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The impact of methylphenidate and its enantiomers on dopamine synthesis and metabolism in vitro


Bartl, Jasmin; Palazzesi, Ferruccio; Parrinello, Michele; Hommers, Leif; Riederer, Peter; Walitza, Susanne; Grünblatt, Edna (2017). The impact of methylphenidate and its enantiomers on dopamine synthesis and metabolism in vitro. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 79(Pt B):281-288.

Abstract

Methylphenidate (MPH), a psychostimulant, is an effective first-line treatment for the symptoms associated with Attention-Deficit/Hyperactivity Disorder (ADHD). Although most MPH formulations are composed of the racemic 1:1 mixture of the two enantiomers (d- and l-threo), converging lines of evidence indicate that d-threo MPH seems to be superior to the l-isomer. We aimed to investigate whether MPH racemic mixture or pure enantiomers influence the enzyme activity of tyrosine hydroxylase (TH), monoamine oxidase B (MAO-B), catechol-O-methyltransferase (COMT), and aldehyde dehydrogenase (ALDH) in vitro in homogenates of rat PC12 cells incubated with racemic, d- and l-threo MPH (1nM up to 100μM), or a vehicle for control. We could observe dose dependent enhancement of TH activity with d-threo MPH, probably due to its higher affinity to the enzyme, which we could confirm for d-threo versus l-threo MPH via docking and molecular dynamic simulations analysis. MAO-B enzyme activity was found to be enhanced when incubated with both d- and l-isomers but not with the racemic mixture. This conflicting result was hypothesized to be due to possible aggregation of the two enantiomers or other molecular conformations. Such a possible interaction was observed indirectly, when TH was incubated with constant d-threo MPH while increasing l-isomer (increasing total MPH concentrations). Hence, TH activity was slightly decreased with increased l-isomer. In conclusion, the current in vitro investigation points to the stereoselectivity of the investigated enzymes and pharmacological effects of MPH enantiomers.

Abstract

Methylphenidate (MPH), a psychostimulant, is an effective first-line treatment for the symptoms associated with Attention-Deficit/Hyperactivity Disorder (ADHD). Although most MPH formulations are composed of the racemic 1:1 mixture of the two enantiomers (d- and l-threo), converging lines of evidence indicate that d-threo MPH seems to be superior to the l-isomer. We aimed to investigate whether MPH racemic mixture or pure enantiomers influence the enzyme activity of tyrosine hydroxylase (TH), monoamine oxidase B (MAO-B), catechol-O-methyltransferase (COMT), and aldehyde dehydrogenase (ALDH) in vitro in homogenates of rat PC12 cells incubated with racemic, d- and l-threo MPH (1nM up to 100μM), or a vehicle for control. We could observe dose dependent enhancement of TH activity with d-threo MPH, probably due to its higher affinity to the enzyme, which we could confirm for d-threo versus l-threo MPH via docking and molecular dynamic simulations analysis. MAO-B enzyme activity was found to be enhanced when incubated with both d- and l-isomers but not with the racemic mixture. This conflicting result was hypothesized to be due to possible aggregation of the two enantiomers or other molecular conformations. Such a possible interaction was observed indirectly, when TH was incubated with constant d-threo MPH while increasing l-isomer (increasing total MPH concentrations). Hence, TH activity was slightly decreased with increased l-isomer. In conclusion, the current in vitro investigation points to the stereoselectivity of the investigated enzymes and pharmacological effects of MPH enantiomers.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Psychiatric University Hospital Zurich > Center for Child and Adolescent Psychiatry
04 Faculty of Medicine > Neuroscience Center Zurich
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:3 October 2017
Deposited On:08 Aug 2017 14:29
Last Modified:09 Aug 2017 07:28
Publisher:Elsevier
ISSN:0278-5846
Publisher DOI:https://doi.org/10.1016/j.pnpbp.2017.07.002
PubMed ID:28690202

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