Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease

Paulien Gm Ravenstijn,Henk-Jan Drenth,Elizabeth Cm De Lange,Michael J O'Neill,Meindert Danhof

doi:10.1186/2045-8118-9-4

Paulien Gm Ravenstijn, Henk-Jan Drenth + Show 3 more

Open Access

https://doi.org/10.1186/2045-8118-9-4

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Abstract

BackgroundChanges in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease.MethodsIn Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg). Serial blood samples and brain striatal microdialysates were analysed for L-DOPA, and the dopamine metabolites DOPAC and HVA. Ex-vivo brain tissue was analyzed for changes in tyrosine hydroxylase staining as a biomarker for Parkinson's disease severity. Data were analysed by population pharmacokinetic analysis (NONMEM) to compare BBB transport of L-DOPA in conjunction with the conversion of L-DOPA into DOPAC and HVA, in control and diseased cerebral hemisphere.ResultsPlasma pharmacokinetics of L-DOPA could be described by a 3-compartmental model. In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere. However, in the diseased compared with the control side, basal microdialysate levels of DOPAC and HVA were substantially lower, whereas following L-DOPA administration their elimination rates were higher.ConclusionsParkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA. Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.

Highlights

Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson’s disease
It may be that this decreased benefit of L-DOPA is solely due to a reduction in the number of viable dopaminergic neurons that can convert L-DOPA into dopamine to reduce the symptoms
L-DOPA kinetics in plasma The results described in this paper are the first in which both plasma and brainECF pharmacokinetics of L-DOPA in control and rotenone-treated conditions are described by a population pharmacokinetic model

Summary

Introduction

Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson’s disease. Tyrosine is usually considered as the starting point in the biosynthesis of dopamine (DA) It is taken up into the brain and subsequently from brain extracellular fluid into dopaminergic neurons where its is converted to 3,4-dihydroxyphenylalanine (L-DOPA), by tyrosine hydroxylase (TH). It is known that in Parkinson’s disease dopaminergic neurons in the nigro-striatal pathway are progressively damaged [4], which causes a decrease in dopamine concentration in the striatum. Current therapy for Parkinson’s disease focuses mainly on symptomatic treatment to replace the lost dopamine in the striatum. It may be that the pharmacokinetics of L-DOPA in the brain for the same dose of L-DOPA may change during disease progression, due to alterations in the functionality of the bloodbrain barrier (BBB) [10]

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