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Deprenyl Prevents Protein Oxidation

Rodriguez-Gomez JA, Venero JL, Vizuete ML, Cano J
Brain Res Mol Brain Res 1997 Jun;46(1-2):31-8

Chronic treatment of aged rats with deprenyl prevents age-induced protein oxidation in substantia nigra and protects tyrosine hydroxylase (TH) enzyme against inactivation [11]. With these precedents, we treated adult rats with deprenyl for 3 weeks in order to get further insight in the mechanism by which deprenyl exerts such actions. After completing the treatment, dopamine (DA) levels markedly increased in both striatum and substantia nigra while levels of the acid DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), decreased in the two brain areas, thus proving MAO-inhibiting properties of the treatment. We then studied the cellular expression of TH mRNA by in situ hybridization. Following treatment with deprenyl, levels of TH mRNA were significantly higher in individual dopaminergic nigral cell bodies than in those of control rats (+74%). Western blotting analysis of TH enzyme amount revealed a positive effect of the treatment in both the terminal field (+44%) and the cell body region (+31%). This correlation between TH mRNA and amount was also extended to TH enzyme activity in the two brain areas studied, which significantly increased in striatum (+57%) and substantia nigra (+35%) following deprenyl treatment. Taken together, our results clearly suggest a TH- inducing effect of deprenyl in the dopaminergic nigrostriatal system, which seems to be independent of its protective action against oxidative stress described previously. These results expand our knowledge about the beneficial effect of deprenyl in the therapy of Parkinson's disease.



Deprenyl And 'Excess Mortality'

Riggs JE
Clin Neuropharmacol 1997 Jun;20(3):276-8

Compared with the findings for an age-matched group not taking deprenyl, a higher risk of mortality in Parkinson's disease patients taking deprenyl has recently been reported. Since a biological basis for this observation was not apparent, an epidemiological explanation was sought. Expected mortality over a 6-year period in four hypothetical age-matched groups was determined. Although groups were age matched, ages of individuals within the groups varied. Variation of individual ages within each group, without affecting the age-match comparability, produced a marked variation in expected group mortality. Mortality comparisons between age-matched groups can be invalid. This epidemiological trap might account for the recent unexplained high mortality observed in a group of Parkinson's disease patients taking deprenyl.



The clinical potential of Deprenyl in neurologic and psychiatric disorders

Journal of Neural Transmission, Supplement (Austria), 1996, -/48 (85-93)

This article reviews the results of clinical studies with Deprenyl in various neurologic and psychiatric disorders except Parkinson's disease. Promising results could be observed both in narcolepsy in a dose of at least 20 mg/day in three different trials and in one study of Tourette's syndrome including attention hyperactivity disorders using an average dosis of 8.1 mg/day. Controversial results were reported for Alzheimer's disease. On the one hand significant improvement of cognitive functions was found by various authors. On the other hand in a more recent study no effect on the progression of the disease could be observed. For depression a higher dosage of deprenyl between 30 to 60 mg/day appears to be necessary for effective treatment. No positive results were found in amyotrophic lateral sclerosis and in tardive dyskinesias.



Monoamine oxidase B inhibitors. Current status and future potential

CNS Drugs (New Zealand), 1996, 6/3 (217-236)

Specific inhibitors of monoamine oxidase type B (MAO-B) constitute a novel and expanding pharmacological class. At present, only one compound from this class is marketed, selegiline (deprenyl). Other MAO-B inhibitors that are in various stages of development include lazabemide and mofegiline, which are differentiated from selegiline by their greater specificity for MAO-B and the absence of active metabolites. The role of MAO-B in the catabolism of amines (essentially, dopamine and phenylethylamine) and the acceleration of the neurodegenerative process (i.e. oxidative stress) justifies the most common indications for these compounds - Parkinson's disease, Alzheimer's disease, pathological aging and, possibly, depression. The possibility that MAO-B inhibitors may antagonise the evolution of neurodegenerative disorders needs further scrutiny. Selegiline is the most extensively studied MAO-B inhibitor and is marketed for Parkinson's disease in most Western countries. A dosage of 10 mg/day improves motor symptoms and delays the need for levodopa in de novo patients. Adverse effects are rare and trivial, although some reports of changes in blood pressure have to be considered seriously. Long term clinical trials with new MAO-B inhibitors are not available. Current data suggest that these drugs are well tolerated and have a low potential for drug interactions.



The effect of L-deprenyl on spatial short term memory in young and aged dogs

Progress in Neuro-Psychopharmacology and Biological Psychiatry (USA), 1996, 20/3 (515-530)

Young and aged dogs were tested on a spatial memory task using a delayed non matching to sample technique, Dogs were tested with 20, 70 and 110 second delay intervals. Animals were pretrained to a stable level of performance prior to treatment. 2. During treatment periods, dogs were orally administered a placebo or l-deprenyl in doses of 0.5 and 1.0 mg/kg in a repeated measures design. 3. Young dogs did not show any significant effects of l-deprenyl, however the sample size was limited. 4. L-deprenyl administration improved spatial memory in aged dogs. 5. The optimal dose or length of treatment time of I-deprenyl varied among individual dogs.



Effects of selegiline (deprenyl) on cognition in early Parkinson's disease

Clinical Neuropharmacology (USA), 1995, 18/4 (348-359)

The influence of selegiline (5 mg b.i.d.) on cognition in 20 levodopa- naive patients with early Parkinson's disease (PD) was examined in an 8- week, randomized, placebo-controlled, double-blind trial. Clinical evaluations and cognitive tests were administered at baseline and at 8 weeks; patients with PD who received placebo were also examined 8 weeks after subsequent selegiline treatment. By comparison with non-PD controls, patients with PD were impaired on the Wisconsin card sorting task and on the advanced progressive matrices test, but not in terms of their performance on the Rivermead behavioral memory test or on the rod (spatial) orientation test. Selegiline improved scores on the mentation/mood part and the activities of daily living part of the Unified Parkinson's Disease Rating Scale, but it did not improve motor scores on this test, nor did it have any clear effects on the specific neuropsychological measures that were examined.



Rationale for (-)-deprenyl (Selegiline) therapy in Parkinson's disease and Alzheimer's disease

Revista Brasileira de Neurologia (Brazil), 1995, 31/3 (131-138)

(-)Deprenil (Selegiline, Jumex, Eldepryl, Movergan), a close structural relative to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. It is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme significantly increases with age. (-)Deprenyl, the first selective inhibitor of MAO-B described in literature, has become the universally used research tool for selectively blocking B-type MAO. It is the only selective MAO-B inhibitor in clinical use. (-)Deprenyl interferes with the uptake of catecholamines and indirectly acting sympathomimetics because it is handled by the catecholaminergic neuron in a way similar to the physiological substances transported through the axonal end organ and vesicular membrane. The unique behavior of (-)deprenyl is that, in striking contrast to PEA and its relatives, it does not displace the transmitter from storage, ie, it is not a releaser. The net result is that (-)deprenyl inhibits the releasing effect of tyramine, and, at present, is the only safe MAO inhibitor than can be administered without dietary precautions. Maintenance on (-)-deprenyl selectively enhances superoxide dismutase (SOD) and catalase activity in the striatum. This effect is unrelated to its effect on MAO-B and the inhibitory effects of the drug on neurotransmitter uptake. Maintenance on (-)deprenyl facilitates the activity of the catecholaminergic system in the brain, and this effect, too, is unrelated to either its effects of MAO or on neurotransmitter uptake. (-)Deprenyl protects the nigrostriatal dopaminergic neurons against selective neurotoxins (6-hydroxy-dopamine, MPTP, DSP-4). Maintenance on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. All in all, (-)deprenyl increases the activity of the nigrostriatal dopaminergic system and slows its age-related decline. Maintenance of male rats on (-)-deprenyl delays the loss of the capacity to ejaculate, slows the decline of learning and memory, and significantly lengthens the lifespan as compared with saline-treated rats. Parkinson's disease patients on levodopa plus (-)deprenyl (10 mg daily) live significantly longer than those on levodopa alone. (-)Deprenyl is the first drug that retards the progress of Parkinson's disease. Newly diagnosed Parkinson's disease patients maintained on (-)deprenyl need levodopa significantly later than their placebo-treated peers. Maintenance on (-)deprenyl improves significantly the performance of patients with Alzheimer's disease. It is concluded that Parkinson's disease and Alzheimer's disease patients need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication. We propose that the healthy be maintained on 10-15 mg (-)deprenyl weekly starting at age 45 in order to combat the age-related decline of the nigrostriatal dopaminergic neurons. Prophylactic (-)deprenyl medication seems to offer a reasonable prospect of improving the quality of life in the later decades, delaying the time of natural death and decreasing the susceptibility of age-related neurological diseases, like Parkinson's disease and Alzheimer's disease.



Rationale for (-)deprenyl (selegiline) medication in Parkinson's disease and in prevention of age-related nigral changes

Biomedicine and Pharmacotherapy (France), 1995, 49/4 (187-195)

-(-)Deprenyl (selegiline, jumex, eldepryl, movergan), a close structural relative to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. It is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme significantly increases with age. (-)deprenyl, the first selective inhibitor of MAO-B described in literature has become the universally used research tool for selectively blocking B-type MAO. It is the only selective MAO-B inhibitor in clinical use. (-)Deprenyl interferes with the uptake of catecholamines and indirectly acting sympathomimetics because it is handled by the catecholaminergic neuron in a way similar to the physiological substances transported through the axonal end organ and vesicular membrane. The unique behavior of (-)deprenyl is that, in striking contrast to PEA and its relatives it does not displace the transmitter from storage, ie it is not a releaser. The net result is that (-)deprenyl inhibits the releasing effect of tyramine, and at present, is the only safe MAO inhibitor than can be administered without dietary precautions. Maintenance on (-)deprenyl selectively enhances superoxide dismutase (SOD) and catalase activity in the striatum. This effect is unrelated to its effect on MAO-B and the inhibitory effects of the drug on neurotransmitter uptake. Maintenance on (-)deprenyl facilitates the activity of the catecholaminergic system in the brain, and this effect, too, is unrelated to either its effects on MAO or on neurotransmitter uptake. (-)Deprenyl protects the nigrostriatal dopaminergic neurons against selective neurotoxins (6-hydroxydopamine, MPTP, DSP-4). Maintenance on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. All in all, (-)deprenyl increases the activity of the nigrostriatal dopaminergic system and slows its age-related decline. Maintenance of male rats on (-)deprenyl delays the loss of the capacity to ejaculate, slows the decline of learning and memory, and significantly lengthens the lifespan as compared with saline-treated rats. Parkinson's disease patients on levodopa plus (-)deprenyl (10 mg daily) live significantly longer than those on)levodopa alone. (-)Deprenyl is the first drug that retards the progress of Parkinson's disease. Newly diagnosed Parkinson's disease patients maintained on (-)deprenyl need levodopa significantly later than their placebo-treated peers. Maintenance on (-)deprenyl improves significantly tile performance of patients with Alzheimer's disease. It is concluded that Parkinson's disease and Alzheimer's disease patients need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication. We propose that the healthy population be maintained on 10-15 mg (-)deprenyl weekly starting at age 45 in order to combat (the age-related decline of the nigrostriatal dopaminergic neurons. Prophylactic (-)deprenyl medication seems to offer a reasonable prospect of improving the quality of life in the later decades, delaying the time of natural death and decreasing the susceptibility of age-related neurological diseases, like Parkinson's diesase and Alzheimer's disease.



Effect of long-term treatment with L-deprenyl on the age-dependent microanatomical changes in the rat hippocampus

Mechanisms of Ageing and Development (Ireland), 1995, 79/2-3 (169-185)

Chronic treatment with L-deprenyl increases both mean and maximum life span and improves cognitive functions in the aged rat. The present study was designed to evaluate whether long-term treatment with L-deprenyl at a dosage not inhibiting the monoamine oxidase-B (MAO-B) (1.25 mg/kg/day) or inhibiting the enzyme activity (5 mg/kg/day) had any effect on the age-dependent microanatomical changes in the rat hippocampus. The hippocampus was chosen in view of its key role in learning and memory functions. Treatment with L-deprenyl started at 19 months and lasted until the 24th month of age. Age-matched untreated rats were used as a control, whereas 11-month-old rats were used as an adult reference group. The number of nerve cell and glial fibrillary acidic protein-immunoreactive astrocyte profiles in the CA1 and CA3 fields of the hippocampus and in the dentate gyrus was decreased and increased, respectively in aged compared with adult rats. Treatment with 5 mg/kg/day, but not with 1.25 mg/kg/day L-deprenyl increased the number of neuronal profiles and decreased the number of astrocytes in the hippocampus of aged rats. The density of zinc stores in the associative intrahippocampal pathway of messy fibres, which was decreased in aged animals, was increased after treatment with the two doses of L-deprenyl. Lipofuscin accumulation within the cytoplasm of pyramidal neurons of the hippocampus was reduced dose dependently by L-deprenyl treatment. These results suggest that long-term treatment with L-deprenyl is able to counter the expression of age-dependent microanatomical changes in the rat hippocampus. These effects seem only partially correlated with the MAO-B inhibitory activity of L-deprenyl.



Therapy with l-deprenyl (selegiline) and relation to abuse liability

CLIN. PHARMACOL. THER. (USA), 1994, 56/6 II SUPPL. (750-756)

This article briefly reviews the clinical aspects and rationale for therapy with l-deprenyl for several neuropsychiatric conditions, including major depression, Alzheimer's disease, and Parkinson's disease. The rationale for the use of l-deprenyl in these conditions is discussed, and evidence for efficacy is reviewed. Lastly, there is a review of the lack of evidence for l-deprenyl's abuse potential and its use as putative nonspecific cognitive enhancer, a so-called 'smart drug'. Although l-deprenyl itself appears to have no abuse potential, it is theoretically possible that it might potentiate the actions and frequency of dosage and use of various drugs of abuse or dependence. This is as yet an underresearched area, and more work is required.



The interaction of L-deprenyl and scopolamine on spatial learning/memory in rats

J. NEURAL TRANSM. PARKINSON'S DIS. DEMENTIA SECT. (Austria), 1993, 6/3 (189-197)

L-Deprenyl, a specific MAO-B inhibitor, has been reported to improve learning/memory in some cognitive tests in aged rats. The present study investigated whether L-deprenyl could alleviate the spatial learning deficit induced by muscarinic blockade and aging in OFA rats. Scopolamine (0.25 mg/kg) impaired the acquisition of a water maze task in adult rats and increased their swimming speeds. L-Deprenyl (0.25 mg/kg, 14 days) had no effect on water maze performance in saline treated adult rats, but markedly alleviated the learning deficit induced by scopolamine and increased the time and distance of swimming in the training quadrant when the platform was removed (spatial probe trial). L-Deprenyl partly reduced the effect of scopolamine on speed of swimming. Nevertheless, administration of l-deprenyl (0.25 mg/kg, 14 days) had no effect on spatial learning/memory in aged rats. We suggest that the l-deprenyl - scopolamine interaction in the water maze test may be considered as a premise for further investigations of l-deprenyl as cognition enhancer.



The pharmacological basis of the beneficial effects of (-)deprenyl (selegiline) in Parkinson's and Alzheimer's diseases

J. NEURAL TRANSM. SUPPL. (Austria), 1993, -/40 (69-91)

(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), structurally closely related to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. It is a highly potent and selective irreversible inhibitor of B- type monoamine oxidase (MAO) and interferes with the uptake of catecholamines and indirectly acting symphathomimetics. In striking contrast to PEA and its relatives, which displace the transmitter from the storage places, (- )deprenyl inhibits the releasing effect of tyramine and is up to the present the only safe MAO inhibitor which can be administered without dietary restrictions. Maintenance on (-)deprenyl enhances selectively superoxide dismutase (SOD) and catalase activities in the striatum. This effect is unrelated to the MAO and uptake inhibitory effects of the drug. Maintenance on (-)deprenyl facilitates the activity of the nigrostriatal dopaminergic neurons with remarkable selectivity and this effect too, is unrelated to either the MAO or the uptake inhibitory effects of the drug. Maintenance on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. As a consequence of its complex spectrum of activity male rats maintained on (- )deprenyl live longer, lose their capacity to ejaculate later, show improved performance in learning tests and maintain this activity for a longer period than their untreated peers. Patients with Parkinson's disease maintained on levodopa plus (-)deprenyl (10 mg daily) live significantly longer than those on levodopa alone. Freshly diagnosed patients treated with (-)deprenyl need levodopa later than their placebo-treated peers. Continuous administration of (-)deprenyl improves the performance of patients with Alzheimer's disease.



An interim report of the effect of selegiline (L-deprenyl) on the progression of disability in early Parkinson's disease

EUR. NEUROL. (Switzerland), 1992, 32/SUPPL. 1 (46-53)

The pathogenesis of Parkinson's disease (PD) has been linked to oxidative-mediated events including increased monoamine oxidase (MAO) and free-radical generation. We are investigating the ability of the MAO inhibitor, selegiline (deprenyl), and of the free-radical scavenger, tocopherol, to delay the onset of disability requiring levodopa therapy (primary end point) in patients with early PD. Eight hundred patients with early, untreated PD were enrolled in the multi-center placebo-controlled, double-blind clinical trial 'Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP)'. Subjects were assigned by 2 x 2 factorial design to receive selegiline (10 mg/day), tocopherol (2,000 IU/day), a combination of both drugs, or placebo, and followed to determine if and when disability occurred requiring levodopa therapy. After 12 plus or minus 5 months of observation, independent monitoring prompted a preliminary analysis indicating that selegiline 10mg/day significantly extended the time to the primary end point. Selegiline therapy, alone or in combination with tocopherol, resulted in a 57% reduction in the rate of developing disability requiring levodopa therapy (p < 10-10) and a 50% reduction in the rate of loss of full-time employment (p = 0.01). Deterioration of motor and mental features was significantly less in selegiline-treated subjects. Adverse effects were minor and infrequent. We conclude from these preliminary results that selegiline (10 mg/day) delays the onset of disability associated with early, otherwise untreated PD. It remains unclear whether these benefits derive from mechanisms that are symptomatic (dopaminergic), protective (anti-neurotoxic), or both. The DATATOP study is ongoing to examine the long-term effects of selegiline and the independent and interactive effects of tocopherol.



Pharmacological basis of the therapeutic effect of (-)deprenyl in age-related neurological diseases

MED. RES. REV. (USA), 1992, 12/5 (505-524)

(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), a close structural relative to phenylethylamine (PEA), is a drug of a unique pharmacological spectrum. (a) It is highly potent and selective irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain, the activity of which significantly increases with age. (-)Deprenyl was the first selective inhibitor of MAO-B described in literature, became the worldwide research tool used for blocking selectively B-type MAO, and is still the only MAO-B inhibitor in clinical use. (b) (-)Deprenyl interferes with the uptake of catecholamines and indirectly acting sympathomimetics because it is handled by the catecholaminergic neuron similarly to the physiological substances transported through the axonal end-organ and vesicular membrane. The unique behavior of (-)deprenyl is that, in striking contrast to PEA and its relatives, it does not push the transmitter from the storage places, i.e., it is not a releaser. The net result is that (-)deprenyl inhibits the releasing effect of tyramine and is presently the only safe MAO inhibitor which can be administered without dietary restrictions. (c) Maintenance on (-)deprenyl enhances selectively superoxide dismutase (SOD) and catalase activity in the striatum. This effect is unrelated to the MAO and uptake inhibitory effects of the drug. (d) Maintenance on (-)deprenyl facilitates the activity of the nigrostriatal dopaminergic neurons with remarkable selectivity. This effect is also unrelated to either the MAO or the uptake inhibitory effects of the drug. All in all, (-)deprenyl maintains the activity of the nigrostriatal dopaminergic machinery on a higher activity level and slows down its age-related decline. Male rats maintained on (-)deprenyl lost their capacity to ejaculate later, retained their learning ability longer, and lived longer than their saline-treated peers. Parkinsonians on levodopa plus (-)deprenyl (10 mg daily) lived significantly longer than those on levodopa alone. (-)Deprenyl is the first drug which retards the progress of Parkinson's disease. Freshly diagnosed parkinsonians maintained on (-)deprenyl did not require levodopa until significantly later than their placebo-treated peers. Maintenance on (-)deprenyl significantly improved the performance of patients with Alzheimer's disease. It is concluded that in Parkinson's disease and Alzheimer's disease patients need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication. The healthy population is proposed to be maintained on 10-15 mg (-)deprenyl weekly from age 45 in order to fight against the age-related decline of the nigrostriatal dopaminergic neurons, the hitherto known most rapidly aging neurons in the brain. Prophylactic deprenyl medication seems to bid fair prospects, on the one hand, to an improved quality of life in the latter decades with hopes to a shift in the time of natural death, and on the other hand, to a decreased susceptibility to agerelated neurological diseases.



(-)Deprenyl-medication: A strategy to modulate the age-related decline of the striatal dopaminergic system

J. AM. GERIATR. SOC. (USA), 1992, 40/8 (839-847)

(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), a close structural relative to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. (1) It is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme significantly increases with age. (-)Deprenyl, the first selective inhibitor of MAO-B described in literature, has become the universally used research tool for selectively blocking B-type MAO. It is the only MAO-B inhibitor in clinical use. (2) (-)Deprenyl interferes with the uptake of catecholamines and indirectly acting sympathomimetics because it is handled by the catecholaminergic neuron in a way similar to the physiological substances transported through the axonal end organ and vesicular membrane. The unique behavior of (-)deprenyl is that, in striking contrast to PEA and its relatives, it does not displace the transmitter from storage, ie, it is not a releaser. The net result is that (-)deprenyl inhibits the releasing effect of tyramine, and, at present, is the only safe MAO inhibitor that can be administered without dietary precautions. (3) Maintenance on (-)deprenyl selectively enhances superoxide dismutase (SOD) and catalase activity in the striatum. This effect is unrelated to its effect on MAO-B and the inhibitory effects of the drug on neurotransmitter uptake. (4) Maintenance on (- )deprenyl facilitates the activity of the nigrostriatal dopaminergic neurons with remarkable selectivity, and this effect, too, is unrelated to either its effects on MAO or on neurotransmitter uptake. (5) Maintenance on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. All in all, (-)deprenyl increases the activity of the nigrostriatal dopaminergic system and slows its age-related decline. Maintenance of male rats on (-)deprenyl delays the loss of the capacity to ejaculate, slows the decline of learning and memory, and significantly lengthens the life-span as compared with saline-treated rats. Parkinson's disease patients on levodopa plus (- )deprenyl (10 mg daily) live significantly longer than those on levodopa alone. (-)Deprenyl is the first drug that retards the progress of Parkinson's disease. Newly diagnosed Parkinson's disease patients maintained on (- )deprenyl need levodopa significantly later than their placebo-treated peers. Maintenance on (-)deprenyl improves significantly the performance of patients with Alzheimer's disease. It is concluded that Parkinson's disease and Alzheimer's disease patients need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication. We propose that the healthy population be maintained on 10-15 mg (-)deprenyl weekly starting at age 45 in order to combat the age-related decline of the nigrostriatal dopaminergic neurons. Prophylactic (-)deprenyl medication seems to offer a reasonable prospect of improving the quality of life in the later decades, delaying the time of natural death and decreasing the susceptibility of age- related neurological diseases.



Monoamine oxidase inhibitors: Reversible and irreversible

PSYCHOPHARMACOL. BULL. (USA), 1992, 28/1 (45-57)

Coincident with and in part fueling advances in diagnostic nosology and drug development, the recent resurgence of interest in monoamine oxidase inhibitors (MAOIs) is reviewed. Accidentally discovered nearly 40 years ago as the first true antidepressants, the MAOIs soon fell into disfavor due to concerns about toxicity and seemingly lesser efficacy compared with the newer tricyclic compounds. Now that we have better understanding of the nature of the hypertensive and hyperpyrexic interactions of MAOIs with other substances, these medications have assumed a role in the treatment of nonendogenous depressive and anxiety syndromes, especially in operationally defined 'atypical depression.' The discovery of two MAO isoenzymes has resulted in a new generation of selective inhibitors in the search for enhanced efficacy (i.e., clorgyline) or safety (i.e., I-deprenyl). Most promising is the emerging class of reversible selective MAO-type A inhibitors, such as moclobemide, which combine antidepressant potency with freedom from the risk of dangerous tyramine-type adverse interactions.



The pharmacological profile of (-)deprenyl (selegiline) and its relevance for humans: A personal view

PHARMACOL. TOXICOL. (Denmark), 1992, 70/5 I (317-321)

(-)Deprenyl (selegiline, jumex, eldepryl, movergan) which is closely related to phenylethylamine (PEA) is a drug with a unique pharmacological spectrum. Single dose effects: (a) It is a highly potent and selective inhibitor of B-type monoamine oxidase (MAO). (b) In contrast to other MAO inhibitors it inhibits the noradrenaline releasing effect of tyramine, is therefore free of the 'cheese effect'. Multiple dose effects unrelated to MAO inhibition: (a) It enhances superoxide dismutase and catalase activity in the striatum. (b) It facilitates the activity of the nigrostriatal dopaminergic neurones. (c) It prevents age-related morphological changes in the neurocytes of the substantia nigra. Consequences of multiple dose effects: Compared to salt solution-treated rats, male rats maintained on (-)deprenyl loose their capacity to ejaculate later on; retain for longer their learning ability; and live longer. Freshly diagnosed Parkinson's patients maintained on (-)deprenyl, require levodopa later than their placebo-treated peers. Patients treated with levodopa plus (-)deprenyl live longer than those on levodopa alone. Chronic treatment with (-)deprenyl improves the performance of patients with Alzheimer's disease.



L-deprenyl therapy improves verbal memory in amnesic alzheimer patients

CLIN. NEUROPHARMACOL. (USA), 1991, 14/6 (523-536)

Altered monoaminergic neurotransmission could play an important role in the cognitive dysfunctions typical of dementia of the Alzheimer type (DAT). DAT is not, however, a homogenous phenomenon inasmuch as two forms are distinguishable: early onset (EO) and late onset (LO). Moreover, focal patterns of neuropsychological deterioration fall into various subgroups. According to our hypothesis, DAT patients, who at the onset of the disease mainly manifest memory disorders, also represent a specific subgroup characterized by impaired cortically projecting catecholaminergic pathways. In a 6-month randomized, double-blind, cross-over study versus placebo we analysed the influence of L-deprenyl on the verbal memory of 19 amnesic EO-DAT patients. Verbal memory was assessed by means of the Rey Auditory Verbal Learning Test. The results obtained show significantly better performances for L-deprenyl treated patients in learning and long-term memory skills. We suggest that L-deprenyl, through selective inhibition of MAO-B and by increasing the activity of the catecholaminergic systems, positively influences cognitive functions and behaviour founded on memory efficiency.



A pilot study of low-dose L-deprenyl in Alzheimer's disease

J. GERIATR. PSYCHIATRY NEUROL. (USA), 1991, 4/3 (143-148)

The use of low-dose L-deprenyl, a selective MAO-B inhibitor, in Alzheimer's disease patients has been associated previously with improvements in agitation and episodic learning and memory. Behavioral, cognitive, and regional electroencephalogram (EEG) measures were obtained in a 4-week open pilot study of 14 patients with probable Alzheimer's disease by NINCDS criteria who were administered 10 mg L-deprenyl per day. L-Deprenyl administration was associated with significant improvements on the agitation and depression factors of the Brief Psychiatric Rating Scale, the Cornell Scale for Depression in Dementia, and spouses' blind ratings. Recall improved on the Buschke Selective Reminding Task, but intrusions also tended to increase; verbal fluency decreased. Absolute EEG delta measures were selectively suppressed in the right frontal region. The pattern of changes suggests that L-deprenyl may be associated with improvement in behavioral and cognitive performance, in part through a mild behavioral disinhibiting effect.



Potential applications for monoamine oxidase B inhibitors

DEMENTIA (Switzerland), 1990, 1/6 (323-348)

Monoamine oxidase inhibitors (MAOIs) are not only effective antidepressants, but also have several other applications. Yet, they are infrequently used as result of their potential to cause toxic side effects such as tyramine-induced hypertensive crisis (cheese effect). A resurgence of interest in MAOIs followed the finding of two forms of MAO. This resulted from the development of drugs that selectively inhibit the metabolism of serotonin and norepinephrine (MAO-A) or dopamine and phenethylamine (MAO-B). MAO-B is the predominant MAO found in the human brain. Theoretically, selective MAO-B inhibition can enhance brain MAO levels while leaving intestinal MAO-A intact, thus bypassing the cheese effect. L-deprenyl is the most extensively studied MAO-B inhibitor. At low doses, it is very selective for MAO-B and is not associated with the cheese effect. At higher doses, it is virtually nonselective. L-deprenyl enhances the effect of L-dopa on Parkinson's disease and may retard its natural progression. Although studies have found L-deprenyl to be an effective antidepressant only at nonselective doses, certain subtypes of depression may respond to selective doses. Also, evidence suggests that L-deprenyl has a positive effect on the general function and cognitive abilities of Alzheimer patients. Studies to date, including those showing a significant increase in the life span of rats following L-deprenyl use have led to the speculation that L-deprenyl may not only treat or retard degenerative diseases and acute brain insults, but may prove to be the first antiaging medication. Several other potential applications of MAO-B inhibitors include panic, ADHD, sexual dysfunction, and PTSD. It remains unclear what role MAO-B inhibition plays in the various therapeutic effects of L-deprenyl. Other potential mechanisms are discussed.



Monoamine oxidase and dementia: Treatment with an inhibitor of MAO-B activity

DEMENTIA (Switzerland), 1990, 1/2 (109-114)

Patients suffering from Alzheimer type dementia have demonstrated an increase in MAO-B activity. Treatment of these patients with an inhibitor of the monoamine oxidase activity, such as L-Deprenyl (LD), might therefore provide a valid therapeutic intervention. The efficacy of LD was examined in a double-blind, drug versus placebo (PL) study on 20 patients diagnosed between stages 3 and 5 of primary degenerative dementia. Treatment duration was 90 days (5 mg twice a day). All patients underwent clinical, behavioral, and memory evaluations every 30 days. Subjects in the LD group demonstrated an improvement on both attention and memory measures; some of the changes were apparent after only 30 days of treatment. PL patients showed no such improvement and also evidenced a decrease in behavior efficiency during the experimental period. Two patients dropped out of the study, 1 from each treatment group. No differences were found in either the type and number of concomitant treatments or side effects between groups.



Neuropsychological effects of L-deprenyl in Alzheimer's type dementia

CLIN. NEUROPHARMACOL. (USA), 1990, 13/2 (147-163)

The monoaminergic neurotransmission defect seen in dementia of the Alzheimer type (DAT) is linked to a known increased activity of type B cerebral monoamine oxidase (MAO-Bs). The use of drugs that are able to block this abnormal activity could therefore be useful in the treatment of some cognitive deficits that characterize DAT. Twenty patients with a clinical diagnosis of DAT and with a slight-moderate mental deterioration were treated with 10 mg/day of L-deprenyl, a selective MAO-B inhibitor, according to a double-blind crossover design vs. placebo. Initial treatment (drug or placebo) was randomly assigned. The patients' cognitive functions were evaluated at baseline and then after 3 and 6 months of treatment with drug or placebo. The patients crossed over treatment after 3 months, without a washout interval. The results of the study show the higher and statistically significant effects of L-deprenyl on memory and attention that seem to be due to an improved function of the monoaminergic systems involved in the process of neuronal degeneration.



The effect of R-(-)-deprenyl in de novo parkinsonian patients pretreated with levodopa and decarboxylase inhibitor correlated to depression and MHPG, HIAA and HVA levels in the cerebrospinal fluid

ACTA NEUROL. SCAND. SUPPL. (Denmark), 1989, 80/126 (153-156)

The effectiveness and tolerability of deprenyl as an adjunct in the therapy of parkinsonism was studied in a double-blind trial comprising 30 de novo patients. Two thirds of the cases that could be evaluated showed a statistically significant improvement while on adjuvant deprenyl therapy. The improvements are shown in the replugging test, a subtest of the Motor Performance Test, and on the Columbia University Rating Scale. There is no statistically significant correlation between improvement of motor response and depression. Deprenyl seems to be less effective in patients with low contents of HIAA and HVA in the cerebrospinal fluid.



Effects of monoamine oxidase inhibitors on levels of catechols and homovanillic acid in striatum and plasma

NEUROPHARMACOLOGY (United Kingdom), 1989, 28/8 (791-797)

Levels of homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG) in plasma and the striatum were measured after inhibition of monoamine oxidase type A (MAO-A) by clorgyline (4 mg/kg i.p.), MAO-B by (-)deprenyl (1 mg/kg i.p.), both MAO-A and MAO-B by nialamide (75 mg/kg i.p.) or peripheral neuronal MAO by debrisoquin (40 mg/kg i.p.). Levels of HVA in plasma decreased by about 60% after single doses of nialamide or clorgyline, by about 80% after repeated doses of nialamide, by about 40% after a single dose of debrisoquin and by about 50% after repeated doses of debrisoquin. The administration of clorgyline, nialamide or debrisoquin significantly decreased concentrations of DOPAC and DHPG in plasma, whereas (-)deprenyl did not affect levels of DHPG or HVA. None of the MAO inhibitors produced more than about 80% depression of levels of any of the deaminated metabolites. The results suggest that most of the HVA in plasma is derived from deamination of DA by MAO-A in peripheral neurons; that DOPAC in plasma is derived from cells outside the central nervous system; that DHPG in plasma is derived virtually exclusively from the metabolism of norepinephrine in sympathetic nerve endings and that residual levels of HVA after treatment with debrisoquin provide an improved but limited indication of central dopaminergic activity.



Selective inhibition of MAO-A, not MAO-B, results in antidepressant-like effects on DRL 72-s behavior

PSYCHOPHARMACOLOGY (Germany, Federal Republic of), 1988, 96/2 (153-160)

The effects of monoamine oxidase inhibitors (MAOIs) that selectively inhibit the MAO-A or MAO-B forms of MAO were studied in rats performing under a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement. Clorgyline and CGP11'305A, irreversible and reversible MAO-A inhibitors, respectively, increased the reinforcement rate, decreased the response rate, and enhanced temporal discrimination. The irreversible MAO-B inhibitor (-)-deprenyl did not produce similar effects. Pargyline did not increase the reinforcement rate at low doses that selectively inhibit MAO-B, but did increase the reinforcement rate at doses that inhibit MAO-A by more than 90%. The present results are in accord with clinical data demonstrating that MAO-A inhibitors are effective therapeutic agents in treating depression while MAO-B inhibitors are of questionable antidepressant efficacy. The present findings provide further evidence that the DRL 72-s schedule may be useful both as a screen for identifying new antidepressants and for investigating the neurochemical effects of antidepressant drugs that are responsible for their therapeutic effects.



Brief information on an early phase-II-study with deprenyl in demented patients

PHARMACOPSYCHIATRY (Germany, Federal Republic of), 1987, 20/6 (256-257)

Eleven elderly female patients (73-88 yrs) suffering from senile dementia of Alzheimer type (7 cases) and from multi-infarct dementia (4 cases) were treated wth (-) deprenyl (Jumex (R)) for 3 and 6 months respectively. Improvement was most frequent in SDAT patients and most pronounced as regards self-care, short-term memory, mental alertness and uncooperativeness.



L-Deprenyl in Alzheimer's disease. Preliminary evidence for behavioral change with monoamine oxidase B inhibition

ARCH. GEN. PSYCHIATRY (USA), 1987, 44/5 (427-433)

Since monoamine neurotransmitter disturbances exist in some cases of dementia of the Alzheimer's type (DAT), monoamine-enhancing drugs may ameliorate some symptoms of DAT. L-Deprenyl is a monoamine oxidase (MAO) inhibitor that is generally free of undesired effects. At low doses (10 mg/d) it selectively inhibits MAO-B, an enzyme whose level is elevated in the brains of patients with DAT who are studied post mortem. At higher doses it has more complex effects, including inhibition of MAO-A plus MAO-B. We administered 10 mg/d and 40 mg/d of L-deprenyl to 17 patients with DAT in a double-blind, placebo-controlled, serial treatment. Total Brief Psychiatric Rating Scale scores decreased significantly during 10-mg/d treatment, with descreases in measures of anxiety/depression, tension, and excitement. Approximately one half of the patients' conditions were judged to be improved clinically, with evidence of increased activity and social interaction along with reduced tension and retardation. Similar but smaller changes were observed during 40-mg/d treatment. The behavioral changes were associated with improvement in performance on a complex cognitive task requiring sustained effort. There were minimal physiologic and side effects. The greater effect of low-dose L-deprenyl therapy suggests that it is the inhibition of MAO-B, and not MAO-A, that may be important in the behavioral effects of L-deprenyl administration to patients with DAT.



Cognitive effects of L-deprenyl in Alzheimer's disease

PSYCHOPHARMACOLOGY (GERMANY, WEST), 1987, 91/4 (489-495)

Monoamine neurotransmitter systems, along with cholinergic systems, are known to play important roles in cognition, and are disrupted in at least some patients with dementia of the Alzheimer type (DAT). This suggests that monoamine-enhancing drugs might ameliorate cognitive symptoms in certain patients with DAT. L-Deprenyl is a monoamine oxidase (MAO) inhibitor which may selectively inhibit MAO-B at low doses, while at high doses it nonselectively inhibits MAO-A as well as MAO-B. We studied its effects on several types of cognitive function in 17 patients with DAT. Two doses of L-deprenyl (10 mg/day and 40 mg/day) and placebo were compared in a double-blind, serial treatment design. Episodic learning and memory, knowledge memory, attention, recognition, and performance on a continuous performance task were assessed at baseline and under these drug and placebo conditions. Statistically significant improvement was noted in performance on an episodic memory and learning task requiring complex information processing and sustained conscious effort during treatment with L-deprenyl 10 mg/day. Knowledge memory, intrusions, and other cognitive functions relevant to DAT were not altered by L-deprenyl at either dose.



Modification of serotonergic and noradrenergic neurotransmissions by repeated administration of monoamine oxidase inhibitors: Electrophysiological studies in the rat central nervous system

J. PHARMACOL. EXP. THER. (USA), 1986, 237/3 (987-994)

The net effect of repeated administration of monoamine oxidase inhibitors (MAOI) on central serotonergic (5-HT) and noradrenergic (NE) neurotransmissions was studied by assessing the responsiveness of hippocampal pyramidal neurons to microiontophoretically applied 5-HT and NE and the response of these neurons to the electrical activation of the 5-HT and NE ascending pathways. Brain monoamine oxidase (MAO) activity as well as the levels of 5-HT, NE and their metabolites were determined in order to verify the biochemical effects of the drugs administered. Twenty-one-day treatments with clorgyline and deprenyl inhibited very selectively MAO-A and MAO-B, respectively, whereas a treatment with phenelzine inhibited both forms of the enzyme. Whole brain concentrations of 5-HT and NE were increased by the antidepressant drugs clorgyline and phenelzine whereas deprenyl, an MAOI type B ineffective in endogenous depression, increased only NE levels after a 21-day treatment. The responsiveness of hippocampal pyramidal neurons to 5-HT was decreased by the long-term clorgyline treatment, but not by deprenyl and phenelzine, whereas that to NE was not altered by any of the treatments. The suppression of firing of these same neurons induced by the stimulation of the 5-HT pathway was increased by clorgyline and phenelzine, but not by deprenyl. The effect of the stimulation of the dorsal NE bundle was not modified by any of the treatments. These data show that prolonged inhibition of MAO-A, but not that of MAO-B, results in an enhanced 5-HT neurotransmission. Because 5-HT, but not NE neurons, progressively recover their normal firing rate during sustained MAO-A inhibition, the enhancement of 5-HT neurotransmission rather than the reduction of NE neurotransmission is more likely to be related to the delayed antidepressant effect of MAOI.



Tyramine pressor sensitivity changes during deprenyl treatment

PSYCHOPHARMACOLOGY (GERMANY, WEST), 1985, 86/4 (432-437)

Deprenyl has previously been reported to be a selective monoamine oxidase (MAO) type B inhibitor, which is associated with little or no enhancement of the pressor effects of tyramine. Employing an intravenous steady-state tyramine infusion technique, the effects of different doses of deprenyl and, for comparison, the mixed inhibitor tranycypromine on the pressor response to tyramine were studied in 11 depressed patients. After 3 weeks of treatment, deprenyl produced dose-proportionate increases in tyramine sensitivity at all three doses (10, 30, and 60 mg/day) when compared to placebo baseline tyramine responses. While only a modest (3.7-fold) increase in tyramine sensitivity was found with the 10 mg/day deprenyl dose, the increase in tyramine sensitivity at the 60 mg/day dose of deprenyl (22-fold) approached that found with tranylcypromine. Reductions in plasma 3-methoxy,4-hydroxyphenylglycol (MHPG), used as a possible index of in vivo MAO-A inhibition, were highly correlated with increases in tyramine pressor sensitivity (r = 0.82). The data suggest that deprenyl acts as a relatively selective MAO-B inhibitor at low doses, but that this selectivity is lost at higher doses, resulting in a significant 'crossover' inhibition of MAO-A and increased tyramine pressor sensitivity.



The facilitation of dopaminergic activity in the aged brain by (-)deprenyl. A proposal for a strategy to improve the quality of life in senescence

MECH. AGEING DEV. (IRELAND), 1985, 30/2 (109-122)

In the aging brain there is a loss of neurons compensated for by a proliferation of glial cells. Because of the increased B-type monoamine oxidase (MAO) activity present in the glia, dopaminergic and 'trace aminergic' modulation in the brain declines in senescence. The significant increase in the incidence of depression in the elderly, the age-dependent decline in male sexual vigor and the frequent appearance of parkinsonian symptoms in the latter decades of life might be attributed to a decrease of dopamine and 'trace amines' in the brain. The outlines of a drug strategy to counteract these biochemical lesions of aging by chronic administration of (-)deprenyl (Jumex(Reg.trademark), Eldepryl(Reg.trademark)), a selective inhibitor of B-type MAO, which facilitates dopaminergic and 'trace-aminergic' activity in the brain, are forwarded. The restitution and long-term maintenance of full scale sexual activity in aged male rats continuously treated with (-)deprenyl and the clinical observation that this drug prolongs in a statistically significant manner, the duration of the Parkinson's disease support the view that (-)deprenyl may improve deteriorating functions due to dopamine deficiency in the aging brain.



l-Deprenyl in atypical depressives

ARCH. GEN. PSYCHIATRY (USA), 1984, 41/8 (777-781)

We investigated the antidepressant efficacy of l-deprenyl (selegiline), a selective monoamine oxidase B inhibitor (MAOl), in a six-week open trial of 17 patients with atypical depression. Such patients have previously been shown to benefit from nonselective MAOls such as phenelzine sulfate. Ten patients (59%) responded to l-deprenyl, but nine required dosages above the 10 to 20 mg/day used in previous investigations. l-Deprenyl was superior to six weeks of placebo administered to diagnostically similar patients in a separate double-blind study. In contrast with previous findings with phenelzine, responders to l-deprenyl differed from nonresponders by having lower baseline anxiety ratings. Even at high dosages, there appeared to be fewer side effects with l-deprenyl than with nonselective MAOls.



The effect of deprenyl (selegiline) on cognition and emotion in parkinsonian patients undergoing long-term levodopa treatment

ACTA NEUROL. SCAND. (DENMARK), 1983, 68/SUPPL. 95 (135-144)

The effects of deprenyl on memory, other cognitive functions, vigilance and emotional processes were investigated in seven parkinsonian patients undergoing long-term levodopa treatment. The patients were selected on the basis of their cognitive impairment, observed during a follow-up study of 8-10 years. Four of the patients had progressive dementia and three did not. After deprenyl treatment lasting 4 weeks, there were two patients of responses. Patients with slow progressive dementia failed to respond to treatment, whereas patients without progressive impairment tended to show improvement in memory and motor speed; the former group also showed more emotional changes than the latter. Typical responses in all patients treated with deprenyl were: increased arousal, paradoxical spells of tiredness, deterioration in vigilance and in set shifting, but improvement of parkinsonian disability. These preliminary findings indicate that there is a dissociation between pure motor responses and cognitive as well as other behavioural responses to deprenyl. It is probable that although enhanced availability of dopamine by MAO-B-inhibition partly explains the present neuropsychological findings, also other brain mechanisms are involved.



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

ACTA NEUROL. SCAND. (DENMARK), 1983, 68/SUPPL. 95 (127-133)

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.



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

ACTA NEUROL. SCAND. (DENMARK), 1983, 68/SUPPL. 95 (123-126)

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 alleviation of dyskinesia and depression. In four further patients with a post-tramuatic parkinsonian syndrome, no improvement of rigidospasticity and vigilance was demonstrable.



L-deprenyl plus L-phenylalanine in the treatment of depression

J. NEURAL TRANSM. (AUSTRIA), 1984, 59/1 (81-87)

The antidepressive efficacy of 1-deprenyl (5-10 mg daily) plus 1-phenylalanine (205 mg/day) has been evaluated in 155 unipolar depressed patients. Both oral and intravenous administration showed beneficial effects in 90% of outpatients and 80.5% of inpatients. It is concluded that this combined treatment has a potent antidepressive action based on the accumulation of 1-phenylethylamine in the brain.



L-deprenyl, a selective monoamine oxidase type-b inhibitor in endogenous depression

LIFE SCI. (ENGLAND), 1980, 26/11 (877-882)

In a group of 12 endogenously depressed patients who failed to respond to a week of placebo medication, L-deprenyl, a selective type-B monoamine oxidase inhibitor, produced a significant improvement over the whole range of depressive symptomatology. This is the first reported study of the antidepressant properties of L-deprenyl using a lower dose range, where both selective inhibition of type-B monoamine oxidase (MAO) would occur and the patient would be protected from the hypertensive cheese reaction. The possibility of an MAO inhibitor relatively free from the risk of a cheese reaction and yet an effective antidepressant would be a valuable new therapeutic agent. In addition, monitoring the degree of inhibition of platelet MAO may be a useful way of determining the therapeutic dosage for individual patients.



Effects of selective monoamine oxidase (MAO) inhibitors on conditioned avoidance responses (CAR) of rats

POL. J. PHARMACOL. PHARM. (POLAND), 1979, 31/4 (251-260)

Dopamine (DA) insufficiency in the ipsilateral corpus striatum produced by unilateral electrolytic lesion of the substantia nigra (SN) resulted in an impairment in rats' behavior as tested by one-way and two-way avoidance techniques. Selective MAO-A inhibitor, clorgyline (1 mg/kg sc daily for 7 days), improved the reduced learning capacity of SN lesioned animals, restored the decreased DA content in the corpus striatum, and caused significant hyperactivity as tested in the open field. At the same time the selective MAO-B inhibitor (-)deprenyl (injected the same way) proved to be ineffective. J-508, a selective MAO-B inhibitor, used in a non-selective dose (1 mg/kg), acted like clorgyline. The results support the hypothesis that in the rat nigrostriatal system (but not in human beings) DA is preferentially deaminated by the A form of MAO.



Deprenyl in Parkinson's disease

LANCET (ENGLAND), 1977, 2/8042 (791-795)

In a double-blind crossover trial, (-)-deprenyl, a fast-acting selective monoamine oxidase-B inhibitor without a 'cheese effect', was given to 41 patients with idiopathic Parkinson's disease who were receiving maximum tolerated doses of levodopa either alone or combined with carbidipa carbidopa In a dose of 10 mg, daily or on alternate days, (-)-deprenyl prolonged the therapeutic effect of levodopa and was effective in mild 'on-off' disabilities with end-of-dose akinesia; the majority of patients with nocturnal and early-morning akinesia also improved. No statistically significant improvement occurred in diurnal akinesia, and there was no improvement in patients with severe on-off disabilities with freezing and rapid oscillations ('yo-yo' effect). Levodopa-induced dyskinesias were aggravated in 14 patients. In 5 previously untreated patients, (-)-deprenyl alone gave no benefit, but when it was used with levodopa and carbidopa a mean dosage reduction of 200 mg levodopa daily was possible. Depression, present in 15 patients, was unchanged. (-)-Deprenyl in combination with smaller total daily doses of levodopa and a peripheral decarboxylase inhibitor may prove useful in reducing the frequency and severity of some types of on-off effect with overall benefit comparable to that obtained with larger doses of levodopa.



The effect of selective MAO inhibitors on the conditioned avoidance response of Wistar rats

POL.J.PHARMACOL.PHARM. (POLAND), 1977, 29/3 (291-296)

Behavioral and biochemical effects of 1-deprenyl and clorgyline were studied in Wistar rats. Behavioral performances was tested in a one-way and in a two-way avoidance system. The two MAO inhibitors were given acutely (1 and 10 mg/kg sc) and chronically (1 mg/kg sc/daily, for 7 days), and their effect on learning and retention performance was tested 24 hr after the last injection. Behavioral reactions remained unchanged after acute administration of the inhibitors, while they were significantly improved following the chronic treatments, either in the one-way or in the two-way experimental situation. Biochemical analysis indicated dissociation between the influence on striatal dopamine content and the behavioral effects of 1-deprenyl and clorgyline.



Deprenyl induces the tyrosine hydroxylase enzyme in the rat dopaminergic nigrostriatal system

Molecular Brain Research (Netherlands), 1997, 46/1-2 (31-38)

Chronic treatment of aged rats with deprenyl prevents age-induced protein oxidation in substantia nigra and protects tyrosine hydroxylase (TH) enzyme against inactivation. With these precedents, we treated adult rats with deprenyl for 3 weeks in order to get further insight in the mechanism by which deprenyl exerts such actions. After completing the treatment, dopamine (DA) levels markedly increased in both striatum and substantia nigra while levels of the acid DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), decreased in the two brain areas, thus proving MAO-inhibiting properties of the treatment. We then studied the cellular expression of TH mRNA by in situ hybridization. Following treatment with deprenyl, levels of TH mRNA were significantly higher in individual dopaminergic nigral cell bodies than in those of control rats (+74%). Western blotting analysis of TH enzyme amount revealed a positive effect of the treatment in both the terminal field (+44%) and the cell body region (+31%). This correlation between TH mRNA and amount was also extended to TH enzyme activity in the two brain areas studied, which significantly increased in striatum (+57%) and substantia nigra (+35%) following deprenyl treatment. Taken together, our results clearly suggest a TH-inducing effect of deprenyl in the dopaminergic nigrostriatal system, which seems to be independent of its protective action against oxidative stress described previously. These results expand our knowledge about the beneficial effect of deprenyl in the therapy of Parkinson's disease.



Selegiline in the treatment of behavioural disturbance in Alzheimer's disease

International Journal of Geriatric Psychiatry (United Kingdom), 1997, 12/3 (319-322)

Objective. The purpose of this study was to examine the behavioural and cognitive effects of selegiline in a group of moderately behaviourally disturbed AD patients. Design. This was a 14-week randomized double-blind placebo-controlled study of selegiline (10 mg) and placebo. Setting. An outpatient clinic in an urban-based tertiary referral centre in the USA. Patients. Twenty-five outpatients meeting NINCDS criteria for probable Alzheimer's disease with associated behavioural disturbance. Measures. The Brief Psychiatric Rating Scale (BPRS), the Dementia Mood Assessment Scale (DMAS) and the Alzheimer Disease Assessment Scale (Cognitive) (ADAS-COG). Results. In the primary analysis, improvement on the BPRS and DMAS scores with selegeline treatment did not reach statistical significance. A secondary analysis using a parallel design showed a significant benefit of drug treatment on BPRS scores with a trend towards improvement on the DMAS. Among the 10 subjects who could be tested, there was a significant improvement in cognitive function on the ADAS-COG with selegiline compared to placebo. Conclusions. Short-term selegiline treatment produced an improvement in behaviour and had a significant effect on cognition in a subset of testable patients.



Deprenyl in the treatment of Parkinson's disease: Clinical effects and speculations on mechanism of action

Journal of Neural Transmission, Supplement (Austria), 1996, -/48 (75-84)