPL. 1 (S27-S29)

As a rule patients with Parkinson's disease receive combined therapy aiming at reducing the levodopa dose and achieving optimum therapeutic results regarding the target symptoms, e.g. tremor and slowing disease progression by neuroprotection. The benefits of combined treatment with levodopa and dopaminergic agonists in the treatment of dyskinesia and fluctuations in advanced disease stages have been established. It is further recommended to combine dopaminergic agonists and levodopa during early disease stages to delay the occurrence of late complications and to administer selegeline because of its possible neuroprotection. Studies on the latter aspects are controversial and discussion is in progress.



In vivo comparison of the effects of inhibition of MAO-A versus MAO-B on striataI L-DOPA and dopamine metabolism

Journal of Neural Transmission - Parkinson's Disease and Dementia Section (Austria), 1995, 10/2-3 (79-89)

Utilizing the cerebral microdialysis technique, we have compared in vivo the effects of selective MAO-A, MAO-B, and nonselective MAO inhibitors on striatal extracellular levels of dopamine (DA) and DA metabolites (DOPAC and HVA). The measurements were made in rats both under basal conditions and following L-DOPA administration. Extracellular levels of dopamine were enhanced and DA metabolite levels strongly inhibited both under basal conditions and following L-DOPA administration by pretreatment with the nonselective MAO inhibitor pargyline and the MAO-A selective inhibitors clorgyline and Ro 41-1049. The MAO-B inhibitor deprenyl had no effect on basal DA, HVA, or DOPAC levels. Nevertheless, deprenyl significantly increased DA and decreased DOPAC levels following exogenous L-DOPA administration, a finding compatible with a significant glial metabolism of DA formed from exogenous L-DOPA. We conclude that DA metabolism under basal conditions is primarily mediated by MAO-A. In contrast, both MAO-A and MAO-B mediate DA formation when L-DOPA is administered exogenously. The efficacy of newer, reversible agents which lack the 'cheese effect' such as Ro 41-1049 are comparable to the irreversible NAG-A inhibitor clorgyline. The possible relevance of these findings for the treatment of Parkinson's disease is discussed.



Selegiline: A review of its clinical efficacy in Parkinson's disease and its clinical potential in Alzheimer's disease

CNS Drugs (New Zealand), 1995, 4/3 (230-246)

Selegiline (deprenyl) increases nigrostriatal dopamine levels by several mechanisms, including selective and irreversible inhibition of cerebral monoamine oxidase type-B. Through this mechanism it may also protect neurons against damage by free radicals and possibly exogenous neurotoxins. When used alone in patients with early Parkinson's disease, oral selegiline 5 mg twice daily initially reduces symptoms severity compared with placebo. During prolonged therapy, selegiline slows the rate of symptoms progression and delays the need for levodopa therapy by 6 to 9 months. The benefits of coadministration of selegiline with levodopa as de novo therapy in early Parkinson's disease compared with levodopa monotherapy remain unclear. Studies have shown either similar disease progression in both treatment groups after 3 years or significantly slowed disease progression and reduced levodopa requirement after 14 to 54 months in patients treated with both drugs compared with levodopa monotherapy. In patients with more advanced disease who have mild levodopa response fluctuations, concomitant selegiline allows a reduction in levodopa dosage. Improvements in overall disability and 'end-of-dose' fluctuations are observed, although benefits are rarely maintained for longer than a year. Improvements in cognitive function, behaviour and activities of daily living have been observed in patients with Alzheimer's disease following administration of selegiline 10 mg/day for up to 15 months, and the drug appeared to be more effective in this regard than 1-acetylcarnitine, oxiracetam and phosphatidylserine in single-blind studies. In addition, preliminary findings suggest that selegiline may have an additive effect when coapministered with cholinergic therapy. At the dosage recommended for Parkinson's disease and Alzheimer's disease, selegiline is not associated with the tyramine ('cheese') reaction. Thus, selegiline is a valuable treatment option for de novo therapy of patients with early Parkinson's disease, improving symptoms and postponing the need for levodopa therapy. Whether it also offers clinically significant neuroprotection remains unclear. Selegiline is a useful adjunct to long term levodopa therapy in patients with more advanced disease experiencing response fluctuations, and recent findings suggest that it may offer some clinical benefit to patients with Alzheimer's disease.



Combined treatment in Parkinson's disease

Neuropsychiatrie (Germany), 1995, 9/SUPPL. 1 (S27-S29)

As a rule patients with Parkinson's disease receive combined therapy aiming at reducing the levodopa dose and achieving optimum therapeutic results regarding the target symptoms, e.g. tremor and slowing disease progression by neuroprotection. The benefits of combined treatment with levodopa and dopaminergic agonists in the treatment of dyskinesia and fluctuations in advanced disease stages have been established. It is further recommended to combine dopaminergic agonists and levodopa during early disease stages to delay the occurrence of late complications and to administer selegeline because of its possible neuroprotection. Studies on the latter aspects are controversial and discussion is in progress.



Treatment of Parkinson's disease

Neurology India (India), 1995, 43/2 (77-82)

Inspite of extensive research the ideal drug therapy for idiopathic Parkinson's disease (PD) and its optimal timing remain uncertain. Levodopa still is the mainstay of therapy for PD. Little evidence exists to incriminate early institution of levodopa therapy in the development of motor fluctuations and dyskinesias in PD. These complications are probably a consequence of disease progression, and resultant inability to synthesize and store dopamine, and buffer the variability in dopamine availability. Therefore, withholding levodopa therapy until late stage of the disease is not warranted. Dopa agnoists provide only a short-term benefit. The neuroprotective effect of selegeline remains to be established. There is not enough evidence to justify the current practice of initiating treatment for PD patients with expensive polypharmacy. Research into the development of inexpensive levodopa containing preparations needs to be encouraged.



Clinical pharmacokinetics of drugs for Alzheimer's disease

Clinical Pharmacokinetics (New Zealand), 1995, 29/2 (110-129)

Pharmacological treatment of patients with Alzheimer's disease is becoming more important, as evidenced by the number of drugs being developed in different countries. It has been shown in the majority of clinical trials that cholinesterase inhibitors, such as tacrine (tetrahydroaminoacridine), are able to induce beneficial effects in cognition and memory. Tacrine, like most of the other oral antidementia agents, is rapidly absorbed from the gastrointestinal tract. It is excreted mainly through the kidney, with a terminal elimination half-life of about 3 hours. Tacrine has nonlinear pharmacokinetics and there are large interindividual differences in pharmacokinetic parameters after oral, intravenous and rectal administration. A positive relationship between cognitive changes and plasma tacrine concentrations has been recently described. Similarly, velnacrine exhibits evidence of nonlinearity in some pharmacokinetic parameters, but renal excretion is a miner route of elimination for this drug. Pharmacokinetic data pertaining to epiastigmine, a third cholinesterase inhibitor, is more limited. However, the drug is rapidly distributed to the tissues after oral administration and readily enters the central nervous system, where it can be expected to effectively inhibit acetylcholinesterase in the brain for a prolonged period. Pharmacokinetic data for the nootropic agents are more limited. However, of the 3 agents reviewed only pramiracetam penetrates the central nervous system (CNS) poorly. Indeed, oxiracetam crosses the blood-brain barrier and persists for longer in the CNS than in the serum. Selegiline (deprenyl), a neuroprotective agent, is readily absorbed from gastrointestinal tract. It is metabolised mainly in the liver; and to a minimal extent in the lung or kidneys. The steady-state concentrations of metabolites in the cerebrospinal fluid (CSF) and serum are very similar, reflecting their easy penetration into the CNS. Idebenone, another neuroprotective agent, likewise is rapidly absorbed and achieves peak concentrations in the brain comparable to those in plasma. Similarly, CSF concentrations of metabolites of ST 200 (acetyl-L-carnitine) parallel those in plasma, suggesting that they easily cross the blood-brain-barrier. Gangliosides (GM1) can be given intramuscularly or subcutaneously, but the latter route of administration provides a concentration 50% higher both in the serum and the ganglioside fraction. However, because of its longer elimination, the intramuscular route is the best form of administration when the brain is the target organ for the treatment. Absorption of nimodipine is quite rapid. The pharmacokinetics of nimodipine during multiple-dose treatment have not been studied extensively; however, the drug does not appear to accumulate during repeated administration of standard doses. Nimodipine has linear pharmacokinetics and is subject to interindividual variability. It is primarily excreted in the urine, but 32% of the dose is excreted in the faeces, possibly as a consequence of biliary excretion. To achieve adequate drug concentrations in the brain, different methods have been devised, both invasive (implantable drug infusion pumps and polymer drug-delivery systems, neural transplantation, etc.) and noninvasive (prodrugs microencapsulated within biocompatible polymers that can protect the drug from degradation, etc.) methods. These methods may provide more effective drug delivery into the CNS, and pharmacokinetic data should be determined when these methods of drug delivery are being assessed in clinical trials.



Anticonvulsant and antiepileptogenic effect of L-deprenyl (selegiline) in the kindling model of epilepsy

Journal of Pharmacology and Experimental Therapeutics (USA), 1995, 274/1 (307-314)

L-Deprenyl (selegiline) is an irreversible inhibitor of monoamine oxidase type B, but also exerts several effects on dopamine and noradrenaline systems independent of monoamine oxidase type B inhibition. Thanks to these properties, L-deprenyl has gained wide acceptance in the therapy of Parkinson's disease by using L-deprenyl both with levodopa and alone. Furthermore, L-deprenyl improves the performance of patients with Alzheimer's disease. Epilepsy, particularly temporal lobe epilepsy with complex-partial seizures, is often associated with disturbances of cognitive function and behavior, and it has been suggested that a drug combining cognition-enhancing and antiepileptic activity would be of benefit in the treatment of epileptic patients. This prompted us to study if L-deprenyl exerts anticonvulsant efficacy in amygdala-kindled rats, i.e., a useful model of complex-partial seizures in humans. In addition to anticonvulsant activity, i.e., effects on already developed seizures, we determined whether L-deprenyl exhibits antiepileptogenic properties, i.e., suppressive effects on development of kindling. In all experiments, behavioral alterations of the rats in response to L-deprenyl were monitored closely. In order to assess the role of active metabolites in the anticonvulsant and behavioral effects of L-deprenyl in the kindling model, the D-enantiomer of deprenyl, which is metabolized to more potent compounds (D-amphetamine and D-methamphetamine) than the L- enantiomer, was used for comparison. In fully kindled rats, L-deprenyl potently increased the threshold for focal afterdischarges. The most marked increase in afterdischarge threshold (up to 250% above control) was seen after a dose of 10 mg/kg, whereas the D-enantiomer was ineffective at this dosage. In contrast to the lack of anticonvulsant activity, D-deprenyl was more potent than L-deprenyl to induce amphetamine-like behavioral adverse effects such as stereotypies, thus indicating that degradation to active metabolites is involved in the behavioral but not anticonvulsant effects of deprenyl. This was substantiated by the observation that increase of dosage of L-deprenyl to 20 or 40 mg/kg induced marked amphetamine-like adverse effects, whereas the anticonvulsant effect was reduced compared to lower doses. Chronic treatment with L-deprenyl during kindling acquisition did not prevent kindling, but significantly retarded the development of some kindling parameters. The present study is the first to demonstrate potent anticonvulsant effects of L-deprenyl. In view of the neuroprotective and cognition-enhancing effects of this drug, L-deprenyl might be of clinical benefit in patients with epilepsy.



Chronic treatment with levodopa and/or selegiline does not affect behavioral recovery induced by fetal ventral mesencephalic grafts in unilaterally 6-hydroxydopamine-lesioned rats

Experimental Neurology (USA), 1994, 130/2 (261-268)

It has been suggested that levodopa (L-dopa), a dopamine precursor used to treat Parkinson's disease, may be toxic to grafted fetal neuroblasts; if so, the use of the monoamine oxidase B inhibitor selegiline might prevent such toxicity. We randomly assigned 30 unilaterally 6-hydroxydopamine-lesioned male Sprague-Dawley rats, whose lesions were verified with low-dose apomorphine-induced rotations, to one of five treatment groups: (i) L-dopa methyl ester (125 mg/kg/day) with benserazide (a peripheral decarboxylase inhibitor; 25 mg/kg/day), (ii) L-dopa methyl ester with benserazide and selegiline (L-deprenyl; 0.5 mg/kg/day), (iii) selegiline only, (iv) and (v) vehicle (ascorbate in normal saline) only. After 2 weeks of twice-daily ip injections, the rats received fetal ventral mesencephalic grafts into the lesioned striatum; one vehicle group received sham grafts. Drug therapy was continued for 2one-half months post grafting. At 1 month after grafting, and every 2 weeks thereafter, the rats were tested using low-dose apomorphine-induced rotation. A 70% decrease in rotations among all grafted groups, relative to the shams, was found. No statistical differences among groups receiving various drug therapies were seen in behavior or in counts or dimensions of tyrosine hydroxylase-positive cells. We therefore conclude that, in the unilaterally lesioned rat model of Parkinson's disease, there is no adverse effect of L-dopa nor any significant effect of selegiline, either alone or coadministered with L-dopa, on behavioral recovery induced by fetal ventral mesencephalic grafts.



What is it that l-deprenyl (selegiline) might do?

CLIN. PHARMACOL. THER. (USA), 1994, 56/6 II SUPPL. (781-796)

There have been many claims that l-deprenyl may have distinct properties in slowing and perhaps even in reversing the progression of Parkinson's disease and other neurodegenerative conditions. This article will consider the paucity of evidence that such is the case in humans and the more detailed results from studies with experimental animals indicating that deprenyl may indeed express such a property. The conflicting data on its mechanism of action are considered, and the concept that it may function to enhance neuronal fitness is advanced as an alternative to the neuroprotection and neurorescue hypotheses. Possible lines of experimental development that would help resolve some of the many unanswered questions regarding l-deprenyl function are outlined.



Slow recovery of human brain MAO B after L-deprenyl (selegeline) withdrawal

SYNAPSE (USA), 1994, 18/2 (86-93)

L-Deprenyl (Selegeline) is an enzyme-activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 1.4.3.4). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L-deprenyl requires the synthesis of new enzyme. We have measured a 40 day half-time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L-deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L- Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L-deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use.



Deprenyl enhances neurite outgrowth in cultured rat spinal ventral horn neurons

J. NEUROL. SCI. (Netherlands), 1994, 125/1 (11-13)

Deprenyl, a selective monoamine oxidase B inhibitor, is effective in Parkinson's disease, and can slow the cognitive deterioration in Alzheimer's disease. However, it is not known whether this agent has a trophic effect on spinal motor neurons. We have studied neurotrophic effects of deprenyl on spinal motor neurons, using explanted ventral spinal cord culture from 13-day-old rat embryos. Deprenyl-treated cultures significantly enhanced neurite outgrowth with cultures of ventral spinal cord. Our data suggest that deprenyl is one of the candidate for neurotrophic factors on spinal motor neurons in vitro. A possible role for deprenyl in amyotrophic lateral sclerosis remains to be defined.



Effect of L-Deprenyl, its structural analogues and some monoamine oxidase inhibitors on dopamine uptake

NEUROPHARMACOLOGY (United Kingdom), 1994, 33/6 (763-768)

The effect on dopamine uptake by L-deprenyl, its structural analogues and different types of monoamine oxidase (MAO) inhibitors was investigated. Both direct (3H)dopamine uptake into rat striatal slices and binding of a specific dopamine uptake inhibitor (3H)GBR-12935 were used in the present study. L-Deprenyl exhibits a relatively weak dopamine uptake inhibitory effect in vitro, while D-deprenyl possesses a very potent inhibitory effect. The potent effect of D-deprenyl on dopamine uptake may be responsible, at least in part, for its behavioral effects and abuse liability. L-Methamphetamine, a metabolite of L-deprenyl, does not inhibit (3H)GBR-12935 binding but it reduces the retention of (3H)dopamine in striatal tissues, suggesting that it may enhance dopamine release. The MAO-A inhibitors clorgyline and brofaromine also exhibit dopamine uptake inhibitory effects. Irreversible and reversible MAO-B inhibitors, however, such as pargyline, aliphatic N-methylpropargylamines, Ro 19-6327 and MDL-72974A and MAO-A inhibitor moclobemide do not possess any appreciable inhibitory effects on dopamine uptake. Dopamine uptake is probably unrelated to the pharmacological actions of L-deprenyl.



Neuropsychological correlates of L-deprenyl therapy in idiopathic parkinsonism

PROG. NEURO-PSYCHOPHARMACOL. BIOL. PSYCHIATRY (United Kingdom), 1994, 18/1 (115-128)

Monoaminergic neurotransmitter systems are known to play an important role in neuropsychological functions and they are impaired in dementia of DAT and PD. L-deprenyl is a monoamine-enhancing drug which at low doses selectively inhibits MAO-B, an enzyme whose brain activity has been reported to increase in normal aging and neurodegenerative dementing disorders. The authors studied the effects of L-deprenyl, 10 mg/day, on several cognitive domains in idiopathic parkinsonians without dementia. Ten out-patients, treated with levodopa plus DDI, were tested before receiving L-deprenyl and retested six months after they had been treated with the drug. A control group of ten parkinsonian out-patients treated with only levodopa plus DDI, matched for age, educational level, severity and duration of extrapyramidal disease, was tested by the same neuropsychological battery and retested after the comparable time interval. Statistically significant changes were noted in the verbal and visuospatial learning performances of PD patients treated with the combination of L-deprenyl and levodopa.



Monoamine oxidase inhibition by L-deprenyl depends on both sex and route of administration in the rat

NEUROCHEM. RES. (USA), 1993, 18/12 (1299-1304)

The monoamine oxidase B (MAO-B) inhibitor L-deprenyl, widely used to treat Parkinson's disease, has frequently been studied in animal models. We have examined the effects of several variables on activity levels of MAO-A and B in rat brain and liver following chronic (3 wks) treatment with L-deprenyl. Significant effects were observed for sex (females showed lower overall MAO- B activity in the liver), dose (MAO-A and B inhibition increased with dose, with females exhibiting greater sensitivity), route of administration (subcutaneous injection was more efficient than oral dosing), and dosing interval (MAO-B was significantly inhibited when dosing interval was increased to as long as 168 hours). Our results thus indicate that the effectiveness of L-deprenyl in vivo is dependent on several factors and that these must be taken into account in studies involving the benefits or risks of this drug.



Monoamine oxidase (MAO): Relationships to foods, poisons and medicines

BIOG. AMINES (Netherlands), 1993, 9/5-6 (355-365)

Monoamine oxidase has an important role in metabolism of biogenic amines and in disposing of exogenous amines. As information about MAO and its inhibitors has unfolded, effects which are deleterious in some patients have proven therapeutically beneficial in other conditions. The central nervous system effects of an antituberculosis drug, iproniazid, led to its use as an antidepressant and to the discovery of MAO inhibitors. Understanding the role of MAO in noradrenergic neurons explained why orthostatic hypotension occurs in some patients treated with a MAO inhibitor and why MAO inhibitors found use as antihypertensive drugs. Reversal of the tranquilizing effects by MAO inhibitors was explained also. Differences among MAO inhibitors in their potency in precipitating hypertensive crises after ingestion of foods with high tyramine content was explained when subtypes MAO-A and MAO-B were defined. MAO-B inhibitors were not associated with these reactions to tyramine ingestion and were deemed 'safe'. MAO-B was found to be important for the bioactivation of MPTP to MPP+ which causes selective destruction of dopaminergic nigrostriatal neurons. In humans and in non-human primates, this results in a motor deficit almost identical to Parkinson's disease. The high levels of MAO-B in the endothelium of brain blood vessels appear to protect the brain of rats from MPTP toxicity. Trials of a 'safe' MAO-B inhibitor, deprenyl, for potentiating the antiparkinsonian effects of DOPA, suggested that this drug slowed the progression of Parkinson's disease. This observation and the demonstrated role of MAO-B in bioactivation MPTP were the bases for a large multicenter placebo-controlled clinical trial of deprenyl for treatment of early Parkinson's disease. The apparent success of this trial has stimulated searches for newer more effective agents to inhibit MAO-B and to retard the progression of degenerative diseases of the central nervous system.



Deprenyl increases survival of rat foetal nigral neurones in culture

NEUROREPORT (United Kingdom), 1993, 4/10 (1183-1186)

To study the potential of L-deprenyl to rescue dopaminergic neurones from natural death in primary cultures, foetal nigral neurones were prepared from the ventral midbrain of 16 day old rat embryos. L-deprenyl, at final concentrations of 0.1, 1 and 10 microM, or vehicle solution was added to the culture medium. The cells were allowed to survive for 1, 5 and 10 days. They were then fixed and stained for tyrosine hydroxylase (TH) immunohistochemistry, with or without histological staining. After 5 and 10 days, deprenyl at 0.1 microM increases the number of TH-positive profiles in treated cultures when compared with controls but the effect was more evident at 1 and 10 microM. This can be interpreted as increased survival of catecholaminergic neurones. We cannot however rule out the possibility that deprenyl stimulates the expression of TH by other neurones.



Chronic treatment of aged mice with L-deprenyl produces marked striatal MAO-B inhibition but no beneficial effects on survival, motor performance, or nigral lipofuscin accumulation

NEUROBIOL. AGING (USA), 1993, 14/5 (431-440)

Male C57BL/6J mice were provided I-deprenyl (at 0, 0.5 mg/kg or 1.0 mg/kg per day) in their drinking water beginning at 18 months of age. A battery of motor tests, including open-field, tightrope, rotorod, inclined screen, runwheel, and rotodrum tests, was administered before treatment and then 6 months later at 24 months of age. A subsample of mice was retested again at 27 months of age. An untreated group of 9-month-old mice served as young controls. Deprenyl treatment reduced striatal MAO-B activity by up to 60% after 6 months on treatment but had no significant effects on striatal catecholamine levels. No significant effects of deprenyl treatment were observed on body weight, fluid intake, or survival of the mice. Chronic deprenyl treatment also did not afect motor performance in any test, except rotodrum performance at 27 months of age, which was significantly better in the 1.0 mg/kg group treated group compared to controls. No age or deprenyl effects were observed with respect to cell counts in the substantia nigra. However, nigral cells containing lipofuscin increased with age, but this neurohistochemical parameter was also unaffected by deprenyl treatment.



Effect of selegiline (deprenyl) on the progression of disability in early Parkinson's disease

ACTA NEUROL. SCAND. SUPPL. (Denmark), 1993, 87/146 (36-42)

In patients with early, otherwise untreated Parkinson's disease, the abilities of selegiline (deprenyl) and tocopherol, antioxidative agents that act through complementary mechanisms, to delay the emergence of more severe disability requiring treatment with levodopa were evaluated. Eight hundred subjects were randomly assigned in a two-by-two factorial design to receive selegiline (10 mg per day), tocopherol (2000 IU per day), selegiline and tocopherol, or placebo and were followed up to determine the frequency of development of disability requiring treatment with levodopa, the primary end point. Interim analysis performed by an independent safety monitoring committee prompted a preliminary comparison of the 401 subjects assigned to tocopherol or placebo with the 399 subjects assigned to selegiline, alone or with tocopherol. During an average of 12 months of follow-up, only 97 subjects who received selegiline reached the end point. In contrast, 176 subjects who did not receive selegiline reached the end point during this period (P < 10-8). Selegiline was also found to be well tolerated and to have a small, but statistically significant symptomatic benefit. These results indicate that use of selegiline (10 mg per day) in patients with early, otherwise untreated Parkinson's disease, delays the emergence of more severe disability.



Parkinson's disease: Past, present, and future

NEUROPSYCHOPHARMACOLOGY (USA), 1993, 9/1 (1-12)

The development of understanding of the pathophysiology and modes of treatment of Parkinson's disease represents one of the triumphs of modern medicine, encompassing astute clinical observation, utilization of basic research findings regarding dopamine to develop the first rational treatment of a degenerative disorder of the central nervous system, and remains at the frontiers of neurologic science. After characterization of the clinical and pathologic features of Parkinson's disease, rational treatment awaited the discovery of the deficit in basal ganglia dopamine. On the basis of this observation and the known biosynthetic pathways for dopamine formation, levodopa was introduced. Use of metabolic inhibitors to prolong and potentiate the effects and avoid the deleterious side effects of levodopa enhanced the efficacy of this neurotransmitter replacement strategy. The discovery and characterization of dopamine receptor subtypes and the availability of selective dopamine agonists provided additional therapeutic approaches, but failed to address the underlying cause of the degenerative process. The discovery and disclosure of the mechanisms of toxicity of the relatively selective nigrostriatal neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), triggered a resurgence of interest in etiological factors which might contribute to the development of parkinsonism and together with the report that inhibition of monoamine oxidase B with deprenyl not only potentiated the effects of levodopa, but appeared to prolong the life of parkinsonian patients, resulted in a large-scale trial of drugs that might arrest the degenerative process. Furthermore, the MPTP primate model of Parkinson's disease has encouraged development of fetal mesencephalic and other tissue implant approaches to reversal of parkinsonism. Although much of this is still in the experimental stages, hopes are high that new and more effective therapies will be developed and that similar techniques might be applicable to a wide variety of neuropsychiatric disorders.



Short-term beneficial effect of deprenyl monotherapy in early Parkinson's disease: A quantitative assessment

CLIN. NEUROPHARMACOL. (USA), 1993, 16/1 (54-60)

It was recently shown that early treatment with deprenyl in patients with Parkinson's disease can delay the need for initiation of levodopa therapy. It was therefore suggested that deprenyl may slow down disease progression. Alternatively, the observed stabilization of clinical disability may merely reflect drug-induced symptomatic benefit. We therefore examined a possible short-term beneficial effect of deprenyl (10 mg/day) as the first and only drug in 15 consecutive de novo patients. Bradykinesia was quantitatively assessed by computerized analysis of isometric force/time curves of biceps and triceps bilaterally and by calculation of simple reaction time (RT) and maximal muscle contraction rate (MMCR). We also measured maximal muscle force, evaluated clinical status by the Unified Parkinson's Disease Rating Scale (UPDRS) motor score, and recorded patients' subjective reports. All tests were carried out before and at 1 and 2 months of treatment. Only one patient reported a beneficial effect. No significant changes in the UPDRS or score or muscle force were observed. In contrast, MMCR and RT improved at 1 month by an average of 12.1 and 7.2%, respectively (p < 0.01, paired t test). This improvement persisted after 2 months of treatment. Study shows that deprenyl monotherapy exerts a short-term beneficial effect in de novo parkinsonian patients. This effect, however, appears to be small, subclinical, and probably cannot account for the observed delay in the need to start levodopa therapy.



Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease

NEW ENGL. J. MED. (USA), 1993, 328/3 (176-183)

Background and Methods. In 1987 we began a multicenter controlled clinical trial of deprenyl (a monoamine oxidase inhibitor) and tocopherol (a component of vitamin E that traps free radicals) in the treatment of early Parkinson's disease. We randomly assigned 800 patients to one of four treatments: placebo, active tocopherol and deprenyl placebo, active deprenyl and tocopherol placebo, or both active drugs. The primary end point was the onset of disability prompting the clinical decision to begin administering levodopa. An interim analysis showed that deprenyl was beneficial (N Engl J Med 1989;321:1364-71). We report the results of tocopherol treatment after a mean (plus or minusSD) follow-up of 14plus or minus6 months, as well as the follow-up results for deprenyl. Results. There was no beneficial effect of tocopherol or any interaction between tocopherol and deprenyl. The beneficial effects of deprenyl, which occurred largely during the first 12 months of treatment, remained strong and significantly delayed the onset of disability requiring levodopa therapy (hazard ratio, 0.50; 95 percent confidence interval, 0.41 to 0.62; P&lt0.001). The difference in the estimated median time to the end point was about nine months. The ratings for Parkinson's disease improved during the first three months of deprenyl treatment; the motor performance of deprenyl-treated patients worsened after the treatments were withdrawn. Conclusions. Deprenyl (10 mg per day) but not tocopherol (2000 IU per day) delays the onset of disability associated with early, otherwise untreated Parkinson's disease. The action of deprenyl that accounts for its beneficial effects remains unclear.



Enhanced hydroxyl radical generation by 2'-methyl analog of MPTP: Suppression by clorgyline and deprenyl

SYNAPSE (USA), 1992, 11/4 (346-348)

Sodium salicylate was infused through a microdialysis probe placed in the striatum of anesthetized rats in order to assay the formation of hydroxyl radical (.OH) in the extracellular fluid in vivo. In addition to causing sustained dopamine release, intrastriatal infusion of the 2'-methyl analog of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2'CH3-MPTP) increased the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA), the nonenzymatic .OH adduct of salicylate in the brain dialysate. Inhibition of monoamine oxidase (MAO) by clorgyline and deprenyl completely blocked the formation of 2,3-DHBA and the sustained dopamine overflow induced by 2'-CH3-MPTP. The results indicate that the enhanced formation of cytotoxic .OH by 2'-CH3-MPTP is suppressed by MAO inhibitors. These data support the hypothesis that the protective effect of MAO inhibitors on the neurotoxicity induced by MPTP analogues may be due not only to the inhibition of MPTP metabolism by MAO but also the blockade of the formation of .OH free radicals. An enhanced generation of cytotoxic .OH free radicals in the striatum which in turn leads to oxidant damage may be relevant to the development of parkinsonism- like changes in animals produced by MPTP analogues.



Neurotoxicity of levodopa on catecholamine-rich neurons

MOV. DISORD. (USA), 1992, 7/1 (23-31)

The human neuroblastoma cells NB69 are a catecholamine-rich cell line with pharmacological properties similar to dopamine neurons. This cell line was used to study the neurotoxicity of levodopa on catecholamine neurons. Levodopa, at 50 x 10-6 M or higher concentrations, produced a dose- and time-dependent reduction in the number of live cells, (3H)thymidine uptake, levels of protein and DNA, and an enhancement of the quinone formation. This is a specific effect of levodopa since it did not happen in NB69 cells incubated with equimolar concentrations of leucine and tryptophan. Treatment with deprenyl, an inhibitor of monoamine oxidase type B, partially prevented levodopa neurotoxicity, suggesting that the mechanism of toxicity was, at least in part, related to an increase in the metabolism of dopamine catalyzed by monoamine oxidase.



A review of the pharmacology of selegiline

ACTA NEUROL. SCAND. SUPPL. (Denmark), 1991, 84/136 (44-59)

Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone. Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity of MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons. Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline. Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article



Parkinson's disease: An epidemiologic method for distinguishing between symptomatic and neuroprotective treatments

CLIN. NEUROPHARMACOL. (USA), 1991, 14/6 (489-497)

Recent studies have suggested that deprenyl may exert a neuroprotective influence and thus retard progression of Parkinson's disease (PD). On the other hand, the data do not disprove that deprenyl is primarily another form of symptomatic therapy like levodopa. Longitudinal Gompertzian analysis demonstrates the absence of beneficial alteration of intrinsic or environmental influences on the epidemiology of PD mortality after the introduction of levodopa. Moreover, this method demonstrates the basis for the enhanced survival in PD that resulted from the efficacy of levodopa as symptomatic therapy. If deprenyl becomes standard therapy in PD and exerts a beneficial (neuroprotective) influence on intrinsic and environmental pathogenic mechanisms, this will become evident by a decrease in the PD mortality rate in the United States in men at age 73.4 years and in women at age 79.1 years. The ability to accurately assess the overall impact of new therapies on the general population is increasingly important in an era of upward spiraling health care costs. Longitudinal Gompertzian analysis is a simple method of detecting and distinguishing between symptomatic (competitive) and protective (intrinsic and environmental) influences on disease mortality at the population level after the introduction of new therapies.



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

CLIN. NEUROPHARMACOL. (USA), 1990, 13/1 (29-35)

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.



New approaches in the use of selegiline for the treatment of Parkinson's disease

ACTA NEUROL. SCAND. SUPPL. (Denmark), 1989, 80/126 (139-145)

Selegiline hydrochloride (deprenyl) is a safe, useful adjuvant therapy in patients with Parkinson's disease treated with L-dopa. The optimum time for its introduction into the treatment regimen of a patient remains controversial. A multi-centre long-term study being conducted by the Parkinson's Disease Research Group of the United Kingdom to attempt to answer whether selegiline improves the natural history of Parkinson's disease is discussed. In a separate study we have been unable to demonstrate that higher doses of selegiline (up to 40 mg a day) produce additional therapeutic benefit above the conventional dose of 10 mg a day in levodopa-treated patients with motor fluctuations. Preliminary data from a neuropsychological study is also presented which suggests that selegiline may have beneficial effects on the speed of psychomotor responses supporting the anecdotal clinical observations of increased mental energy and alacrity.



Two weeks of treatment with deprenyl (selegiline) does not prolong L-dopa effect in parkinsonian patients: A double-blind cross-over placebo-controlled trial

NEUROLOGY (USA), 1988, 38/9 (1387-1391)

We investigated the influence of 2 weeks of treatment with deprenyl on the acute effect of a single dose of 200 mg of L-dopa in a double-blind cross-over placebo-controlled trial in 16 parkinsonian patients with wearing-off phenomena. Deprenyl induced no significant benefite in the duration or the maximal improvement of L-dopa's effect. Moreover, deprenyl treatment did not improve the patient's motor status.



Deprenyl in the treatment of symptom fluctuations in advanced Parkinson's disease

CLIN. NEUROPHARMACOL. (USA), 1988, 11/1 ( 45-55)

Deprenyl, a selective inhibitor of monoamine oxidase, type B, which is free of the 'tyramine effect', may ameliorate symptom fluctuations in advanced Parkinson's disease (PD). We randomized 96 patients with marked symptom fluctuations at three centers to receive either deprenyl 5 mg b.i.d. or placebo in parallel fashion in addition to a previously optimized levodopa/carbidopa (Sinemet) regimen. Disability was recorded hourly at home by patients 3 days weekly during the 2-week baseline and the 6-week treatment period. Disability during the 'on' state was assessed each week by examination. Mean hourly self-assessment of gait improved in 28 of 50 patients (56%) receiving deprenyl (mean degree of improvement 0.25 points on a 0-2 scale) and in 14 of 46 (30.4%) taking placebo (mean 0.15). Mean hourly overall symptom control improved in 29 (58%) taking deprenyl (mean 0.34) and in 12 (26.1%) taking placebo (mean 0.15) (p < 0.01 for each parameter). No significant improvement occurred in the objective quality of the 'on' state with deprenyl. Mean daily Sinemet dosage decreases were 17% in the deprenyl group and 7% in the placebo group. Adverse effects included nausea, light-headedness, dyskinesias, and hallucinations, all of which abated after the Sinemet dose was reduced. We conclude that deprenyl is of moderate benefit in a majority of patients with symptom fluctuations complicating PD and is generally well tolerated.



Selegiline (1-deprenyl) and low-dose levodopa treatment of Parkinson's disease. A double-blind crossover trial

ACTA NEUROL. SCAND. (DENMARK), 1987, 76/3 (200-203)

Fifteen parkinsonian patients previously untreated with levodopa were treated with daily doses of 200 mg Madopar and randomized to addition of 10 mg selegiline (1-deprenyl) in a double-blind, placebocontrolled, crossover trial. According to the patients own evaluations 6 reported additional therapeutic effect from selegiline to Madopar; 2 reported possible additional effect, whereas a further 6 reported no improvement; 1 did not complete the trial. Statistically significant positive therapeutic effect of selegiline could not be found on Webster's rating sclare or on a sensimotoric test designed for parkinsonian disabilities. Side effects of selegiline were minimal. It is concluded that selegiline may be of some value in addition to levodopa in early treatment of parkinsonian patients, but positive therapeutic effect has to be tested individually. Even in these patients the additional therapeutic effect of selegiline to levodopa seems to be quantitatively small.



Neurochemical insights into monoamine oxidase inhibitors, with special reference to deprenyl (selegiline)

ACTA NEUROL. SCAND. (DENMARK), 1983, 68/SUPPL. 95 (43-55)

Monoamine oxidase (MAO) is distributed in neurons and nonneuronal tissue in the human central nervous system. It occurs there as MAO type A and MAO type B. It is not, however, established where both types are located intra- and/or extra-neuronally. Recently, the use of selective MAO-B blockers has shown beneficial effects in the treatment of Parkinson's disease (PD). Knowledge about the locus of action of MAO inhibitors is therefore of great importance. Our findings indicate that MAO-B inhibitors like deprenyl act by blocking neuronal and extra-neuronal MAO-B. This demonstrates that in the early stages of PD the action of deprenyl improves dopamine neurotransmission and hormonal action, whereas in the advanced stages of the disease, when there is progressive loss of dopaminergic neurons accompanied by gliosis, the drug seems to exert beneficial effects via the hormonal route.



Problems associated with long-term levodopa treatment of Parkinson's disease

ACTA NEUROL. SCAND. (DENMARK), 1983, 68/SUPPL. 95 (19-26)

Levodopa treatment improves significantly not only the parkinsonian disability but also the most morality rate. However, during long-term levodopa treatment the therapeutic benefit gradually declines. Furthermore, most cognitive skills improve initially, but long-term levodopa treatment is associated with declining intellectual capacity and dementia. In patients on long-term levodopa treatment there seems to be a low threshold for certain clinical side-effects, especially postural hypotension, psychiatric disturbances and various types of fluctations in disability. Low age at onset of Parkinson's disease, and at the commencement of levodopa therapy, the duration of levodopa treatment and a high dose of levodopa seem to be significant risk factors for the development of response fluctuations, but not the pretreatment duration of parkinson's disease nor disability of the patients. A readjustment of the levodopa dosage, and as an adjuvant drug treatment deprenyl, a specific inhibitor of MAO type B, or a direct-acting dopamine agonist may prove helpful in the management of fluctuation in disability. It is important, moreover, to try to prevent these phenomena by taking into account the predictive risk factors of response fluctuations in the treatment strategy of Parkinson's disease.



Overview of present day treatment of Parkinson's disease

J. NEURAL TRANSM. (AUSTRIA), 1978, 43/3-4 (227-238)

In the light of present day knowledge, augmenting striatal dopaminergic activity is the most effective means for controlling the symptoms of parkinsonism. This is best accomplished by the administration of levodopa with a peripheral decarboxylase inhibitor. However, limitations in its benefits develop after long-term administration in a substantial number of patients. In an attempt to overcome these a number of pharmacological agents acting on striatal dopaminergic mechanisms have undergone clinical trial. Of those tried Deprenyl, an MAO-B inhibitor, given with levodopa and carbidopa has shown the most promise. Preliminary results in 35 patients indicate that it is useful in diminishing the incidence of 'on-off' phenomena - one of the most limiting reactions to levodopa - as well as enabling some patients to recoup their loss of therapeutic benefits. Though far from resolving all of the therapeutic difficulties encountered with prolonged use of levodopa, it appears to be a valuable adjunctive agent for the long-term problem patient.



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

J. NEURAL TRANSM. (AUSTRIA), 1978, 43/3-4 (177-198)

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. With the aid of N-methyl-N-propargyl-/1-indenyl/-ammonium. HC1 (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 also stimulating the presynaptic 'autoreceptors', the activity of nigrostriatal dopaminergic neurons. (-)Deprenyl acts as a 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.