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The Role of Pericytes at the Blood-Brain Barrier - Comparative Transcriptome and Proteome Analysis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Vascular Biology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
SciLife, Karolinska Institute, Stockholm, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Translational PKPD)
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-345941OAI: oai:DiVA.org:uu-345941DiVA, id: diva2:1189928
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13
In thesis
1. Pericyte Influence on Drug Delivery Across the Blood-Brain Barrier: Implications for Therapy of Neurodegenerative Diseases
Open this publication in new window or tab >>Pericyte Influence on Drug Delivery Across the Blood-Brain Barrier: Implications for Therapy of Neurodegenerative Diseases
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The blood-brain barrier (BBB) represents a complex interface between the brain parenchyma and systemic blood circulation, strictly controlling exchange of substances between the two sites. Pericytes are mural cells located on the abluminal membrane of the brain endothelium, involved in BBB formation and maintenance. Previous studies have implied that pericyte-deficiency causes alterations in BBB integrity for larger molecules, mainly by upregulated transcytosis pathways.

 The aim of the thesis was to examine the role of pericytes for small-molecular drug transport across the BBB, by providing a closer insight into different aspects of transport in a pericyte-deficient state. PDGF-B retention motif knockout mice were used as a well-established pericyte-deficient model. Small-molecular drugs, namely diazepam, digoxin, imatinib, levofloxacin, oxycodone and paliperidone were selected based on utilization of different BBB transport mechanisms. Surprisingly, the extent of BBB transport expressed as the unbound brain-to-unbound plasma partition coefficients indicated no difference between pericyte-deficient and control mice for all tested drugs. In addition, no difference was observed in the rate of BBB transport estimated by trans-cardiac in situ brain perfusion experiments. These results imply preserved BBB features in terms of tight junctions that limit para-cellular transport, as well as unaltered transporter functionality and expression. Thus, BBB aspects relevant for small-molecular drug transport seem to be maintained regardless of pericyte presence at the BBB. In addition, data from proteome and transcriptome analysis of the brain microvasculature fragments were in line with these findings, showing no difference in major transporter expressions at the BBB in pericyte-deficient mice. Finally, experiments with tyrosine kinase (TK) inhibitors suggested a potential relevance of the imatinib-like TK target profiles for the stabilization of compromised BBB integrity in pericyte-deficiency.

 In conclusion, the present thesis work provided comprehensive insight into pharmacokinetics of small-molecular drugs in a pericyte-deficient state. It represents an important initial platform for future extensive investigations of BBB transport in pericyte-deficiency, towards the ultimate goal of developing novel therapeutics for the treatment of different neurodegenerative diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 61
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 250
Keywords
Blood-brain barrier, pericytes, pericyte-deficiency, pharmacokinetics, small-molecular drugs, drug distribution, transporters, P-glycoprotein, tyrosine kinase inhibitors
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-345949 (URN)978-91-513-0271-3 (ISBN)
Public defence
2018-05-04, B21, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 13:15 (English)
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Supervisors
Available from: 2018-04-10 Created: 2018-03-13 Last updated: 2018-04-24

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