Selegiline Research Articles

(-)-Deprenyl fails to promote axonal regeneration of retinal ganglion cells in vitro and in vivo.

(-)-Deprenyl ( L-deprenyl, selegiline hydrochloride), a selective monoamine oxidase B (MAO-B) inhibitor employed in the pharmacological therapy of Parkinson's disease, increases neuronal survival in both animal models of neurodegenerative disorders and acute CNS lesions. Despite intensive investigations, the mechanisms of (-)-deprenyl-mediated neuroprotection remain poorly understood. To test the hypothesis that (-)-deprenyl might have a beneficial effect not only on neuronal survival, but also on axonal regeneration, we describe here experiments performed in vitro and in vivo which clearly demonstrate that (-)-deprenyl fails to promote axonal regeneration of severed rat retinal ganglion cells (RGCs). Furthermore, (-)-deprenyl was not able to overcome free-radical-induced RGC axon degeneration. These results challenge the notion that (-)-deprenyl might be useful as a monotherapy for acute CNS lesions and give rise to a more critical viewpoint of the trophic-like function of this widely used therapeutic agent.

Urinary excretion of selegiline N -oxide, a new indicator for selegiline administration in man

1. The metabolism of selegiline (SG) has been studied by investigating the timecourse of urinary excretion of SG and its metabolites using high-performance liquid chromatography-electrospray ionization mass spectrometry (LC-ESI MS) in combination with solid-phase extraction. 2. The excretion profiles of SG and its four major metabolites, selegiline- N -oxide (SGO), N -desmethylselegiline (DM-SG), methamphetamine (MA) and amphetamine (AP), were investigated in six healthy volunteers after oral administrations of SG hydrochloride in a single dose of 2.5 or 7.5mg, and a repeat twice-daily dose of 5.0 mg day -1 (for 3 days). 3. The cumulative amount of SGO excreted within approximately the first 8-12h was comparable with MA, and the amount in the first 72 h was 2.0-7.8 times larger (2.8-13.2% of the dose) than that of DM-SG. 4. These results demonstrate that SGO can be used in place of DM-SG, which is known to be a main specific metabolite of SG, as a new indicator for the discrimination of SG use compared with MA abuse.

Metabolism of Selegiline Hydrochloride, a Selective Monoamine B-type Inhibitor, in Human Liver Microsomes

The participation of cytochrome P-450 (CYP) isoforms in the metabolism of selegiline was investigated. Experiments using recombinant CYP isoforms expressed in human lymphoblastoid cells showed CYP2B6 to be the major CYP isoform involved with the metabolism of selegiline. CYP1A2 and CYP3A4 also contributed to the metabolism of selegiline but their catalytic activities were much less than that of CYP2B6. CYP2B6 had a higher affinity for both N-depropagylation (K(m)=21.4 microM) and N-demethylation (K(m)=25.2 microM) of selegiline than CYP3A4 and CYP1A2. In immunoinhibition studies using mixed human hepatic microsomes, selegiline N-depropagylation activity was most strongly inhibited by anti-CYP2B and anti-CYP3A antibodies, while selegiline N-demethylation activity was most inhibited by anti-CYP2B antibody. In CYP2B6-rich human hepatic microsomes, anti-CYP2B antibody had the strongest inhibitory effects on both activities. Selegiline inhibited CYP2B6-mediated (S)-mephenytoin N-demethylation activity and CYP2C19-mediated (S)-mephenytoin 4'-hydroxylation activity. These findings suggest that attention should be paid to the drug-drug interaction associated with CYP2B6 and CYP2C19. In conclusion, CYP2B6 participates in the metabolism of selegiline but the degree of its contribution varies with the level of its expression in human liver.

The effects of oral selegiline hydrochloride on learning and training in the dog: a psychobiological interpretation

1. Twenty two healthy, non-problem dogs were assessed for their acquisition of three different learning tasks on consecutive days and on the extinction of the response in the third. In Task 1, dogs were trained to walk in a circle on command. In Task 2, dogs were trained to retreat and sit on a mat. In Task 3, dogs were assessed for the acquisition and extinction of an operant response (pawing a panel). 2. Dogs were orally administered a placebo or selegiline hydrochloride at a dose of 0.5mg/kg for a period of three weeks prior to testing and during the test period. 3. Dog's treated with selegiline tended to perform better at tasks which were clearly lured with a motivationally significant cue, performing a first correct response sooner and requiring fewer reinforcements to reach the success criterion. They were also significantly more likely to walk over a novel object placed on the floor of the test arena. In the absence of a significant lure, the selegiline treated dogs took significantly longer to reach the required performance criterion for the operant task. These dogs also extinguished their response more rapidly than the control group 4. In the third task, selegiline treated dogs were significantly less likely to look away and throughout all tasks these dogs tended to be less distracted than the placebo group. 5. These findings and other reports associated with the effects of selegiline on learning may be explained by reference to the effects of selegiline on dopaminergic structures associated with positive incentive motivation.

Simultaneous determination of selegiline- N-oxide, a new indicator for selegiline administration, and other metabolites in urine by high-performance liquid chromatography–electrospray ionization mass spectrometry

In order to discriminate selegiline (SG) use from methamphetamine (MA) use, the urinary metabolites of SG users have been investigated using high-performance liquid chromatography (HPLC)–electrospray ionization mass spectrometry (HPLC–ESI–MS). Selegiline- N-oxide (SGO), a specific metabolite of SG, was for the first time detected in the urine, in addition to other metabolites MA, amphetamine (AP) and desmethylselegiline (DM-SG). A combination of a Sep-pak C 18 cartridge for the solid-phase extraction, a semi-micro SCX column (1.5 mm I.D.×150 mm) for HPLC separation and ESI–MS for detection provided a simple and sensitive procedure for the simultaneous determination of these analytes. Acetonitrile–10 m M ammonium formate buffer adjusted to pH 3.0 (70:30, v/v) at a flow-rate of 0.1 ml/min was found to be the most effective mobile phase. Linear calibration curves were obtained over the concentration range from 0.5 to 100 ng/ml for all the analytes by monitoring each protonated molecular ion in the selected ion monitoring (SIM) mode. The detection limits ranged from 0.1 to 0.5 ng/ml. Upon applying the scan mode, 10–20 ng/ml were the detection limits. Quantitative investigation utilizing this revealed that SGO was about three times more abundant (47 ng/ml, 79 ng/ml) than DM-SG in two SG users’ urine samples tested here. This newly-detected, specific metabolite SGO was found to be an effective indicator for SG administration.

Attenuation of Paraquat-Induced Dopaminergic Toxicity on the Substantia Nigra by (−)-Deprenyl in Vivo

(−)-Deprenyl (DEP) had been shown to slow of progression of Parkinson's disease (PD). The present study sought to determine whether DEP would attenuate the nigrostriatal system damage induced by intranigral administration of the herbicide paraquat (PQ) as a model of parkinsonism in vivo. Neurochemical and behavioral observations of Wistar rats were the focus of our study. In the neurochemical observation, the PQ injected in the rats caused dose-dependent depletion of dopamine (DA) in the ipsilateral striata. The coadministration of DEP with PQ partially increased the striatal DA level. The prediction of the striatal DA levels was calculated by regression coefficients obtained from multiple linear regression (r2 = 0.82): DA level (% of control) = 103.34 − 9.58 PQ (nmol) + 0.79 DEP (nmol). It was demonstrated that the high dose of 20 nmol DEP could significant attenuate the PQ (5 nmol)-elicited dopaminergic toxicity (p < 0.05). In the behavioral observation, the intranigral injection of PQ into the rats caused a rotation behavior contralateral to the lesioned side in response to apomorphine administration (0.5 mg/kg, sc). This apomorphine-induced rotational behavior could also be attenuated significantly by coadministration of DEP (20 nmol) and PQ (5 nmol) compared with PQ-treated (5 nmol) animals (p < 0.05). The above observations indicate that DEP could provide a protective effect on the moderate injury elicited by PQ toxicity of the nigrostrital dopaminergic system. DEP might be a useful therapeutic agent in treating patients with early-stage PD.

Enhancement of central nervous system pathology in early simian immunodeficiency virus infection by dopaminergic drugs.

Human immunodeficiency virus infection (HIV) at late stages of the disease is accompanied by neurological complications, including motor, behavioral and cognitive impairment. Using simian immunodeficiency virus (SIV)-infected rhesus monkeys, an animal model of HIV infection, we found that during the asymptomatic SIV infection dopamine (DA) deficits are early components of central nervous system (CNS) dysfunction. To investigate the role of the DA system in SIV infection and to restore the DA deficiency, we administered selegiline, an agent with DAergic and neuroprotective properties, to SIV-infected monkeys. Selegiline increased DA availability but induced CNS vacuolization, SIV encephalitic lesions, and enhanced CNS viral replication during early SIV infection. The pathological changes seem to be mediated by DA, as treatment with L-DOPA, the precursor of DA, had similar effects. We propose that any natural or induced DAergic dysregulation which results in increased DA availability may potentiate HIV-associated neurological disease (ND). Our findings raise new questions regarding the pathogenesis of HIV-ND and generate concerns about the safety of dopaminergic drugs in the clinical management of HIV-infected patients.

N-methyl,N-propargyl-2-phenylethylamine (MPPE), an analog of deprenyl, increases neuronal cell survival in thiamin deficiency encephalopathy

Wernicke encephalopathy (WE) is a neurological disorder attributable to thiamin deficiency (TD). Severe TD, in humans and animals, results in highly selective lesions with a symmetrical distribution in brain regions including the mammillary bodies, thalamus, inferior colliculi, periaqueductal and periventricular regions, and inferior olivary nuclei. Experimental TD in the rat provides a robust and reproducible model that allows investigations of mechanisms underlying both apoptotic and necrotic neuronal death. (-)-Deprenyl (DEP), a selective monoamine oxidase B (MAO-B) inhibitor, has been reported to be clinically effective in the treatment of neurodegenerative disorders and to have neuroprotective and/or neurorescue properties in a variety of ex vivo and in vitro paradigms, including experimental TD. Because the metabolites of DEP, amphetamine, and methamphetamine may have adverse behavioral effects, a DEP analog, N-methyl,N-propargyl-2-phenylethylamine (MPPE) that is not metabolized to amphetamine or methamphetamine was examined in the present studies. Results showed that TD rats treated with MPPE had significantly increased neuronal cell counts compared to vehicle-treated TD rats. MPPE, like DEP, also significantly decreased the density of reactive astrocytes and the infiltration of microglia/macrophages. Chronic treatment with DEP or MPPE resulted in significant inhibition of MAO-A and MAO-B activity compared to VEH-treated animals. Thus, MPPE, an inhibitor of MAO activity, was shown to be neuroprotective in the TD model of neuronal cell death. Drug Dev. Res. 51:244–252, 2000. © 2001 Wiley-Liss, Inc.

Differential effects of l-deprenyl on MPP +- and MPTP-induced dopamine overflow in microdialysates of striatum and nucleus accumbens

The present studies investigated the effects of l-deprenyl, 1-methyl-4-phenylpyridinium ion (MPP +) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the efflux of dopamine and its metabolites in microdialysates of striatum and nucleus accumbens in rats. l-Deprenyl or l-amphetamine perfusion into striatum had no effects on basal dopamine efflux, though l-deprenyl reduced the basal efflux of dihydroxyphenylacetic acid and homovanillic acid. MPP + or MPTP perfusion into striatum significantly increased the dopamine efflux, and the action of MPTP was more potent than that of MPP +. Pretreatment with l-deprenyl antagonized the actions of MPP + and MPTP. The striatal dopamine efflux of rats was gradually restored by itself after the overflow caused by 2-h perfusion of the dopaminergic neurotoxins, while l-deprenyl could not accelerate the recovery. Perfusion with l-deprenyl or l-amphetamine, but not pargyline, into nucleus accumbens increased the dopamine efflux in a dose-dependent fashion, which could be antagonized by haloperidol pretreatment. MPP + or MPTP perfusion into nucleus accumbens also increased the dopamine efflux, and the action of MPTP was also more potent than that of MPP +. Pretreatment with l-deprenyl could not antagonize the actions of MPP + and MPTP. These findings suggest that l-deprenyl, MPP + and MPTP induce differential effects on nigrostriatal and mesolimbic dopaminergic pathways in vivo. l-Deprenyl has neuroprotective rather than neurorestorative action against MPP +- and MPTP-induced dopamine overflow from striatum. Further, l-deprenyl-induced dopamine overflow from nucleus accumbens may explain the amphetamine-like reinforcing property of l-deprenyl.

Prospects for Pharmacological Intervention in Alzheimer Disease

Alzheimer disease (AD) involves neuronal degeneration with impaired cholinergic transmission in the cerebral cortex and hippocampus in areas of the brain particularly associated with memory and higher intellectual functioning. Other neurotransmitter deficits also occur, but the mechanisms underlying the widespread impairment of synaptic functions remain uncertain. Research on the molecular basis of AD has elucidated a pathogenic pathway from which a range of rational pharmacological interventions has emerged. Although at least 3 cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine tartrate) are now available and provide patients with modest relief, the most promising strategy involves approaches to retarding, halting, or preventing the formation or accumulation of beta-amyloid (Abeta) plaques. Estrogen is believed to have antioxidant or other anti-Abeta effects, as hormonal replacement therapy in women with menopause is associated with a reduced risk or delayed onset of AD. The association between nonsteroidal anti-inflammatory drugs and a reduced risk of AD has not yet been confirmed, but these agents may protect the brain from the reactive glial and microglial responses associated with Abeta deposition. Also, recent studies suggested that antioxidants, such as vitamin E taken alone or in combination with selegiline hydrochloride, can delay the progression of AD. Despite these encouraging results, no current therapy has been shown to halt or reverse the underlying disease process. The proof of the principle that anti-Abeta drugs will work in the transgenic models of AD is eagerly awaited with the expectation that they will eventually prove successful in humans.

The Anxiolytic-Like Properties of Two Selective MAOIs, Moclobemide and Selegiline, in a Standard and an Enhanced Light/Dark Aversion Test

DE ANGELIS, L., AND C. FURLAN. The anxiolytic-like properties of two selective MAOIs, moclobemide and selegiline, in a standard and an enhanced light/dark aversion test. PHARMACOL BIOCHEM BEHAV 65(4) 649–653, 2000.—The present study was designed to investigate the putative anxiolytic effects of moclobemide (MOC), a reversible inhibitor of type A monoamine oxidase enzyme (RIMA) antidepressant, in an experimental model of anxiety in mice. The test selected was the light/dark aversion test. In the present investigation, an anxiogenic-like behavior was induced by light, alone as the stimulus (standard version of the test) or by pretreatment with a subconvulsant dose of pentylenetetrazole (PTZ) (15 mg/kg IP) 45 min before testing (“enhanced” version of the test). In mice, the effect of repeated administration for 2 weeks of MOC (0.5, 1, and 5 mg/kg IP) was compared with those of selegiline (SEL) (5, 10, and 20 mg/kg IP), an irreversible and selective MAO-B inhibitor. For comparative purpose, the chronic effect of an established reference anxiolytic, such as lorazepam (LOR) (0.025, 0.05, and 0.10 mg/kg IP), was also evaluated. Results demonstrated that PTZ-treated mice showed a decrease in the number of transitions as well as in the time spent in the lit area, when compared with vehicle controls, an effect characteristic of an anxiogenic response. This anxiogenic-like behavior was reduced by chronic administration of LOR as well as MOC, suggesting an anxiolytic-like effect (as shown in the “standard” version of the test). In addition, the increased aversion of mice for the light compartment of the light/dark box was significantly reduced compared to PTZ-treated mice or vehicle controls. SEL failed to significantly alter the anxiogenic-like behavior induced by subconvulsant doses of PTZ. These data provide additional evidence for the anxiolytic-like effects of MOC administered chronically in the mouse.

Narcolepsy. Signs, symptoms, differential diagnosis, and management.

Narcolepsy is a chronic neurologic disorder characterized by excessive daytime sleepiness and cataplexy and less often by hypnagogic hallucinations and sleep paralysis. While patients report excessive daytime sleepiness and cataplexy as the more frequent symptoms of this condition, excessive daytime sleepiness is generally believed to be the most debilitating. Narcolepsy often is undiagnosed or misdiagnosed for a variety of reasons. Although confirmation of an initial diagnosis requires monitoring of physiologic variables conducted at a sleep center by specialists, the primary care physician has a critical role in the identification and management of this incurable affliction. This article provides recommendations for the diagnosis and management of narcolepsy. The cataplexy associated with narcolepsy can be managed with tricyclic antidepressants. The excessive sleepiness is managed with stimulants but newer agents, such as modafinil, which will be marketed as Provigil, and selegiline hydrochloride, with fewer adverse effects and less abuse potential, may offer means of promoting daytime wakefulness. Groups such as the National Sleep Foundation, Washington, DC, and the Narcolepsy Network, Cincinnati, Ohio, can provide patients with needed support and information.

Mortality not increased in selegiline recipients

Mortality not increased in selegiline recipients

More on Early Selegiline Treatment in Parkinson's.

A controversial trial from the U.K. previously reported increased mortality in patients with early, mild Parkinson's disease when they were treated

Increased mortality with selegiline + levodopa

Increased mortality with selegiline + levodopa

Increased mortality with selegiline + levodopa

Increased mortality with selegiline + levodopa

Using entacapone and selegiline in Parkinson??s disease

Using entacapone and selegiline in Parkinson??s disease

Vitamin E and Selegiline for Alzheimer's Disease?

Because oxidative damage plays a role in the pathogenesis of Alzheimer's disease, antioxidant drugs could potentially delay disease progression. This

Pharmacokinetics and safety of a selegiline transdermal system relative to single-dose oral administration in the elderly.

This open-label, two-phase cross-over study compared the safety and pharmacokinetics of transdermally administered selegiline and orally administered selegiline hydrochloride in elderly men and women (n = 6/gender). Single oral doses of 10 mg selegiline hydrochloride and single 1/2 and 1 selegiline transdermal system (STS) (delivering similar3.4 and 6.3 mg over 24 h) administered topically were safe and well tolerated in all subjects. Plasma concentrations of selegiline (SEL) and its N-desmethylselegiline (DMS), L-amphetamine (AMP), and L-methamphetamine (MET) metabolites were measured using an HPLC/MS/MS method with lower quantitation limits of 10, 50, 200, and 200 pg/mL, respectively. No significant gender-related differences were observed following single 10-mg oral doses of selegiline hydrochloride or single 24-h applications of 1/2 and 1 STS to elderly males and females. The low level of dermal irritation as assessed by erythema and edema rating scales suggests that the STS was similar to Band-Aid (Johnson & Johnson, Skillman, NJ) controls. The transdermal administration of SEL bypasses the first-pass metabolism, that is significant after oral administration (first-pass extraction >90%). Peak plasma levels of 1.19, 23.22, 4.78, and 14.08 ng/mL were observed for SEL, DMS, AMP, and MET after a single 10-mg oral dose to the elderly. By contrast, peak plasma levels of 2.10, 0.85, 1.06, and 2.71 ng/mL were observed for SEL, DMS, AMP, and MET after a single 24-h application of 1 STS. Comparison of dose-corrected areas under the curve (AUCs) (made under the assumption of linear pharmacokinetics) indicate the SEL exposure after transdermal application was more than 50-fold greater than that obtained orally. This increase in systemic SEL exposure at the expense of metabolite formation that is reduced to <70% of that obtained orally for N-DMS, L-AMP, and L-MET is hypothesized to be of therapeutic value in patients with a variety of neurodegenerative and psychiatric disorders.

Current trends in the pharmacologic and surgical treatment of Parkinson's disease.

Recently, there has been a surge in the research regarding the pharmacologic and surgical treatment of Parkinson's disease. This article reviews the latest modes of medical and surgical therapy for Parkinson's disease. The latest drug therapy has consisted of levodopa, a combination of levodopa and carbidopa (Sinemet/Sinemet CR), and monoamine oxidase type B (MAO-B) inhibitors (selegiline hydrochloride). The surgical treatment modalities have been stereotaxic implantations of dopamine-producing tissues (such as adrenal medulla and fetal mesencephalon) into the caudate nucleus and ventral pallidotomy of patients with Parkinson's disease. The most recent work has been in the field of gene therapy. The implantation of cells genetically modified to express trophic factors and tyrosine hydroxylase for the synthesis of L-dopa from tyrosine has been proposed as a possible route for the treatment of Parkinson's disease. Although the etiology of the disease is still unknown, two recent theories are discussed.