xp Neurol 2000 Dec;166(2):458-64 Related Articles, Books, LinkOut R-(-)-Deprenyl inhibits monocytic THP-1 cell neurotoxicity independently of monoamine oxidase inhibition. Klegeris A, McGeer PL Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. [Medline record in process] R-(-)-Deprenyl (deprenyl, selegiline), a monoamine oxidase B (MAO-B) inhibitor, delays progression of Parkinson's disease. This action could be mediated by inhibition of MAO-B but there may also be unrelated mechanisms. Direct neuroprotective and antiapoptotic actions of deprenyl have previously been observed in vitro. Here we describe an antineurotoxic action of deprenyl which is independent of direct neuronal effects. We employed a previously described assay in which human neuroblastoma SH-SY5Y cells are exposed to cell-free supernatants of stimulated human monocytic THP-1 cells. Deprenyl reduced the secretion of neurotoxic products by such stimulated cells in a concentration-dependent manner, while the MAO inhibitors iproniazid, isocarboxazid, nialamide, tranylcypromine, phenelzine, and clorgyline were without effect. No antineurotoxic action was observed when deprenyl was added directly to SH-SY5Y cells. Messenger RNAs for MAO-A and MAO-B were not detected in THP-1 cells by reverse transcriptase-polymerase chain reaction analysis of total RNA extracts. Such mRNAs were easily detected in extracts of SH-SY5Y cells under comparable conditions. MAO enzymatic activity was also undetectable in THP-1 cell lysates, while it was readily observed in SH-SY5Y cells. It was concluded that the effect of deprenyl on THP-1 cells was not mediated by MAO and that deprenyl itself was not protecting neurons. These data suggest that deprenyl may have utility in neurodegenerative diseases due to its antineurotoxic actions. Copyright 2000 Academic Press. PMID: 11085911, UI: 20539914 2: Neurobiology (Bp) 2000;8(2):179-99 Related Articles, Books (-)Deprenyl (Selegiline): past, present and future. Knoll J Department of Pharmacology, Semmelweis University of Medicine, Budapest, Hungary. [Medline record in process] (-)Deprenyl (Selegiline), the N-propargyl analogue of (-)methamphetamine, is the only drug in clinical case which, by enhancing the impulse propagation mediated release of noradrenaline and dopamine in the brain (catecholaminergic activity enhancer, CAE, effect), keeps in small doses without side-effects the catecholaminergic brain system on a higher activity level. (-)Deprenyl stimulates the catecholaminergic neurons selectively in the brain because, in contrast to PEA and the amphetamines which induce the continuous release of noradrenaline and dopamine from their intraneuronal stores, (-)deprenyl is devoid of this property. It is due to the CAE effect that a) the maintenance of rats on (-)deprenyl during the postdevelopmental phase of their life slows the age-related decline of sexual and learning performances and prolongs life significantly; b) patients with early, untreated Parkinson's disease maintained on (-)deprenyl need levodopa significantly later than their placebo-treated peers, and when on levodopa plus (-)deprenyl, they live significantly longer than patients on levodopa alone; and c) in patients with moderately severe impairment from Alzheimer's disease, treatment with (-)deprenyl slows the progression of the disease. It is reasonable to expect that a prophylactic low dose administration of a safe catecholaminergic activity enhancer substance during the postdevelopmental phase of life will slow the age-related decline of behavioral performances, delay natural death and decrease susceptibility to Parkinson's disease and Alzheimer's disease. PMID: 11061214, UI: 20513392 3: J Neuroimmunol 2000 Sep 22;109(2):95-104 Related Articles, Books, LinkOut Anti-tumor effect of L-deprenyl is associated with enhanced central and peripheral neurotransmission and immune reactivity in rats with carcinogen-induced mammary tumors. ThyagaRajan S, Madden KS, Stevens SY, Felten DL Center for Neuroimmunology, Loma Linda University School of Medicine, 11021 Campus Street, Loma Linda, CA 92350, USA. sthyagarajan@som.llu.edu L-Deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, has previously been shown to improve immune responses and restore noradrenergic (NA) nerve fibers in the spleen of old rats. In tumor-bearing rats, L-deprenyl inhibited tumor incidence and enhanced tuberoinfundibular dopaminergic (TIDA) neurotransmission in the hypothalamus. The aim of the present study was to investigate whether alterations in sympathetic NA activity and cellular immune responses in the spleen, and TIDA activity in the hypothalamus, accompany deprenyl-induced regression of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced mammary tumors. Rats with DMBA-induced mammary tumors were treated with 0, 2.5 mg, or 5.0 mg/kg body weight of deprenyl daily for 13 weeks. Saline-treated tumor-bearing rats exhibited reduced splenic IL-2 and IFN-gamma levels, and lowered splenic norepinephrine (NE) concentration and hypothalamic dopaminergic activity, compared to rats without tumors. In contrast, treatment with 2.5 mg/kg and 5.0 mg/kg of deprenyl reduced the number and size of mammary tumors. Deprenyl-induced tumor regression was accompanied by increased immune measures in the spleen, including enhanced IL-2 and IFN-gamma production, and NK cell activity. Neural measures enhanced by deprenyl included NE concentration in the spleen and TIDA neuronal activity in the hypothalamus. These results suggest that (1) mammary tumorigenesis is associated with the inhibition of sympathetic NA activity in the spleen, TIDA activity in the hypothalamus, and cell-mediated immunity, and (2) reversal of the inhibition of catecholaminergic neuronal activities of the central nervous system and peripheral nervous system by deprenyl may enhance anti-tumor immunity. PMID: 10996211, UI: 20453324 4: Am J Physiol Heart Circ Physiol 2000 Sep;279(3):H1283-90 Related Articles, Books, LinkOut Selegiline improves cardiac sympathetic terminal function and beta-adrenergic responsiveness in heart failure. Shite J, Dong E, Kawai H, Stevens SY, Liang CS Cardiology Unit, Department of Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA. Selegiline is a centrally acting sympatholytic agent with neuroprotective properties. It also has been shown to promote sympathetic reinnervation after sympathectomy. These actions of selegiline may be beneficial in heart failure that is characterized by increased sympathetic nervous activity and functional sympathetic denervation. Twenty-seven rabbits with rapid cardiac pacing (360 beats/min, 8 wk) and twenty-three rabbits without pacing were randomly assigned to receive selegiline (1 mg/day, 8 wk) or placebo. Rapid pacing increased plasma norepinephrine (NE) and decreased left ventricular fractional shortening, baroreflex sensitivity, cardiac sympathetic nerve terminal profiles, cardiac NE uptake activity, and myocardial beta-adrenoceptor density. Selegiline administration to animals with rapid ventricular pacing attenuated the increase in plasma NE and decreases in fractional shortening, baroreflex sensitivity, sympathetic nerve profiles, NE uptake activity and beta-adrenoceptor density. Thus selegiline appears to exert a sympatholytic and cardiac neuroprotective effect in pacing-induced cardiomyopathy. The effects are potentially beneficial because selegiline not only improves cardiac function but also increases baroreflex sensitivity in heart failure. PMID: 10993795, UI: 20451347 5: Ann Pharmacother 2000 Sep;34(9):1020-4 Related Articles, Books A hypertensive reaction induced by concurrent use of selegiline and dopamine. Rose LM, Ohlinger MJ, Mauro VF Department of Pharmacy, Fairview Hospital, Cleveland, OH 44111, USA. lori.rose@fairviewhospital.org [Medline record in process] OBJECTIVE: To describe a hypertensive reaction induced by concurrent use of selegiline and dopamine. CASE SUMMARY: A 75-year-old critically ill white man who was receiving selegiline 5 mg twice daily for Parkinson's disease was initiated on an intravenous dopamine infusion for decreased urine output and hypotension. Within minutes of starting the dopamine infusion, the patient's systolic blood pressure increased from 105 to 228 mm Hg. Similar reactions occurred during two subsequent rechallenges. DISCUSSION: Since monoamine oxidase is involved in the metabolism of catecholamines, selegiline may have affected the metabolism of the dopamine administered to the patient. Although selegiline is known to be a monoamine oxidase inhibitor specific for type B, evidence exists stating that selegiline may not be as specific as previously thought. CONCLUSIONS: Dopamine should be used cautiously, if at all, in patients who are chronically receiving selegiline or who have received selegiline within the prior two weeks. Eur J Clin Pharmacol 2000 Feb-Mar;55(11-12):815-9 Related Articles, Books, LinkOut Selegiline treatment and the extent of degenerative changes in brain tissue of patients with Alzheimer's disease. Alafuzoff I, Helisalmi S, Heinonen EH, Reinikainen K, Hallikainen M, Soininen H, Koivisto K Department of Neuroscience and Neurology, Kuopio University, Finland. irina.alafuzoff@uku.fi BACKGROUND: A beneficial effect of selegiline (L-deprenyl) in Alzheimer's disease (AD) has been reported in several clinical studies. METHODS: The brain tissue from 17 deceased patients, members of a double-blind clinical trial to assess the potential benefit of selegiline in AD, were analysed. FINDINGS: In our study, the decrease in the Mini-Mental State Examination (MMSE) scores during the progress of the disease had been significantly influenced by selegiline treatment. Prior to death, the MMSE scores were significantly higher in those patients receiving selegiline than in those receiving placebo. However, according to our results, none of the lesions critical for AD diagnosis, such as counts of senile/neuritic plaques, neurofibrillary tangles or beta-A4 load, were influenced by the selegiline treatment. INTERPRETATION: In conclusion, according to our study, mechanisms other than neuronal degeneration seen as lesions critical for AD diagnosis are influenced by selegiline treatment, leading to the functional benefit found in AD. PMID: 10805059, UI: 20262809 2: Biochem Pharmacol 2000 Jun 15;59(12):1589-95 Related Articles, Books, LinkOut Protective effect of L-deprenyl against apoptosis induced by okadaic acid in cultured neuronal cells. Suuronen T, Kolehmainen P, Salminen A Department of Neuroscience and Neurology, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland. L-Deprenyl, an irreversible MAO-B (monoamine oxidase B, EC 1.4.3.4) inhibitor, is used for the treatment of Parkinson's disease and to delay the progression of Alzheimer's disease. L-Deprenyl also exhibits protective effects against neuronal apoptosis which are independent of its ability to inhibit MAO-B. The purpose of this study was to compare the antiapoptotic efficacy of L-deprenyl against different types of apoptotic inducers in three neuronal cell culture models. The level of apoptosis was quantified by measuring the activation of caspase-3 enzyme, which is the main apoptotic executioner in neuronal cells. MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] and LDH (lactate dehydrogenase, EC 1. 1.1.27) assays were used to demonstrate the cytotoxic response of apoptotic treatments. Our results showed that okadaic acid, an inhibitor of protein phosphatase 1 and 2A, induced a prominent increase in caspase-3 activity both in cultured hippocampal and cerebellar granule neurons as well as in Neuro-2a neuroblastoma cells. Interestingly, L-deprenyl offered a significant protection against the apoptotic response induced by okadaic acid in all three neuronal models. The best protection appeared at the concentration level of 10(-9) M. L-Deprenyl also provided a protection against apoptosis after AraC (cytosine beta-D-arabinoside) treatment in hippocampal neurons and Neuro-2a cells and after etoposide treatment in Neuro-2a cells. However, L-deprenyl did not offer any protection against apoptosis caused by serum withdrawal or potassium deprivation. Okadaic acid treatment in vivo is known to induce an Alzheimer's type of hyperphosphorylation of tau protein, formation of beta-amyloid plaques, and a severe memory impairment. Our results show that the okadaic acid model provides a promising tool to study the molecular basis of Alzheimer's disease and to screen the neuroprotective capacity of L-deprenyl derivatives. PMID: 10799657, UI: 20261310 3: Int J Immunopharmacol 2000 Jul;22(7):523-36 Related Articles, Books, LinkOut Restoration of splenic noradrenergic nerve fibers and immune reactivity in old F344 rats: a comparison between L-deprenyl and L-desmethyldeprenyl. ThyagaRajan S, Madden KS, Stevens SY, Felten DL Center for Neuroimmunology, Loma Linda University School of Medicine, 11021 Campus Street, Loma Linda, USA. sthyagarajan@som.llu.edu L-deprenyl, a monoamine oxidase-B inhibitor, partially reversed the age-associated decline in splenic sympathetic noradrenergic (NA) innervation and immune reactivity in old male rats. The purpose of the present study was to examine whether the effects of deprenyl on splenic sympathetic NA nerve fibers and immune functions are mediated through a metabolite of deprenyl, L-desmethyldeprenyl. Old male F344 rats were treated with 0, 0.25, or 1.0 mg L-(-)-deprenyl/kg BW; 0.025, 0.25, or 1.0 mg L-(-)-desmethyldeprenyl/kg BW; and 1.0 mg D-(+)-desmethyldeprenyl/kg BW i.p. daily for 8 weeks. The animals were sacrificed after a 10-day drug wash-out period and the spleens were removed for histofluorescence, immunocytochemistry, neurochemical, and immunological analysis. The volume density of NA nerve fibers was increased in the spleens of deprenyl- and L-desmethyldeprenyl-treated old rats. Con A-induced IFN-gamma production by spleen cells was elevated in 1.0 mg/kg deprenyl- and L-desmethyldeprenyl-treated rats in comparison to saline- and D-desmethyldeprenyl-treated old rats. Deprenyl and desmethyldeprenyl treatment did not alter the percentage of CD5+ T cells, but treatment with 1.0 mg/kg deprenyl and 0.025 mg/kg L-desmethyldeprenyl prevented the decline in the percentage of sIgM(+)B cells in the spleens of old rats. These results suggest that L-desmethyldeprenyl may be as equipotent as deprenyl in preventing age-associated diminution in splenic sympathetic NA innervation and immunocompetence. PMID: 10785549, UI: 20249136 4: J Assoc Physicians India 1999 Aug;47(8):784-6 Related Articles, Books, LinkOut Effect of selegiline on cognitive functions in Parkinson's disease. Dixit SN, Behari M, Ahuja GK Department of Neurology, All India Institute of Medical Sciences, New Delhi. BACKGROUND: Selegiline hydrochloride, a selective MAO-B inhibitor is known to improve motor functions in Parkinson's disease (PD). The present study was undertaken to study the effect of selegiline on memory and intelligence of PD patients. MATERIAL AND METHOD: Thirty two patients of PD were divided in two groups: selegiline group (n = 17) received 10 mg selegiline per day and control group (n = 15) did not receive selegiline. Patients receiving trihexyphenidyl and selegiline were excluded. All other treatment remained unchanged. All patients were examined at baseline and after three months for change in UPDRS score, WAIS score, memory test and P300. RESULTS: Patients in selegiline group had less severe disease (UPDRS score 24.11 +/- 14.07) as compared to controls (UPDRS score 40.53 +/- 18.52). There was significant improvement in UPDRS score (p < 0.05), WAIS (p < 0.001) and memory (p < 0.001) in selegiline group. In the control group there was a significant prolongation of P300 latency (p < 0.05). CONCLUSION: The study suggests that selegiline improves memory functions and intelligence in PD patients in addition to motor functions. It also prevents prolongation of P300 latency which is a marker of cognitive function. Publication Types: Clinical trial PMID: 10778622, UI: 20241090 Anticancer Res 1999 Nov-Dec;19(6B):5023-8 Related Articles, Books, LinkOut Inhibition of tumor growth by L-deprenyl involves neural-immune interactions in rats with spontaneously developing mammary tumors. Thyagarajan S, Madden KS, Stevens SY, Felten DL Center for Neuroimmunology, Loma Linda University School of Medicine, CA 92350, USA. sthyagarajan@som.llu.edu L-deprenyl, a monoamine oxidase-B inhibitor, has been shown to reverse the age-related decline in sympathetic noradrenergic innervation and immune function in old rats and enhance T cell and NK cell activity in tumor-bearing rats. The objective of the present study was to examine whether deprenyl treatment of old female rats with mammary tumors could augment sympathetic nervous system and immune responses to inhibit the tumor growth. Female Sprague-Dawley rats with spontaneous mammary tumors were administered 0, 2.5 mg, or 5.0 mg/kg body weight (BW)/day deprenyl for i.p. 9 weeks. Tumor diameter, tumor number and body weight were measured throughout the treatment period. At the end of the treatment period, norepinephrine (NE) concentration, interferon-gamma production (IFN-gamma), Con A-induced T lymphocyte proliferation, and percentage of T and B lymphocytes and natural killer cells were measured in the spleen, and the concentrations of monoamines were measured in the medial basal hypothalamus. Relative to saline-treated controls, treatment with deprenyl reduced tumor growth, increased NE concentration, IFN-gamma production and percentage of the CD8+ T lymphocytes in the spleen. In the medial basal hypothalamus, deprenyl treatment increased the concentrations of catecholamines and indoleamine. These results suggest that the anti-tumor effects of deprenyl on spontaneous rat mammary tumors may be achieved via neural-immune signaling in the spleen and medial basal hypothalamus. PMID: 10697505, UI: 20162613 7: Mech Ageing Dev 1999 Nov;111(2-3):211-21 Related Articles, Books, LinkOut Pharmacological modifications of endogenous antioxidant enzymes with special reference to the effects of deprenyl: a possible antioxidant strategy. Kitani K, Kanai S, Ivy GO, Carrillo MC National Institute for Longevity Sciences, Aichi, Japan. kitani@nils.go.jp Limited information is available on the upregulation of endogenous antioxidant enzymes by means of administering various pharmaceuticals and/or chemicals. It has been reported that ursodeoxycholic acid (UDCA), a bile acid originally identified from black bear bile (a Chinese medicine, Yutan) increased glutathione S-transferase (GST) activities in mouse livers, resulting in a decrease in systemic lethal toxicity of orally challenged 1-2-dichloro-4-nitrobenzene (DCNB). Also, ursolic acid found in herbal medicines (e.g. leaves of loquat) was reported to increase catalase (CAT) activities in mouse liver. Interestingly, the chemical structures of these two compounds are surprisingly similar to each other, despite the difference in their original sources. These results suggest that in the future, more and more compounds will be found to have effects on increasing endogenous antioxidant enzyme activities. Deprenyl is a monoamine oxidase B inhibitor but also possesses many other different pharmacological activities. Among these various pharmacological effects of deprenyl, a possible causal relationship between two effects of deprenyl, namely the prolongation of the survival of animals and upregulation of antioxidant enzymes in selective brain regions, has been postulated by the authors. In at least four different animal species (rats, mice, hamsters and dogs), a significant prolongation of survival by chronic administration of the drug has been reported by different groups including that of the authors. This group has reported that repeated administration of the drug for 2-3 weeks can significantly increase activities of both types of superoxide dismutase (SODs) (Cu, Zn-, and Mn-SODs) as well as of CAT selectively in brain dopaminergic regions. Both effects are dose dependent but excessive dosages become less effective and even cause an adverse effect (i.e. a decrease in enzyme activities and shortening of life span). The parallelism of the dose-effect relationship between the two phenomena suggests that modification of SOD and CAT levels is one possible mechanism for deprenyl's ability to prolong the life span of animals. PMID: 10656538, UI: 20120331 8: Mech Ageing Dev 1999 Nov;111(2-3):189-200 Related Articles, Books, LinkOut Neuroprotection by (-)-deprenyl and related compounds. Maruyama W, Naoi M Department of Basic Gerontology, National Institute for Longevity Sciences, Obu, Japan. maruyama@nils.go.jp There is an increasing number of data by in vitro and in vivo experiments, indicating that (-)-deprenyl is neuroprotective to dopamine neurons, even though detailed mechanism remains to be clarified. In this paper neuroprotection by (-)-deprenyl and structurally related compounds was examined in concern with the suppression of apoptosis induced by a reactive oxygen species, peroxynitrite generated from SIN-1. The apoptotic DNA damage was quantitatively determined using dopaminergic SH-SYSY cells and by a single cell gel electrophoresis (comet) assay. DNA damage induced by peroxynitrite was proved to be apoptotic by prevention of the damage by cycloheximide or actinomycin-D. (-)-Deprenyl and other propargylamines protected the cells from apoptosis in a dose-dependent way. (-)-Deprenyl protected the cells even after it was washed out, suggesting that it may initiate the intracellular process to repress the apoptotic death program. The study on the structure-activity relationship of (-)-deprenyl analogues revealed that a N-propargyl residue with adequate size of hydrophobic structure is essentially required for the anti-apoptotic activity. These results suggest that (-)-deprenyl and related compounds may protect neurons from apoptosis and be applicable to delay the deterioration of neurons during advancing ageing and in neurodegenerative disorders. PMID: 10656536, UI: 20120329 9: Neurobiology (Bp) 1999;7(2):175-90 Related Articles, Books, LinkOut Neuroprotective and neuronal rescue effects of selegiline: review. Magyar K, Haberle D Department of Pharmacodynamics, Semmelweis University of Medicine, Budapest, Hungary. The effect of selegiline [(-)-deprenyl] cannot be considered as a simple, selective inhibitor of MAO-B. Pretreatment with the drug prevented the effect of specific neurotoxins like MPTP, 6-OH-dopamine, DSP-4 and AF64A. Selegiline pretreatment prevented the depletion of noradrenaline (NA) induced by DSP-4 in the rat hippocampus. This can be due to the uptake inhibitory effect of selegiline and mainly to its metabolite methylamphetamine (MA), which is more potent inhibitor of the re-uptake than the parent compound. SKF-525A pretreatment diminished the protective effect of selegiline against DSP-4, while phenobarbital pretreatment decreased its MAO-B inhibitory potency. Selegiline in low oral doses also prevented the effect of DSP-4 due to its intensive "first pass" metabolism. Selegiline treatment can rescue damaged neurones. It inhibited the apoptosis in M-1 human melanoma cells in a rather low concentration (10(-13)M). The mode of action of the drug regarding the inhibition of apoptosis is not known. Publication Types: Review Review literature PMID: 10591051, UI: 20058580 10: Br J Pharmacol 1999 Dec;128(8):1754-60 Related Articles, Books, LinkOut Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl. Behan WM, McDonald M, Darlington LG, Stone TW Institute of Biomedical & Life Sciences, West Medical Building, University of Glasgow, Glasgow G12 8QQ. 1. There are differences between the excitotoxic actions of quinolinic acid and N-methyl-D-aspartate (NMDA) which suggest that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors. The present study was designed to examine the effect of a potent antioxidant, melatonin, and the potential neuroprotectant, deprenyl, as inhibitors of quinolinic acid-induced brain damage. Injections were made into the hippocampus of anaesthetized rats, which were allowed to recover before the brains were taken for histology and the counting of surviving neurones. 2. Quinolinic acid (120 nmols) induced damage to the pyramidal cell layer, which was prevented by the co-administration of melatonin (5 nmols locally plus 2x20 mg kg(-1) i.p.). This protective effect was not prevented by the melatonin receptor blocker luzindole. Neuronal damage produced by NMDA (120 nmols) was not prevented by melatonin. 3. Quinolinic acid increased the formation of lipid peroxidation products from hippocampal tissue and this effect was prevented by melatonin. 4. Deprenyl also prevented quinolinic acid-induced damage at a dose of 50 nmols but not 10 nmols plus 2x1.0 mg kg(-1) i.p. The non-selective monoamine oxidase inhibitor nialamide (10 and 50 nmols plus 2x25 mg kg(-1)) did not afford protection. 5. The results suggest that quinolinic acid-induced neuronal damage can be prevented by a receptor-independent action of melatonin and deprenyl, agents which can act as a potent free radical scavenger and can increase the activity of endogenous antioxidant enzymes respectively. This suggests that free radical formation contributes significantly to quinolinic acid-induced damage in vivo. PMID: 10588931, UI: 20057720 J Neural Transm Suppl 1998;52:315-20 Related Articles, Books, LinkOut Long-term administration of (-)-deprenyl increases mortality in male Wistar rats. Gallagher IM, Clow A, Glover V Department of Paediatrics, Queen Charlotte's & Chelsea Hospital, London, United Kingdom. Long-term administration of the monoamine oxidase inhibitor (-)-deprenyl (0.5 mg/Kg) for up to 20 months significantly increased mortality in the male Wistar rat, whereas the dopamine agonist pergolide (0.4 mg/Kg) and the antioxidant diethyldithiocarbamate (400 mg/Kg) had no significant effect on mortality. The increased mortality was not related to dietary intake or body weight of the rats. This is of interest in the light of recent evidence that (-)-deprenyl increases mortality in humans. PMID: 9564632, UI: 98225820 Life Sci 1997;61(11):1037-44 Related Articles, Books, LinkOut Treatment with L-deprenyl prolongs life in elderly dogs. Ruehl WW, Entriken TL, Muggenburg BA, Bruyette DS, Griffith WC, Hahn FF Deprenyl Animal Health, Overland Park, KS 66210, USA. Eighty two beagle dogs ranging in age from 2.8 to 16.4 years and in weight from 6.3 to 15.8 kg were allotted to 41 pairs and administered placebo or 1 mg/kg L-deprenyl orally once daily for 2 years and 10 weeks. When survivorship for all dogs in the study was analyzed there was no significant difference between the L-deprenyl and placebo treated groups, most likely due to the (expected) survival of virtually all young dogs in both groups for the duration of the study. To assess whether L-deprenyl treatment begun in later life might enhance canine longevity in a fashion similar to that documented in rodents we also examined survival in a subset of elderly dogs who were between the ages of 10 and 15 yrs at the start of tablet administration and who received tablets for at least 6 months. In this subset, dogs in the L-deprenyl group survived longer (p < 0.05) than dogs in the placebo group. Twelve of 15 (80%) dogs in the L-deprenyl group survived to the conclusion of the study, in contrast to only 7 of 18 (39%) of the dogs who received placebo (P=0.017). Furthermore, by the time the first L-deprenyl treated dog died on day 427, 5 placebo treated dogs had already succumbed, the first on day 295. Specifically with respect to dogs, the findings reported herein suggest daily oral administration of 1 mg/kg L-deprenyl prolongs life when begun in relatively healthy dogs 10-15 years of age and maintained for the duration of the individual's life, but in any event for no less than six months. PMID: 9307048, UI: 97450607 Eur J Pharmacol 1997 May 30;327(2-3):215-20 Related Articles, Books, LinkOut (-)-Deprenyl treatment restores serum insulin-like growth factor-I (IGF-I) levels in aged rats to young rat level. De la Cruz CP, Revilla E, Rodriguez-Gomez JA, Vizuete ML, Cano J, Machado A Departamento de Bioquimica, Bromatologia y Toxicologia, Facultad de Farmacia, Universidad de Sevilla, Spain. We studied the effects of treatment with (-)-deprenyl, a monoamine oxidase B inhibitor, on plasma levels of insulin-like growth factor-I (IGF-I) (as indicator of growth hormone (GH) secretion), levels of monoamines and their metabolites, and the activity and content of tyrosine hydroxylase - the rate-limiting enzyme in the biosynthesis of catecholamines - in the hypothalamus and hypophysis of old male rats. Male Wistar rats (22 months old) were treated with 2 mg deprenyl/kg body weight s.c. three times a week for 2 months. At the end of the treatment period, blood was collected for measurement of plasma IGF-I levels by radioimmunoassay (RIA). The concentrations of dopamine, serotonin (5-HT) and their main metabolites were determined by high performance liquid chromatography (HPLC) with electrochemical detection, and the tyrosine hydroxylase content in hypothalamus and hypophysis was determined by enzyme-linked immunoabsorbent assay (ELISA). (-)-Deprenyl treatment produced a pronounced increase in dopamine and 5-HT in both the hypothalamus and hypophysis (P < 0.01). The main dopaminergic metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), decreased in hypothalamus but not in hypophysis, and treatment had no effect on the concentration of 5-hydroxyindole-3-acetic acid (5-HIAA). The tyrosine hydroxylase activity and tyrosine hydroxylase content increased in hypothalamus and hypophysis (P < 0.05). In the hypophysis the increase in tyrosine hydroxylase activity was consistent with the increase in tyrosine hydroxylase amount. Moreover, (-)-deprenyl treatment restored the IGF-I plasma levels in old rats to a concentration similar to those found in young animals. Postulated anti-aging effects of (-)-deprenyl could hence be due to restoration of hypothalamic hormones such as GH. PMID: 9200562, UI: 97344035 Neurobiol Aging 1997 May-Jun;18(3):309-18 Related Articles, Books, LinkOut Long-term treatment of male F344 rats with deprenyl: assessment of effects on longevity, behavior, and brain function. Bickford PC, Adams CE, Boyson SJ, Curella P, Gerhardt GA, Heron C, Ivy GO, Lin AM, Murphy MP, Poth K, Wallace DR, Young DA, Zahniser NR, Rose GM Medical Research Service, Veterans Affairs Medical Center, Denver, CO 80220, USA. L-Deprenyl (selegiline) was chronically administered to male Fischer 344 rats via their drinking water beginning at 54 weeks of age (estimated daily dose: 0.5 mg/kg/day). Beginning at 84 weeks of age, the rats were behaviorally evaluated using a sensorimotor battery, a motor-learning task, and the Morris water maze. At 118 weeks of age, cerebellar noradrenergic function was evaluated in the surviving rats using in vivo electrochemistry. The rats were then sacrificed to measure brain monoamine oxidase activity and perform quantitative autoradiography to evaluate the effect of chronic deprenyl treatment on beta-adrenergic receptors in the cerebellum, alpha 2-adrenergic receptors several brain regions, and D1 and D2 dopamine receptors in the striatum. Deprenyl treatment reduced brain monoamine oxidase B activity by 85%, but had no effect on brain monoamine oxidase A. A clear effect of chronic deprenyl treatment upon longevity was not observed. Several measures of CNS function were altered in the deprenyl-treated animals: 1) spatial learning in the Morris water maze was improved; 2) electrochemical signals recorded following local application of NE were reduced, and the responsiveness to the reuptake blocker nomifensine was enhanced, in the cerebellum; 3) beta-adrenergic receptor binding affinity was increased in the cerebellum; 4) alpha 2-adrenergic receptor density was increased in the inferior colliculus; and 5) striatal D1 dopamine receptor density was reduced but binding affinity was enhanced. In contrast, chronic deprenyl treatment did not cause changes in: 1) sensorimotor function, as evaluated by balance beam, inclined screen, or wire hang tasks; 2) motor learning; 3) alpha 2-adrenergic receptor density in any region examined except for the inferior colliculus, or binding affinity in any region examined; or 4) striatal D2 dopamine receptor number or affinity. Thus, long-term oral administration of deprenyl extended the functional life span of rats with respect to cognitive, but not motor, performance. PMID: 9263197, UI: 97408678 J Gerontol A Biol Sci Med Sci 1996 Nov;51(6):B448-53 Related Articles, Books, LinkOut L-deprenyl treatment in aged mice slightly increases life spans, and greatly reduces fecundity by aged males. Archer JR, Harrison DE Jackson Laboratory, Bar Harbor, Maine, USA. Male and female B6D2F1 (C57BL/6J x DBA/2J)F1 and B6CBAF1 (C57BL/6J x CBA/CaHT6J)F1 mice were injected subcutaneously 3 times a week with L-deprenyl (0.25 mg/kg) starting at mean ages of 26 months and 18.5 months, respectively. Life spans of aging mice were increased 6-9% by the drug. While none of the life span effects were significant for a single genotype and gender, life spans were significantly longer in L-deprenyl-treated animals (p = .011) when all data were combined. L-deprenyl-injected mice consumed about the same amounts of food as controls: L-deprenyl 3.1 g/day, control 3.3 g/day, after 7 months of treatment. There were no significant effects of L-deprenyl on measures of changes with age in the following biological systems: activity, excitement, red blood cell mass, collagen denaturation rate, and wound healing rate. L-deprenyl-treated B6CBAF1 males and females were significantly heavier than controls after 4-6 months of treatment. To measure fecundity, B6CBAF1 males at an average age of 750 days were each caged with two young B6 females; 10 of 17 L-deprenyl-injected males sired an average of 31.3 pups per male, while 14 of 24 controls sired 82.1 pups per male. PMID: 8914495, UI: 97071649 Acta Physiol Hung 1996;84(3):277-8 Related Articles, Books, LinkOut Longevity treatment with (-)deprenyl in female rats: effect on copulatory activity and lifespan. Dallo J, Koles L Department of Pharmacology, Semmelweis University of Medicine, Budapest, Hungary. Six months old ovariectomized female rats (n = 9) were treated with (-)deprenyl in a dose of 0.25 mg/kg s.c. three times a week, and (n = 9) with physiologic saline (0.1 ml/100 g) till decay. It was found that control females (n = 9) decayed within the age of fifteen months while the members of the (-)deprenyl treated group were all alive at that age. Moreover three (-)deprenyl treated female rats reached 36 months of age. Sexual activity was quite absent in both groups. The data suggests that (-)deprenyl extended the lifespan of female rats only in total absence of gonadal hormones and sexual activity. PMID: 9219605, UI: 97363311 Neurology 1998 Sep;51(3):825-30 Related Articles, Books, LinkOut Effect of selegiline on mortality in patients with Parkinson's disease: a meta-analysis. Olanow CW, Myllyla VV, Sotaniemi KA, Larsen JP, Palhagen S, Przuntek H, Heinonen EH, Kilkku O, Lammintausta R, Maki-Ikola O, Rinne UK Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. INTRODUCTION: The Parkinson's Disease Research Group of the United Kingdom (PDRG-UK) reported increased mortality in PD patients treated with levodopa plus selegiline compared with those treated with levodopa alone. METHODS: We performed a meta-analysis on five long-term, prospective, randomized trials of selegiline in patients with untreated PD. Included in the analysis were four randomized, double-blind, placebo-controlled studies and one randomized, double-blind, placebo-controlled study of 2 years' duration followed by long-term, open follow-up. RESULTS: The mean duration of follow-up was 4.1 +/- 1.8 years. There were 14 deaths in 297 selegiline-treated patients (4.7%) and 17 deaths in 292 non-selegiline-treated patients (5.8%). The hazard ratio for mortality was 1.02 (95% CI 0.44 to 2.37; p = 0.96). An analysis restricted to patients receiving only levodopa with or without selegiline noted 11 deaths in 257 levodopa/selegiline-treated patients (4.3%) and 11 deaths in 254 patients treated with levodopa alone (4.3%). The hazard ratio was 1.06 (95% CI 0.44 to 2.55; p = 0.90). Death rate per 1,000 patient years was 11.4 in the selegiline group and 14.2 in the nonselegiline group. Kaplan-Meier survival curves reflecting pooled survival data showed no significant difference in duration of survival. The hazard ratio was 0.84 (95% CI 0.41 to 1.70; p = 0.63) for selegiline- versus non-selegiline-treated patients and 1.05 (95% CI 0.46 to 2.43; p = 0.91) for selegiline/levodopa- versus levodopa-treated patients. CONCLUSION: These results contrast with those of the PDRG-UK study and demonstrate no increase in mortality associated with selegiline treatment whether or not patients also received levodopa. Publication Types: Meta-analysis PMID: 9748034, UI: 98418830 BMJ 1998 Jul 25;317(7153):252-4 Related Articles, Books, LinkOut Mortality in people taking selegiline: observational study. Thorogood M, Armstrong B, Nichols T, Hollowell J Health Promotion Research Unit, London School of Hygiene and Tropical Medicine, London WC1E 7HT. m.thorogood@lshtm.ac.uk OBJECTIVE: To evaluate mortality among patients with Parkinson's disease receiving different treatment. DESIGN: Cohort study based on computerised medical records. SETTING: UK General Practice Research Database. SUBJECTS: 12 621 patients aged between 35 and 90 years who had received a prescription for an antiparkinsonian drug, whether or not a diagnosis of Parkinson's disease had been recorded. Patients prescribed an antipsychotic drug before or at the same time as their first antiparkinsonian drug or before age 35 were excluded to avoid including drug-induced Parkinsonism. MAIN OUTCOME MEASURE: Death from any cause. RESULTS: 1720 deaths occurred during 14 000 person-years of observation. There was a non-significant 11% (95% confidence interval 0% to 23%) increase in the risk of death associated with taking selegiline either alone or in combination with levodopa. The death rate was higher among younger patients (aged under 80 years) and those with a recorded diagnosis of Parkinson's disease taking selegiline alone. CONCLUSIONS: The results are compatible with a small excess mortality in people taking selegiline and suggest a larger excess in patients under 80 years of age and those with a confirmed diagnosis of Parkinson's disease taking selegiline without levodopa. Publication Types: Clinical trial Randomized controlled trial PMID: 9677215, UI: 98342288 full text articles on BMJ: http://bmj.com/cgi/search?author1=&author2=&titleabstract=selegiline&fulltext=&fmonth=Jan&fyear=1994&tmonth=Dec&tyear=2000&hits=50&sendit=Search&volume=&firstpage=&fdatedef=1+January+1994&tdatedef=16+December+2000