The blood–brain barrier is intact after levodopa-induced dyskinesias in parkinsonian primates—Evidence from in vivo neuroimaging studies

Massachusetts General Hospital (MGH) Nuclear Magnetic Resonance Center, Athinoula A. Martinos Center for Biomedical Imaging, Boston, MA, USA
Neurobiology of Disease (Impact Factor: 5.08). 09/2009; 35(3):348-351. DOI: 10.1016/j.nbd.2009.05.018
Source: PubMed


It has been suggested, based on rodent studies, that levodopa (l-dopa) induced dyskinesia is associated with a disrupted blood–brain barrier (BBB). We have investigated BBB integrity with in vivo neuroimaging techniques in six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned primates exhibiting l-dopa-induced dyskinesia. Magnetic resonance imaging (MRI) performed before and after injection of Gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) revealed an intact BBB in the basal ganglia showing that l-dopa-induced dyskinesia is not associated with a disrupted BBB in this model.

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    • "Earlier it was proposed that endothelial proliferation after exposure to high concentrations of l-DOPA can lead to breach in the blood-brain barrier (BBB) that itself can be the cause of dyskinesia [45]. This finding is controversial because a later study using in vivo neuroimaging demonstrated that the BBB is intact after l-DOPA-induced dyskinesias in parkinsonian animals [46]. Also, Müller and coauthors [47] showed that the level of 3-O-methyldopa does not affect significantly l-DOPA pharmacokinetics and motor responses in patients and they concluded that the BBB was not affected. "
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    ABSTRACT: Astrocyte endfeet surround brain blood vessels and can play a role in the delivery of therapeutic drugs for Parkinson's disease. However, there is no previous evidence of the presence of LAT transporter for L-DOPA in brain astrocytes except in culture. Using systemic L-DOPA administration and a combination of patch clamp, histochemistry and confocal microscopy we found that L-DOPA is accumulated mainly in astrocyte cell bodies, astrocytic endfeet surrounding blood vessels, and pericytes. In brain slices: (1) astrocytes were exposed to ASP(+), a fluorescent monoamine analog of MPP(+); (2) ASP(+) taken up by astrocytes was colocalized with L-DOPA fluorescence in (3) glial somata and in the endfeet attached to blood vessels; (4) these astrocytes have an electrogenic transporter current elicited by ASP(+), but intriguingly not by L-DOPA, suggesting a different pathway for monoamines and L-DOPA via astrocytic membrane. (5) The pattern of monoamine oxidase (MAO type B) allocation in pericytes and astrocytic endfeet was similar to that of L-DOPA accumulation. We conclude that astrocytes control L-DOPA uptake and metabolism and, therefore, may play a key role in regulating brain dopamine level during dopamine-associated diseases. These data also suggest that different transporter mechanisms may exist for monoamines and L-DOPA.
    Full-text · Article · Jul 2012
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    • "In contrast, in the unilateral rat rotenone model for progressive Parkinson's disease, no changes in BBB transport were found for fluorescein [14]. Also, in the primate brain, Astradson, et al. [15] found no disruption of the BBB using in vivo neuroimaging techniques with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). With regard to BBB transport for L-DOPA being dependent on the L-type amino acid influx transporter 1 (LAT1) [16], it is of interest that Ohtsuki et al. [17] found a ~50% reduction of LAT1 mRNA expression at the BBB in mice, 7 days after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in conjunction with motor deficits and a loss of dopaminergic neurons. "
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    ABSTRACT: Changes 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. In 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. Plasma 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. Parkinson'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.
    Full-text · Article · Feb 2012 · Fluids and Barriers of the CNS
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    • "Moreover, pharmacological inhibition of the ERK1/2 signaling cascade reduced both LID and the microvascular changes induced by l-DOPA (Lindgren et al., 2009). However, these changes in the blood brain barrier were not corroborated by functional methods in a primate model of LID (Astradsson et al., 2009), so more work is needed to understand the functional significance of these findings. Changes in the microvasculature may be secondary to the higher metabolic demands imposed by chronic D1R receptor stimulation in rats with nigrostriatal lesion (Trugman and Wooten, 1986, 1987) or result from more direct actions of dopamine agonists on blood vessels (Hirano et al., 2008). "
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    ABSTRACT: Parkinson’s disease is a common neurodegenerative disorder caused by the degeneration of midbrain substantia nigra dopaminergic neurons that project to the striatum. Despite extensive investigation aimed at finding new therapeutic approaches, the dopamine precursor molecule, 3,4-dihydroxyphenyl-L-alanine (L-DOPA), remains the most effective and commonly used treatment. However, chronic treatment and disease progression lead to changes in the brain’s response to L-DOPA, resulting in decreased therapeutic effect and the appearance of dyskinesias. L-DOPA-induced dyskinesia (LID) interferes significantly with normal motor activity and persists unless L-DOPA dosages are reduced to below therapeutic levels. Thus, controlling LID is one of the major challenges in Parkinson’s disease therapy. LID is the result of intermittent stimulation of supersensitive D1 dopamine receptors located in the very severely denervated striatal neurons. Through increased coupling to Gαolf, resulting in greater stimulation of adenylyl-cyclase, D1 receptors phosphorylate DARPP-32 and other protein kinase A targets. Moreover, D1 receptor stimulation activates ERK and triggers a signaling pathway involving mTOR and modifications of histones that results in changes in translation, chromatin modification and gene transcription. In turn, sensitization of D1 receptor signaling causes a widespread increase in the metabolic response to D1 agonists and changes in the activity of basal ganglia neurons that correlate with the severity of LID. Importantly, different studies suggest that dyskinesias may share mechanisms with drug abuse and long term memory involving D1 receptor activation. Here we review evidence implicating D1 receptor signaling in the genesis of LID, analyze mechanisms that may translate enhanced D1 signaling into dyskinetic movements, and discuss the possibility that the mechanisms underlying LID are not unique to the Parkinson’s disease brain.
    Full-text · Article · Aug 2011 · Frontiers in Neuroanatomy
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