Amphetamine and 2-phenylethylamine in post-mortem Parkinsonian brain after (-)deprenyl administration

Reynolds, Gavin P.; Riederer, Peter; Sandler, M.; Jellinger, K. A.; Seemann, D

doi:10.1007/bf01246964

Cited by 125 publications

(25 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The main metabolites: methamphetamine (MA) and amphetamine (A) were identified in the brain of the animals after intraperitoneal [62] and subcutaneous [34,58] administration of R-deprenyl. These metabolites were also detected post mortem in various brain regions of treated parkinsonian patients [66]. In the experiments performed in our laboratory, using dual-labeled R-deprenyl, both 14 C-propargyl, indicating the parent compound, and 3 H-phenyl, indicating all metabolites were detected in plasma and various brain regions.…”

Section: Pharmacokinetic Characteristics Of R-deprenylmentioning

confidence: 93%

R-Deprenyl: Pharmacological Spectrum of its Activity

et al. 2010

View full text Add to dashboard Cite

Deprenyl has been discovered by Knoll and co-workers. The R-enantiomer of deprenyl (selegiline) is a selective and irreversible inhibitor of the B-isoform of monoamine oxidase (MAO-B) enzyme. Due to its dopamine potentiating and possible neuroprotective properties it has an established role in the treatment of parkinsonian patients. By inhibiting MAO-B enzyme, R-deprenyl decreases the formation of hydrogen peroxide, alleviating the oxidative stress also reduced by increased expression of antioxidant enzymes (superoxide dismutases and catalase) reported during chronic treatment. It was shown to prevent the detrimental effects of neurotoxins like MPTP and DSP-4. R-Deprenyl elicits neuroprotective and neuronal rescue activities in concentrations too low to inhibit MAO-B. It is extensively metabolized and some of the metabolites possess pharmacological activities, thus their contribution to neuroprotective properties was also suggested. The recently identified deprenyl-N-oxide is extensively studied in our laboratory. Effects other than neuroprotection, like influencing cell adhesion and proliferation cannot be neglected.

show abstract

Section: Pharmacokinetic Characteristics Of R-deprenylmentioning

confidence: 93%

R-Deprenyl: Pharmacological Spectrum of its Activity

et al. 2010

View full text Add to dashboard Cite

show abstract

“…It has been assumed that MAO-A exists both intraneuronally as well as extraneuronally (glia). By contrast MAO-B is known to occur mainly in the extraneuronal compartment comprizing ._c in phenylethylamine as compared to the 40-70% in DA (Riederer etal., 1978(Riederer etal., , 1987Reynolds et al, 1978). This in part can be explained by PEA being almost exclusively oxidized by MAO-B, which is totally inhibited (Riederer and Youdim, 1986).…”

Section: Mao-b Inhibitionmentioning

confidence: 95%

Dopamine metabolism and neurotransmission in primate brain in relationship to monoamine oxidase A and B inhibition

Youdim

Riederer

1993

J. Neural Transmission

Self Cite

View full text Add to dashboard Cite

The "cheese effect", potentiation of sympathomimetic action of indirectly acting amines such as tyramine, the main side effect of irreversible non-selective and selective monoamine oxidase (MAO) A inhibitors, has largely been eliminated in the new generation of reversible selective MAO-A and B and irreversible MAO-B inhibitors. These selective inhibitors are demonstrating unique pharmacology and initial controlled clinical studies are providing evidence to support their action as anti-depressants and anti-Parkinson's disease drugs and possibly as neuroprotectors. Thirty years of experience with non-selective MAO inhibitors has resulted in a better understanding and management of the new generation of MAO inhibitors. Because of their selective action on the specific forms of MAO, which results in selective elevation of brain noradrenaline and serotonin on the one hand and dopamine and phenylethylamine on the other, it is hoped that these drugs will be able to elucidate the functional roles of MAO-A and B subtypes with regards to dopamine metabolism in the human brain.

show abstract

“…The evidence that selegiline and its metabolites can cross the blood-brain barrier comes from postmortem analysis of human brain tissues in patients with Parkinson's disease who have been treated with selegiline (Gerlach et al, 1996). Reynolds et al (1978) also showed higher concentrations of amphetamine and phenylethylamine in Parkinson brains following administration of deprenyl. In the brain, CYP2B6 is expressed in neurons and glial cells in the hippocampus, cerebellum, caudate nucleus, and putamen (Miksys and Tyndale, 2002), and the highest levels of MAO (both A and B) activity are found in caudate nucleus and putamen.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Bupropion Metabolism by Selegiline: Mechanism-Based Inactivation of Human CYP2B6 and Characterization of Glutathione and Peptide Adducts

2012

View full text Add to dashboard Cite

ABSTRACT:Selegiline, the R-enantiomer of deprenyl, is used in the treatment of Parkinson's disease. Bupropion, an antidepressant, often used to treat patients in conjunction with selegiline, is metabolized primarily by CYP2B6. The effect of selegiline on the enzymatic activity of human cytochrome CYP2B6 in a reconstituted system and its effect on the metabolism of bupropion were examined. Selegiline was found to be a mechanism-based inactivator of the 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation (7-EFC) activity of CYP2B6 as well as bupropion metabolism. The inactivations were time-, concentration-, and NADPH-dependent and were characterized by K I values of 0.14 and 0.6 M, k inact values of 0.022 and 0.029 min ؊1, and t 1/2 values of 31.5 and 24 min, respectively. In standard inhibition assays, selegiline increased the K m of CYP2B6 for bupropion from 10 to 92 M and decreased the k cat by ϳ50%. The reduced carbon-monoxide difference spectrum revealed over a 50% loss in the cytochrome P450 spectrum in the inactivated sample, with no loss in heme, and there was ϳ70% loss in enzyme activity. Trapping of the reactive metabolite using GSH led to the identification of a GSH-selegiline conjugate with a m/z 528 that could be explained by hydroxylation of selegiline followed by the addition of glutathione to the propargyl moiety after oxygenation to form the ketene intermediate. Liquid chromatography-tandem mass spectrometry analysis of the labeled protein following digestion with trypsin revealed the peptide 64 DVFTVHLGPR 73 as the peptide modified by the reactive metabolite of selegiline and the site of adduct formation is Asp64.

show abstract

Amphetamine and 2-phenylethylamine in post-mortem Parkinsonian brain after (-)deprenyl administration

Cited by 125 publications

References 8 publications

R-Deprenyl: Pharmacological Spectrum of its Activity

R-Deprenyl: Pharmacological Spectrum of its Activity

Dopamine metabolism and neurotransmission in primate brain in relationship to monoamine oxidase A and B inhibition

Inhibition of Bupropion Metabolism by Selegiline: Mechanism-Based Inactivation of Human CYP2B6 and Characterization of Glutathione and Peptide Adducts

Contact Info

Product

Resources

About