Selegilin scientific update |
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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.
A stuy to determine the use of deprenyl from chemical synthesis to neuroprotection. It has some dopamine potentiating and antioxidant properties. Deprenyl is capable to reduce the toxicity of certain selective neurotoxins.
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.
A study to find out the effectiveness of newly formulated selegiline orally disintegrating tablets as an adjunct to levodopa. The study is focused on the management of 'off' episodes in patients with Parkinson's disease using selegiline tablets. Long-term use of selegiline is effective, safe, and well tolerated in patients with Parkinson's disease.
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.
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.
A study to evaluate the role of selegiline in the treatment of negative symptoms associated with schizophrenia. Selegiline has some dopamine-enhancing property. Low-dose of oral selegiline is less effective 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.
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.
Here the author suggests the efficacy of l-deprenyl on tissue mRNA expressions of NOS isoforms and NO levels in a new diabetes mellitus model. l-Deprenyl can reduce the tissue NOS expressions. This may benefit the patient by protecting the organism from the toxic radical effects of NO.
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.
J Clin Psychiatry. 2006 Sep;67(9):1354-1361.
Feiger AD, Rickels K, Rynn MA, Zimbroff DL, Robinson DS.
From the Department of Psychiatry, University of Colorado School of Medicine, Denver; Research Training Associates (RTA) Colorado, Lakewood; and Feiger Health Research Center, Wheat Ridge, Colo. (Dr. Feiger); the Department of Psychiatry, University
Selegiline Transdermal System for the Treatment of Major Depressive Disorder: An 8-Week, Double-Blind, Placebo-Controlled, Flexible-Dose Titration Trial.
An 8-week, double-blind, placebo-controlled, flexible-dose titration trial. on selegiline transdermal system for the treatment of major depressive disorder. Assessments were conducted from the first to eighth week. Great imporvmen was shown in patients treated with selegiline.
OBJECTIVE: This study investigated the efficacy, safety, and tolerability of the selegiline
transdermal system (STS) administered in a dose range of 6 mg/24 hours to 12 mg/24 hours for
treating major depressive disorder (MDD). METHOD: Patients meeting DSM-IV criteria for MDD (N
= 265) were randomly assigned to blinded treatment with STS or a matching placebo patch for 8
weeks. Patients failing to meet or maintain protocol-defined therapeutic response criteria at
predetermined time points had their STS (or placebo) dose increased. Assessments were
conducted at weeks 1, 2, 3, 5, 6, and 8. Patients were not required to follow a
tyramine-restricted diet. The study ran from September 2001 through August 2002. RESULTS:
Selegiline transdermal system treatment resulted in significantly greater improvement (p
J Neurocytol. 2003 May;32(4):329-43.
Sharma SK, Carlson EC, Ebadi M.
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, North Dakota, USA.
Neuroprotective actions of Selegiline in inhibiting 1-methyl, 4-phenyl, pyridinium ion (MPP+)-induced apoptosis in SK-N-SH neurons.
A study to evaluate the neuroprotective actions of selegiline in inhibiting 1-methyl, 4-phenyl, pyridinium ion (MPP+)-induced apoptosis in SK-N-SH neurons. Partial neuroprotection is provided by selegiline at higher concentrations of MPP(+). It has the capability to provide neuroprotection by preserving mitochondrial membranes.
We have examined mitochondrial membranes and molecular hallmarks of apoptosis in response to increasing concentrations of 1-Methyl, 4-phenyl, Pyridinium ion (MPP(+)) in SK-N-SH neurons and have evaluated the neuroprotective potential of Selegiline with a primary objective to explore its mechanism(s) of neuroprotection. MPP(+)-induced apoptosis was characterized by spherical appearance, suppressed neuritogenesis, phosphatidyl serine externalization, plasma membrane perforations, mitochondrial membrane potential (Delta Psi) collapse, mitochondrial aggregation, and nuclear DNA fragmentation and condensation. At lower concentrations, MPP(+) (10-100 microM) produced mitochondrial swelling and loss of cristae, and at higher concentrations (300-500 microM), degeneration and aggregation of mitochondrial membranes in the peri-nuclear region, which were attenuated by Selegiline (10-50 microM) pre-treatment. At still higher concentrations, MPP(+) (>500 microM) produced necrotic changes represented by mitochondrial and plasma membrane ballooning and perforations. Selegiline provided partial neuroprotection at higher concentrations of MPP(+). MPP(+)-induced increases in reactive oxygen species, lipid peroxidation, cytochrome-C release, necrosis factor kappa-B (NF-kappa-B) activation, 8-hydroxy, 2 deoxy guanosine synthesis, alpha-synuclein indices, and reductions in glutathione, ATP, and superoxide dismutase were attenuated by Selegiline. Selegiline also attenuated MPP(+)-induced transcriptional activation of c-fos, c-jun, GAPDH, and caspase-3, suggesting that it may provide neuroprotection by preserving mitochondrial membranes, by attenuating molecular markers of apoptosis, by scavenging free radicals, and by regulating immediate early genes involved in neurodegeneration.
Pharmacol Res. 2004 Mar;49(3):253-8.
Takahata K, Shimazu S, Yoneda F.
Research Institute, Fujimoto Pharmaceutical Corporation, 1-3-40 Nishiotsuka, Matsubara, Osaka 580-0011, Japan.
(--)-Deprenyl inhibits tyramine-induced noradrenaline release, but not tyramine-induced dopamine release or potassium-induced noradrenaline release, from rat brain synaptosomes.
A study to check the effect of (-)-deprenyl (selegiline). (--)-Deprenyl inhibits tyramine-induced noradrenaline release, instead of tyramine-induced dopamine release or potassium-induced noradrenaline release, from rat brain synaptosomes. Selegiline is a therapeutic agent for Parkinson's disease.
The effect of (-)-deprenyl (selegiline), a therapeutic agent for Parkinson's disease, on the tyramine-induced release of catecholamine from rat brain synaptosomes was studied using a superfusion system. Tyramine (10(-7) to 10(-5)M) enhanced the release of [3H]noradrenaline (NA) and [3H]dopamine (DA) from forebrain and striatal synaptosomes in a dose-dependent manner. (-)-Deprenyl (5x10(-5)M) had no effect on spontaneous catecholamine release, suggesting that it has no tyramine-like catecholamine releasing effect. Pretreatment with (-)- or (+)-deprenyl (5x10(-5)M) significantly prevented the tyramine (10(-6)M)-induced NA release, but not DA release. The inhibitory action of (-)-deprenyl was not observed on potassium (15mM)-induced NA release. (-)-Desmethyldeprenyl (5x10(-5)M), a metabolite of (-)-deprenyl, and a monoamine oxidase-A (MAO-A) inhibitor, clorgyline (5x10(-5)M), failed to block the tyramine-induced NA and DA release. Although (+)-deprenyl, a potent DA uptake inhibitor, did not inhibit tyramine-induced DA release, a catecholamine uptake inhibitor nomifensine (5x10(-5)M) did. In summary, (-)-deprenyl at a dose inhibiting tyramine-induced NA release did not have any effect on tyramine-induced DA release or potassium-induced NA release.
Neurosci Lett. 2004 Jan 30;355(3):169-72.
Am OB, Amit T, Youdim MB.
Eve Topf and US National Parkinson Foundation Center of Excellence for Neurodegenerative Diseases Research, Technion-Faculty of Medicine, Efron St PO Box 9697, Haifa 31096, Israel.
Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline.
The neuroprotective and neurotoxic actions of metabolites such as rasagiline and selegiline which are used for the treatment of Parkinson’s disease. These monoamine oxidase B inhibitor drugs possess neuroprotective activities in cell culture and in vivo models. The researchers found several positive factors of rasagiline in treatment of Parkinson's disease.
The anti-Parkinson selective irreversible monoamine oxidase B inhibitor drugs, rasagiline and selegiline, have been shown to possess neuroprotective activities in cell culture and in vivo models. While rasagiline is metabolized to its major metabolite aminoindan, selegiline gives rise to L-methamphetamine. Cultured PC-12 cells in absence of serum and nerve growth factor (NGF) die by an apoptotic process. Pretreatment of PC12 cells in absence of serum and NGF for 24 h with either rasagiline (1 microM) or selegiline (1 microM) is neuroprotective and anti-apoptotic as determined by ELISA and MTT tests. However, while aminoindan (1 microM), the major metabolite of rasagiline does not interfere with the neuroprotective activities of rasagiline or selegiline in PC-12 cells deprived of serum and NGF, the major metabolite of selegiline, L-methamphetamine (1 microM), inhibits them. In contrast to L-methamphetamine, aminoindan is itself is neuroprotective in this system. Recently it has been demonstrated that rasagiline directly activates PKC-MAP kinase pathway by a concentration and time dependent phosphorylation of p42 and p44 MAP kinase. In the present studies the neuroprotective activity of rasagiline is blocked by ERK inhibitor, PD98059 (20 microM), suggesting the involvement of PKC-MAP kinase pathway in the neuroprotection. These findings may have implication for the possible disease modifying action of rasagiline in treatment of Parkinson's disease.
Cell Mol Neurobiol. 2004 Feb;24(1):87-100.
Maia FD, Pitombeira BS, Araujo DT, Cunha GM, Viana GS.
Laboratory of Neuropharmacology, Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, Brazil.
l-Deprenyl prevents lipid peroxidation and memory deficits produced by cerebral ischemia in rats.
Lipid peroxidation and memory deficits produced by cerebral ischemia in rats can be prevented by l-Deprenyl. Treatment using l-Deprenyl showed significant improvement in memory deficits. The parameters studied during the study include memory acquisition and memory retention, locomotor activity and thiobarbituric acid reactive substances.
1. The present work shows the results on behavior and on biochemical parameters of l-deprenyl (0.1, 5, and 10 mg/kg, p.o.) administered daily for 5 days to rats submitted to global cerebral ischemia. 2. The transient global ischemia was carried out by clamping the animals bilateral common carotid arteries for 20 min. The parameters studied were memory acquisition and memory retention, locomotor activity and thiobarbituric acid reactive substances, as an index of lipid peroxidation. 3. l-Deprenyl treatment significantly improved memory deficits as compared to the ischemic group as measured by the elevated T maze test. A similar result was observed on the passive avoidance test where l-deprenyl improved late but not early memory as compared to the ischemic group. Except for an increased locomotor activity observed in the group treated with 5 mg/kg, no other alteration was detected in this behavioral test. Rats submitted to transient global ischemia (and without l-deprenyl) showed an increase in MDA levels in the hippocampus and the treatment with l-deprenyl (5 or 10 mg/kg) significantly reversed this effect bringing values close to those of the sham-operated controls. A similar profile was observed with nitrite levels. 4. In conclusion, the work showed a significant protective effect of l-deprenyl on memory deficits and lipid hyperperoxidation observed after cerebral ischemia. Possibly, the drug is acting at least in part through its antioxidant activity.
Selegilin description...
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Drug category:Antiparkinson agents
 Selegilin scientific update
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