Deprenyl scientific update |
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Ann N Y Acad Sci. 2006 May;1067:375-82
Kitani K, Kanai S, Miyasaka K, Carrillo MC, Ivy GO.
National Institute for Longevity Sciences, Morioka-cho, Obu-shi, Aichi, Japan.
The necessity of having a proper dose of (-)deprenyl (D) to prolong the life spans of rats explains discrepancies among different studies in the past.
This study is based on increasing life span with deprenl(D) was studied in rats and the result clearly indicated that a proper dose of D within a certain dose range can significantly increase the life span of rats, but a greater dose becomes less effective and may adversely affect the life span of rats.
(-)Deprenyl (D) has been shown to be effective in prolonging life span in experimental animals, although, there are some discrepancies in its effect on the life span the even within the same species (rats). The present study aims to clarify the reason for these discrepancies. Male F344/DuCrj rats began receiving subcutaneous (s.c.) injections of D at the age of 18 months. Doses used were 0.25, 0.50, and 1.0 mg/kg/injection (inj.), three times a week. Average life spans of animals were significantly longer in male rats given 0.25 and 0.5 mg/kg/inj.; however, rats given a 1.0 mg/kg dose began dying earlier than control rats, leading to an inverse U-shaped dose-efficacy relationship, a hormesis. Old (27-month-old) rats given different doses of D for 1 month showed a typical hormetic response for antioxidant enzyme activities, indicating a significant increase in superoxide dismutase (SOD) and catalase (CAT) activities in brain dopaminergic regions with four lower doses (0.25 to 2 mg/kg/inj., 3 times a week), but a significantly negative response with the highest dose (4 mg/kg/inj.). Our results clearly indicate that a proper dose of D within a certain dose range can significantly increase the life span of rats, but that a greater dose becomes less effective and may actually adversely affect the life span of rats. A similar hormetic response for its effect on antioxidant enzyme activities and the parallel between the two different effects of D suggest a possible causal relationship between these two effects of D. The presence of this effective dose range of D may explain previously reported discrepancies in the effect of D on the life span of animals.
Life Sci. 1994; 54(15):1047-57
Knoll J, Yen TT, Miklya I.
Department of Pharmacology, Semmelweis University of Medicine, Budapest, Hungary.
Sexually low performing male rats die earlier than their high performing peers and (-)deprenyl treatment eliminates this difference.
For this study out of 1600 sexually inexperienced 28 weak old Wistar-Logan male rats, 94 sexually inactive and 99 highly active rats were selected. And this study became successful with long life span of sexually low performing male rats.
Out of 1600 sexually inexperienced 28-week old Wistar-Logan male rats 94 sexually inactive ('low performing', LP) and 99 highly active ('high performing', HP) rats were selected. The rats were treated from the 8th month of their life three times a week, subcutaneously, with either 0.9% NaCl or 0.25 mg/kg (-)deprenyl until they died. Their copulatory activity was tested once a week and their learning performance was measured in the shuttle box once in three months. The salt treated LP rats (n = 44) never displayed ejaculation during their life time, they were extremely dull in the shuttle box and lived 134.58 +/- 2.29 weeks. Their (-)deprenyl-treated peers (n = 48) became sexually active, their mating performance was substantially increased and lived 152.54 +/- 1.36 weeks, significantly longer than their salt-treated peers and as long as the salt-treated HP rats. The salt treated HP rats (n = 49) displayed 14.04 +/- 0.56 ejaculations during the first 36-week testing period and due to aging they produced 2.47 +/- 0.23 ejaculations between the 73-108th week of testing. Their learning performance was high. They displayed 78.45 +/- 3.01 conditioned avoidance responses (CAR) during the first 36-week testing period and this dropped to 50.67 +/- 2.99 (p < 0.01) during the 73-108th week of testing. They lived 151.24 +/- 1.36 weeks, significantly (p < 0.001) longer than their LP peers. The (-)depre-nyl-treated HP rats (n = 50) were sexually much more active than their salt-treated peers. They displayed 30.04 +/- 0.85 ejaculations during the first 36-week testing period and 7.40 +/- 0.32 ejaculations between the 73-108th week of testing. Also their learning performance was substantially increased. They produced 113.98 +/- 3.23 CARs during the first 36-week-testing period and 81.68 +/- 2.14 CARs during the 73-108th week of testing. They lived 185.30 +/- 1.96 weeks, significantly more than their salt-treated peers and out of the 50 rats 17 lived longer than the estimated technical life span (TLS).
J Neural Transm Suppl. 2006;(71):143-56.
Magyar K, Palfi M, Jenei V, Szoko E.
Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary.
Deprenyl: from chemical synthesis to neuroprotection.
Deprenyl has variety of pharmacological effects. It became a golden standard of MAO-B inhibitors. It possesses dopamine potentiating and antioxidant properties, deprenyl showed neuroprotective features in a variety of in vitro and in vivo models.
During the last decades (-)-deprenyl has become the golden standard of MAO-B inhibitors. It possesses dopamine potentiating and antioxidant properties; however, its effects cannot be explained solely by the enzyme inhibitory action. (-)-Deprenyl prevents the toxicity of certain selective neurotoxins and recently it was demonstrated to increase cell-cell adhesion as well. The complexity of its pharmacological effects reflects the action of both the parent compound and the active metabolites. (-)-Deprenyl and related propargylamines (DRPs) show neuroprotective features in a variety of in vitro and in vivo models that is dependent on the propargyl moiety. The main presumptive targets to date include glyceraldehyde-3-phosphate dehydrogenase, poly(ADP-ribose) polymerase, some kinase cascades, as well as pro- and antiapoptotic proteins, beside the inhibition of MAO-B. The antiapoptotic activity of DRPs converges upon the maintenance of mitochondrial integrity, due to the initiation of a complex transcriptional program, the details of which are yet to be elucidated.
Curr Med Res Opin. 2007 Apr;23(4):741-50.
Lew MF, Pahwa R, Leehey M, Bertoni J, Kricorian G; The Zydis Selegiline Study Group.
Keck/University of Southern California School of Medicine, Los Angeles, CA 90033, USA.
Safety and efficacy of newly formulated selegiline orally disintegrating tablets as an adjunct to levodopa in the management of 'off' episodes in patients with Parkinson's disease.
Patients receiving levodopa for Parkinson’s disease experience motor fluctuation and immobility between dose. This study is to assess the effectiveness of selegiline orally disintegrating tablet (ODT) and reached the conclusion that long term selegiline ODT was effective, safe and well tolerated in patients with Parkinson’s disease experiencing off episodes during levopoda therapy.
OBJECTIVE: Patients receiving levodopa for Parkinson's disease experience motor fluctuations and immobility ('off' episodes) between doses. This study assessed adjunctive Zelapar (selegiline orally disintegrating tablet (ODT)) for managing off episodes and for long-term safety. METHODS: This open-label extension evaluated long-term safety, efficacy, and tolerability of adjunctive selegiline ODT 2.5 mg in patients who completed either of two large phase 3 double-blind studies. The study was to end after 12 months but was amended to be open-ended. Investigators could increase levodopa doses and introduce controlled-release formulations of levodopa or dopamine agonists if warranted. Additionally, results of a small randomized trial of open-label selegiline ODT 1.25 mg in comparison to conventional selegiline was added only to the safety analysis. Efficacy variables included changes in daily off time and Patient's Global Impression of Improvement (PGI-I) and Clinical Global Impressions Severity of Disease (CGI-S) ratings. Safety assessments included adverse events and oropharyngeal findings. RESULTS: This study enrolled 254 patients: 248 from the large phase 3 studies (efficacy analysis) and an additional six from the prior open-label comparison (safety analysis) in order to evaluate a larger population for safety purposes. Mean reduction from baseline in daily off time was 9.4% (1.6 h) for patients previously given selegiline ODT, 6.0% (1.2 h) for those switched from placebo, and 8.1% (1.4 h) overall. PGI-I and CGI-S ratings indicated little or no change from baseline. Treatment-related adverse events occurred in 132 (52%) patients. No severe oral irritations were attributed to selegiline ODT or prompted discontinuation. CONCLUSIONS: Long-term selegiline ODT 2.5 mg/day was effective, safe, and well tolerated in patients with Parkinson's disease experiencing off episodes during levodopa therapy.
J Neural Transm. 2007 Apr 20;
Irer SV, Alper GE, Sezer ED, Duman E, Saatcioglu F, Yilmaz C.
Department of Biochemistry, Ege University Medical School, Izmir, Turkey.
The effect of l-deprenyl on tissue mRNA expressions of NOS isoforms and NO levels in an experimental diabetes mellitus model.
Diabetes and aging share some common mechanisms in their parthenogenesis and diabetics. Synchronized treatment for ageing and diabetics is possible by using I-deprenyl, a selective monoamine oxidase (MAO-B) inhibitor with its antioxidant, antiapoptotic and neuroprotective properties.
Diabetes and aging share some common mechanisms in their pathogenesis and diabetics are more prone to diseases of the elderly. Seeking for therapies likely to be proposed in the synchronised treatment of aging and diabetes is of great interest and l-deprenyl, a selective monoamine oxidase (MAO-B) inhibitor, is a possible candidate with its antioxidant, antiapoptotic and neuroprotective properties. Tissue MAO, NO and mRNA expression of nitric oxide (NO) synthase (NOS) isoforms were assessed in streptozotocin (STZ)-induced diabetic rats to evaluate the effect of l-deprenyl treatment. Twelve weeks of treatment had no significant effect on NO levels. Four-weeks treatment decreased tissue MAO activities and caused a decrease in expression of NOS-2 and NOS-3 in heart tissue of both controls and diabetics, and a decrease of liver NOS-3 expression in controls (p<0.05). l-Deprenyl, causing a decrease in tissue NOS expressions, might be of benefit by protecting the organism from the toxic radical effects of NO.
Ann Pharmacother. 2007 May;41(5):851-6.
Fohey KD, Hieber R, Nelson LA.
School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
The role of selegiline in the treatment of negative symptoms associated with schizophrenia.
OBJECTIVE: To evaluate the role of selegiline in the treatment of negative symptoms associated with schizophrenia. DATA SOURCES: MEDLINE (1966-January 2007) and PsychINFO (1967-January 2007) were searched, using the terms schizophrenia, negative symptoms, and selegiline. A bibliographic search was conducted, as well.
STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the search were evaluated. All primary literature was included in the review. DATA SYNTHESIS: Based on its dopamine-enhancing property, selegiline has been studied as augmentation to antipsychotic therapy for the treatment of negative symptoms associated with schizophrenia. The efficacy of low-dose oral selegiline for the treatment of negative symptoms has been evaluated in 1 case report, 2 open-label trials, and 2 controlled trials. The case report and both open-label trials report improvement of negative symptoms associated with low-dose oral selegiline. In 1 of the controlled trials, selegiline showed no difference in effect from that of placebo. These data are limited by small sample sizes. The largest controlled trial demonstrated a statistically significant difference between selegiline and placebo; however, the clinical significance is questionable, given that patients treated with selegiline were still experiencing marked negative symptoms at study completion. No comparative studies evaluating low-dose oral selegiline versus other augmentative treatment options for negative symptoms associated with schizophrenia exist at this time. CONCLUSIONS: Given the limitations of current literature, low-dose oral selegiline cannot be recommended for treatment of negative symptoms associated with schizophrenia. Additional controlled trials are needed to better delineate whether there is a role for selegiline in decreasing the burden of negative symptoms associated with schizophrenia.
Schizophr Res. 2006 Aug 23;
Murphy BP, Chung YC, Park TW, McGorry PD.
ORYGEN Youth Health, Melbourne, Victoria, Australia; Department of Psychiatry, University of Melbourne, Victoria, Australia.
Pharmacological treatment of primary negative symptoms in schizophrenia: A systematic review.
BACKGROUND: Optimal treatment of primary negative symptoms is important because their presence is associated with poor outcome. AIMS: To systematically review all studies dealing with the efficacy of pharmacological agents on primary negative symptoms. METHOD: A comprehensive search of the relevant literature was undertaken using electronic database, reference lists and personal contact. RESULTS: There is a lack of standardized research designs. Amisulpride is the most extensively studied drug with respect to efficacy against primary negative symptoms. At low doses it demonstrates a consistent, modest effect compared to placebo, though not to conventional antipsychotics and has yet to be tested against other atypicals. Evidence from multiple studies that used simple statistical analyses and inclusion criteria for patients with primary negative symptoms does not support a direct effect for clozapine. Path-analysis studies support the direct effects of risperidone, olanzapine, sertindole and aripiprazole, however, different statistical analyses of the same risperidone study produced conflicting results and the direct effects of olanzapine were not confirmed in selected patients with primary negative symptoms. There are no studies supporting the use of ziprasidone or quetiapine. The effects of typical antipsychotics on primary negative symptoms are inconclusive and likely to depend on drug dosages. Selective serotonin reuptake inhibitors (SSRIs), mirtazepine and NMDA agonists show early promise but require further study. Novel agents such as selegiline, naltrexone, dehydroepiandrosterone, galantamine, Ginkgo, nitric oxide, l-deprenyl and pergolide show positive effects on general negative symptoms but remain untested against primary negative symptoms. CONCLUSIONS: Further studies using standardized selective inclusion criteria and controlling for chronicity are needed. Research guidelines are discussed.
Ann Neurol 2002 May;51(5):604-12
Shoulson I, Oakes D, Fahn S, Lang A, Langston JW, LeWitt P, Olanow CW, Penney JB, Tanner C, Kieburtz K, Rudolph A;
Parkinson Study Group
Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson's disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial
Deprenyl (selegiline) delays the need for levodopa therapy in patients with early Parkinson's disease, but the long-term benefits of this treatment remain unclear. During 1987 to 1988, 800 patients with early Parkinson's disease were randomized in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism trial to receive deprenyl, tocopherol, combined treatments, or a placebo and were then placed on active deprenyl (10mg/day). A second, independent randomization was carried out in early 1993 for 368 subjects who by that time had required levodopa and who had consented to continuing the deprenyl treatment (D subjects) or changing to a matching placebo (P subjects) under double-blind conditions. The first development of wearing off, dyskinesias, or on-off motor fluctuations was the prespecified primary outcome measure. During the average 2-year follow-up, there were no differences between the treatment groups with respect to the primary outcome measure (hazard ratio, 0.87; 95% confidence interval, 0.63, 1.19; p = 0.38), withdrawal from the study, death, or adverse events. Although 34% of D subjects developed dyskinesias and only 19% of P subjects did (p = 0.006), only 16% of D subjects developed freezing of gait but 29% of P subjects did (p = 0.0003). Decline in motor performance was less in D subjects than P subjects. Levodopa-treated Parkinson's disease patients who had been treated with deprenyl for up to 7 years, compared with patients who were changed to a placebo after about 5 years, experienced slower motor decline and were more likely to develop dyskinesias but less likely to develop freezing of gait.
Mech Ageing Dev 2002 Apr 30;123(8):1087-100
Kitani K, Minami C, Isobe K, Maehara K, Kanai S, Ivy GO, Carrillo MC
National Institute for Longevity Sciences, 36-3, Gengo, Morioka-cho, Obu-shi, Aichi 474-8522, Japan.
Why (--)deprenyl prolongs survivals of experimental animals: increase of anti-oxidant enzymes in brain and other body tissues as well as mobilization of various humoral factors may lead to systemic anti-aging effects
(--)Deprenyl, a monoamine oxidase B (MAO B) inhibitor is known to upregulate activities of anti-oxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) in brain dopaminergic regions. The drug is also the sole chemical which has been repeatedly shown to increase life spans of several animal species including rats, mice, hamsters and dogs. Further, the drug was recently found to enhance anti-oxidant enzyme activities not only in brain dopaminergic regions but also in extra-brain tissues such as the heart, kidneys, adrenal glands and the spleen. We and others have also observed mobilization of many humoral factors (interferone (INF)-gamma, tumor necrosis factor (TNF)-alpha, interleukine (IL)-1beta,2,6, trophic factors, etc.) and enhancement of natural killer (NK) cell functions by (-)deprenyl administration. An apparent extension of life spans of experimental animals reported in the past may be better explained by these new observations that (-)deprenyl upregulate SOD and CAT activities not only in the brain but also in extra-brain vital organs and involve anti-tumorigenic as well as immunomodulatory effect as well. These combined drug effects may lead to the protection of the homeostatic regulations of the neuro-immuno-endocrine axis of an organism against aging.
J Clin Psychiatry. 2003;64 Suppl 9:23-8
Bronx Veterans Medical Research Development, Bronx, NY 10468-3904, USA
Noncholinergic treatment options for Alzheimer's disease
Approved treatments for Alzheimer's disease have focused primarily on cholinergic enhancement. New attention, however, is being turned toward preventative treatments such as vitamin E, estrogen, and lipid-lowering agents. Preventative treatments focus on intervening prior to the onset of disease. These treatments are designed to modify the amyloid load. These new approaches require designs that select nonimpaired or minimally impaired populations, using new outcomes with prolonged assessment. The cost of these studies is high, but the potential benefit of delay or prevention of disease is the valuable goal.
Selegiline reduces N-methyl-D-aspartic acid induced perturbation of neurotransmission but it leaves NMDA receptor dependent long-term potentiation intact in the hippocampus.
Niittykoski M, Haapalinna A, Sirvio J.
Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio.
J Neural Transm. 2003 Nov;110(11):1225-40.
This study examined the effects of monoamine oxidase (MAO) inhibitors on N-methyl-D-aspartic acid (NMDA)-induced perturbation of neurotransmission and normal NMDA-receptor dependent function (long-term potentiation, LTP) in the CA1 field of hippocampus. During baseline recording, neurotransmission was unaffected by long-term bath perfusion with MAO inhibitors (selegiline, pargyline). After NMDA (100 micro M) infusion, the presence of selegiline (1 micro M) promoted the recovery rate and increased the size of recovered extracellular field excitatory postsynaptic potentials (fEPSPs). Selegiline (1 micro M) also prevented the NMDA-induced increase in paired pulse facilitation (PPF). The induction and maintenance of LTP were normal with this same concentration of selegiline. The presence of lower concentration (10 nM) of selegiline or pargyline (1 micro M) did not improve the recovery process. These results suggest that selegiline partially protects the function of CA3-CA1 hippocampal connections against overactivation of NMDA receptors. Further, the same concentration of selegiline does not interfere with the physiological function of NMDA receptors in the CA1 field of the hippocampus. The exact mechanism of action remains to be determined, but it is apparently downstream to the overactivation of NMDA receptors.
J Neural Transm. 2003 Nov;110(11):1225-40.
Stryjer R, Klein C, Treves TA, Rabey JM.
Department of Neurology, Assaf Harofeh Medical Center, Zerifin, Israel.
The effects of acute loading with levodopa and levodopa with selegiline on blood pressure and plasma norepinephrine levels in chronic Parkinson's disease patients.
OBJECTIVES: Contradictory possible cardiovascular side effects of selegiline have been reported. Therefore, we studied the effect of acute administration of selegiline with levodopa (LD) compared with LD alone, on blood pressure, pulse and norepinephrine (NE) plasma levels, during an orthostatic test on chronically treated Parkinson's disease patients (PDpts) and controls. MATERIALS AND METHODS: Twelve PDpts treated with LD (group D), 12 PDpts treated with selegiline and LD (group S) and eight volunteers (CTRL) underwent the orthostatic test. Patients repeated the test twice, before and after acute loading with 125 mg LD (group D) and 125 mg LD +5 mg selegiline (group S). RESULTS: Group S showed more episodes of postural hypotension (n = 10; two symptomatic) than group D (n = 4) and CTRL (n = 2), however not statistically significant. Plasma NE also rose significantly higher (P < 0.001) in group S. CONCLUSION: PD patients treated with selegiline showed more orthostatism and higher plasma NE after submission to the orthostatic test. These findings may be relevant to explain its deleterious effect.
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Drug category:Antiparkinson agents
 Deprenyl scientific update
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