Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson’s disease, PSP and MSA. J Neural Transm

Department of Neurology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
Journal of Neural Transmission (Impact Factor: 2.4). 08/2008; 115(7):1001-9. DOI: 10.1007/s00702-008-0030-y
Source: PubMed

ABSTRACT Decreased blood-brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson's disease (PD). This study investigated in vivo BBB P-gp function in patients with parkinsonian neurodegenerative syndromes, using [11C]-verapamil PET in PD, PSP and MSA patients. Regional differences in distribution volume were studied using SPM with higher uptake interpreted as reduced P-gp function. Advanced PD patients and PSP patients had increased [11C]-verapamil uptake in frontal white matter regions compared to controls; while de novo PD patients showed lower uptake in midbrain and frontal regions. PSP and MSA patients had increased uptake in the basal ganglia. Decreased BBB P-gp function seems a late event in neurodegenerative disorders, and could enhance continuous neurodegeneration. Lower [11C]-verapamil uptake in midbrain and frontal regions of de novo PD patients could indicate a regional up-regulation of P-gp function.

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Available from: Anna L Bartels, Sep 26, 2015
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    • "Similarly, various toxin-induced PD models have shown BBB disruption, including 6-OHDA treated rats and MPTP-treated mice (Carvey et al., 2005; Chen et al., 2008). On the other hand, a growing body of evidence has shown the importance of ABC multidrug transporters such as P-gp in BBB disruption (Kortekaas et al., 2005; Bartels et al., 2008; Bartels, 2011). In this aspect, KO mice for P-glycoprotein have shown an increased accumulation of neurotoxin ivermectin and the carcinostatic drug vinblanstine in the brain, suggesting the importance of P-glycoprotein in the clearance of toxic substances and a possible BBB disruption in PD (Schinkel et al., 1994). "
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    ABSTRACT: The blood-brain barrier (BBB) is a tightly regulated interface in the Central Nervous System (CNS) that regulates the exchange of molecules in and out from the brain thus maintaining the CNS homeostasis. It is mainly composed of endothelial cells (ECs), pericytes and astrocytes that create a neurovascular unit (NVU) with the adjacent neurons. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted factors that lead to the adequate association between the cells of the BBB and the formation of strong tight junctions. Under neurological disorders, such as chronic cerebral ischemia, brain trauma, Epilepsy, Alzheimer and Parkinson's Diseases, a disruption of the BBB takes place, involving a lost in the permeability of the barrier and phenotypical changes in both the ECs and astrocytes. In this aspect, it has been established that the process of reactive gliosis is a common feature of astrocytes during BBB disruption, which has a detrimental effect on the barrier function and a subsequent damage in neuronal survival. In this review we discuss the implications of astrocyte functions in the protection of the BBB, and in the development of Parkinson's disease (PD) and related disorders. Additionally, we highlight the current and future strategies in astrocyte protection aimed at the development of restorative therapies for the BBB in pathological conditions.
    Frontiers in Cellular Neuroscience 08/2014; 8. DOI:10.3389/fncel.2014.00211 · 4.29 Impact Factor
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    • "Another common strategy is to induce Treg (regulatory T cells)/tolerance. Indeed, Treg transfer into MPTP-treated animals attenuated loss of nigral DA neurons [84, 85]. Of particular interest is the stem cell transplant therapy. "
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    ABSTRACT: Parkinson’s disease (PD) is a chronic neurodegenerative disease underpinned by both genetic and environmental etiologic factors. Recent findings suggest that inflammation may be a pathogenic factor in the onset and progression of both familial and sporadic PD. Understanding the precise role of inflammatory factors in PD will likely lead to understanding of how the disease arises. In vivo evidence for inflammation in PD includes dysregulated molecular mediators such as cytokines, complement system and its receptors, resident microglial activation, peripheral immune cells invasion, and altered composition and phenotype of peripheral immune cells. The growing awareness of these factors has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Influences of ageing and differential exposure to environmental agents suggest potential host-pathogen specific pathophysiologic factors. There is a clear need for research to further unravel the pathophysiologic role of immunity in PD, with the potential of developing new therapeutic targets for this debilitating condition.
    BioMed Research International 06/2014; 2014(8):308654. DOI:10.1155/2014/308654 · 3.17 Impact Factor
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    • "One of the first in vivo pieces of evidence was provided by Bartels and colleagues in an investigation of ABC transporter function in patients with neurodegenerative syndromes: PD, progressive supranuclear palsy (PSP), and multi-system atrophy (MSA), which are characterized by accumulation of aSyn or Tau (Bartels et al., 2008b). These disorders were examined by positron-emission tomography (PET) using an ABC transporter-specific probe, [ 11 C]verapamil , that is exported exclusively by ABCB1 (Bartels et al., 2008b). They demonstrated a specific accumulation of the radioprobe in brain regions where these diseases primarily start, e.g. "
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    ABSTRACT: Ageing is the main risk factor for the development of dementing neurodegenerative diseases (NDs) and it is accompanied by the accumulation of variations in mitochondrial DNA. The resulting tissue-specific alterations in ATP production and availability cause deteriorations of cerebral clearance mechanisms that are important for the removal of toxic peptides and its aggregates. ABC transporters were shown to be the most important exporter superfamily for toxic peptides, e.g. β-amyloid and α-synuclein. Their activity is highly dependent on the availability of ATP and forms a directed energy-exporter network, linking decreased mitochondrial function with highly impaired ABC transporter activity and disease progression. In this paper, we describe a network based on interactions between ageing, energy metabolism, regeneration, accumulation of toxic peptides and the development of proteopathies of the brain with a focus on Alzheimer's disease (AD). Additionally, we provide new experimental evidence for interactions within this network in regenerative processes in AD.
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