MAO and L-DOPA treatment of Parkinson’s disease

Tyce, Gertrude M.; Dousa, M. K.; Muenter, Manfred D.

doi:10.1007/978-3-7091-9050-0_22

Cited by 6 publications

(4 citation statements)

References 15 publications

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“…Selegiline, a MAO inhibitor, has long been used as a therapeutic treatment for PD [56]–[59]. Beyond the prediction on ultimate effects of MAO inhibition, our results also suggest that inhibition of MAO may have undesired side effects.…”

Section: Discussionmentioning

confidence: 68%

“…Our model results showing that the dopamine concentration in the brain increases if the enzyme MAO is inhibited are consistent with clinical observations. Selegiline, a MAO inhibitor, has long been used as a therapeutic treatment for PD [56] – [59] . Beyond the prediction on ultimate effects of MAO inhibition, our results also suggest that inhibition of MAO may have undesired side effects.…”

Section: Discussionmentioning

confidence: 99%

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Computational Systems Analysis of Dopamine Metabolism

Miller

Voit

2008

PLoS ONE

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A prominent feature of Parkinson's disease (PD) is the loss of dopamine in the striatum, and many therapeutic interventions for the disease are aimed at restoring dopamine signaling. Dopamine signaling includes the synthesis, storage, release, and recycling of dopamine in the presynaptic terminal and activation of pre- and post-synaptic receptors and various downstream signaling cascades. As an aid that might facilitate our understanding of dopamine dynamics in the pathogenesis and treatment in PD, we have begun to merge currently available information and expert knowledge regarding presynaptic dopamine homeostasis into a computational model, following the guidelines of biochemical systems theory. After subjecting our model to mathematical diagnosis and analysis, we made direct comparisons between model predictions and experimental observations and found that the model exhibited a high degree of predictive capacity with respect to genetic and pharmacological changes in gene expression or function. Our results suggest potential approaches to restoring the dopamine imbalance and the associated generation of oxidative stress. While the proposed model of dopamine metabolism is preliminary, future extensions and refinements may eventually serve as an in silico platform for prescreening potential therapeutics, identifying immediate side effects, screening for biomarkers, and assessing the impact of risk factors of the disease.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Computational Systems Analysis of Dopamine Metabolism

Miller

Voit

2008

PLoS ONE

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“…MAO B inhibitors, such as Selegiline, have long been used as a therapeutic agent for PD (Fernandez and Chen, 2007; Stocchi et al, 2006; Tyce et al, 1990; Youdim and Bakhle, 2006). This inhibition is thought to prevent the breakdown of extracellular dopamine by MAO B .…”

Section: Discussionmentioning

confidence: 99%

Computational analysis of determinants of dopamine (DA) dysfunction in DA nerve terminals

Miller

Voit

2009

Synapse

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Dopamine signaling is involved in a number of brain pathways and its disruption has been suggested to be involved in the several disease states, including Parkinson's disease (PD), schizophrenia, and attention deficit hyperactivity disorder (ADHD). It has been hypothesized that altered storage, release, and reuptake of dopamine contributes to both the hypo-and hyperdopaminergic states that exist in various diseases. Here we use our recently described mathematical model of dopamine metabolism, combined with a comprehensive Monte Carlo simulation analysis, to identify key determinants of dopamine metabolism associated with the dysregulation of dopamine homeostasis that may contribute to the pathogenesis of dopaminebased disorders. Our model reveals that the dopamine transporter (DAT), the vesicular monoamine transporter (VMAT2), and the enzyme monoamine oxidase (MAO) are the most influential components controlling the synaptic level of dopamine and the formation of toxic intracellular metabolites. The results are consistent with experimental observations and point to metabolic processes and combinations of processes that may be biochemical drivers of dopamine neuron degeneration. Since many of the identified components can be targeted therapeutically, the model may aid in the design of combined therapeutic regimens aimed at restoring proper dopamine signaling with toxic intermediates under control.

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“…Under normal conditions, dopamine homeostasis is maintained at a stable level through feedback controls that govern the dopamine cycle through vesicular sequestration, release, and reuptake. However, homeostasis can be severely disturbed by a variety of factors or actions that affect key players such as VMAT2, DAT, MAO, and COMT [10,25,28,43,62,63] . Animal experiments and clinical observations of drug users have shown that a single high dose or repeated low doses of dopamine-like drugs can cause severe dopamine dysregulation [22,25,42,44,70] .…”

Section: Introductionmentioning

confidence: 99%

A Mathematical Model of Presynaptic Dopamine Homeostasis: Implications for Schizophrenia

Zhou¹,

Miller²,

Voit³

2008

Pharmacopsychiatry

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Several lines of evidence implicate altered dopamine neurotransmission in schizophrenia. Current drugs for schizophrenia focus on postsynaptic sites of the dopamine signaling pathways, but do not target presynaptic dopamine metabolism. We have begun to develop a mathematical model of dopamine homeostasis, which will aid our understanding of how genetic, environmental, and pharmacological factors alter the functioning of the presynaptic dopamine neuron. Formulated within the modeling framework of BIOCHEMICAL SYSTEMS THEORY, the mathematical model integrates relevant metabolites, enzymes, transporters, and regulators involved in the control of the biochemical environment within the dopamine neuron. In this report we use the model to assess several components and factors that affect the dopamine neuron and have been implicated in schizophrenia. These include the enzymes COMT, MAO, and TH, different dopamine transporters, as well as administration of amphetamine or cocaine. We also investigate scenarios that could increase (or decrease) dopamine neurotransmission and thus exacerbate (or alleviate) symptoms of schizophrenia. Our results indicate that the model predicts the effects of various factors related to schizophrenia on the homeostasis of the presynaptic dopamine neuron rather well. Upon further refinements and testing, the model has the potential of serving as a tool for screening novel therapeutics aimed at altering presynaptic dopamine function and thereby potentially ameliorating some of the symptomology of schizophrenia.

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MAO and L-DOPA treatment of Parkinson’s disease

Cited by 6 publications

References 15 publications

Computational Systems Analysis of Dopamine Metabolism

Computational Systems Analysis of Dopamine Metabolism

Computational analysis of determinants of dopamine (DA) dysfunction in DA nerve terminals

A Mathematical Model of Presynaptic Dopamine Homeostasis: Implications for Schizophrenia

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