Enhancing Aromatic L‐amino Acid Decarboxylase Activity: Implications for L‐DOPA Treatment in Parkinson's Disease

Hadjiconstantinou, Maria; Neff, Norton H.

doi:10.1111/j.1755-5949.2008.00058.x

Cited by 67 publications

(39 citation statements)

References 119 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The down-regulation of the expression and to some extent the activity of AAAD by L-DOPA may help to emphasize the utility of AAAD as the limiting step in the catecholamine pathway during L-DOPA therapy of PD as noted by Hadjiconstantiou and Neff (2008). Moreover, the mystery underlying the mechanisms of the failure of the oral L-DOPA treatment (Colosimo and De Michele 1999) and the requirements for increasing the dosage of L-DOPA to achieve a better control of PD symptoms may also be related to the down-regulation of the activity of AAAD by L-DOPA.…”

Section: Discussionmentioning

confidence: 99%

L-Dihydroxyphenylalanine modulates the steady-state expression of mouse striatal tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine and its metabolites in an MPTP mouse model of Parkinson's disease

et al. 2011

View full text Add to dashboard Cite

Aims L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective symptomatic treatment for Parkinson’s disease (PD), but PD patients usually experience a successful response to L-DOPA therapy followed by a progressive loss of response. L-DOPA efficacy relies on its decarboxylation by aromatic L-amino acid decarboxylase (AAAD) to form dopamine (DA). So exogenous L-DOPA drives the reaction and AAAD becomes the rate limiting enzyme in the supply of DA. In turn, exogenous L-DOPA regulates the expression and activity of AAAD as well as the synthesis of DA and its metabolites, changes that may be linked to the efficacy and side-effects of L-DOPA. Main Methods One-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model was utilized to study the effects of L-DOPA on the steady-state level and activity of AAAD, tyrosine hydroxylase (TH), DA and the metabolites of DA. The MPTP and control mice were treated twice daily with PBS or with 100 mg/kg of L-DOPA for 14 days and the expression and activity of AAAD, the expression of TH and the levels of DA and its metabolites were determined 24 hrs after L-DOPA or PBS treatment, when exogenous L-DOPA is eliminated. Key Findings In the MPTP model, L-DOPA reduced the steady-state expression and the activity of striatal AAAD by 52% and 50%, respectively, DA and metabolites were also significantly decreased. Significance The outcome shows that while L-DOPA replenishes striatal DA it also down-regulates AAAD and the steady-state synthesis and metabolic capability of the dopaminergic system. These findings are important in the precipitation of L-DOPA induced side effects and the management of L-DOPA therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

L-Dihydroxyphenylalanine modulates the steady-state expression of mouse striatal tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine and its metabolites in an MPTP mouse model of Parkinson's disease

et al. 2011

View full text Add to dashboard Cite

show abstract

“…AADC is regulated at transcriptional level and at post-translational level [115-117]. At transcriptional level AADC can be differentially expressed by alternative promoter usage and by alternative splicing [118].…”

Section: Dopamine Biosynthesismentioning

confidence: 99%

“…At transcriptional level AADC can be differentially expressed by alternative promoter usage and by alternative splicing [118]. At protein level AADC is regulated by phosphorylation [119] and DA receptor stimulation [117,120,121]. Based on the two different regulation types: transcriptional and post-translational regulation, AADC is regulated by a quick acting, short- term mechanism, via regulation of the protein activity and in a slower longer lasting regulation, by adapting the gene expression [115,116].…”

Section: Dopamine Biosynthesismentioning

confidence: 99%

Complexity of dopamine metabolism

2013

View full text Add to dashboard Cite

Parkinson’s disease (PD) coincides with a dramatic loss of dopaminergic neurons within the substantia nigra. A key player in the loss of dopaminergic neurons is oxidative stress. Dopamine (DA) metabolism itself is strongly linked to oxidative stress as its degradation generates reactive oxygen species (ROS) and DA oxidation can lead to endogenous neurotoxins whereas some DA derivatives show antioxidative effects. Therefore, DA metabolism is of special importance for neuronal redox-homeostasis and viability.In this review we highlight different aspects of dopamine metabolism in the context of PD and neurodegeneration. Since most reviews focus only on single aspects of the DA system, we will give a broader overview by looking at DA biosynthesis, sequestration, degradation and oxidation chemistry at the metabolic level, as well as at the transcriptional, translational and posttranslational regulation of all enzymes involved. This is followed by a short overview of cellular models currently used in PD research. Finally, we will address the topic from a medical point of view which directly aims to encounter PD.

show abstract

“…However, in healthy brain tissue L-DOPA treatment could decrease evoked dopamine release by D2-mediated autoinhibition of DA release 65 . Additionally, the principal enzymes involved in DA synthesis, TH and AADC, are both regulated by DA autoreceptor-mediated second-messenger systems, such that DA synthesis is decreased when extracellular DA concentrations are increased 66–68 .…”

Section: Resultsmentioning

confidence: 99%

Unmasking the Effects of L-DOPA on Rapid Dopamine Signaling with an Improved Approach for Nafion Coating Carbon-Fiber Microelectrodes

Thomas

White

et al. 2016

Anal. Chem.

View full text Add to dashboard Cite

L-DOPA has been the gold standard for symptomatic treatment of Parkinson’s disease. However, its efficacy wanes over time as motor complications develop. Very little is known about how L-DOPA therapy affects the dynamics of fluctuating dopamine concentrations in the striatum on a rapid timescale (seconds). Electrochemical studies investigating the effects of L-DOPA treatment on electrically evoked dopamine release have reported conflicting results with significant variability. We hypothesize that the uncertainty in the electrochemical data is largely due to electrode fouling caused by polymerization of L-DOPA and endogenous catecholamines on the electrode surface. Thus, we have systematically optimized the procedure for fabricating cylindrical, Nafion-coated, carbon-fiber microelectrodes. This has enabled rapid and reliable detection of L-DOPA’s effects on striatal dopamine signaling in intact rat brain using fast-scan cyclic voltammetry. An acute dose of 5 mg/kg L-DOPA had no significant effect on dopamine dynamics, demonstrating the highly efficient regulatory mechanisms at work in the intact brain. In contrast, administration of 200 mg/kg L-DOPA significantly increased the amplitude of evoked dopamine release by ~200%. Overall, this work describes a reliable tool that allows a better measure of L-DOPA augmented dopamine release in vivo, measured using fast-scan cyclic voltammetry. It provides a methodology that improves the stability and performance of the carbon fiber microelectrode when studying the molecular mechanisms underlying L-DOPA therapy, and also promises to benefit a wide variety of studies because Nafion is so commonly used in electroanalytical chemistry.

show abstract

Enhancing Aromatic L‐amino Acid Decarboxylase Activity: Implications for L‐DOPA Treatment in Parkinson's Disease

Cited by 67 publications

References 119 publications

L-Dihydroxyphenylalanine modulates the steady-state expression of mouse striatal tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine and its metabolites in an MPTP mouse model of Parkinson's disease

L-Dihydroxyphenylalanine modulates the steady-state expression of mouse striatal tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine and its metabolites in an MPTP mouse model of Parkinson's disease

Complexity of dopamine metabolism

Unmasking the Effects of L-DOPA on Rapid Dopamine Signaling with an Improved Approach for Nafion Coating Carbon-Fiber Microelectrodes

Contact Info

Product

Resources

About