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Pericyte Influence on Drug Delivery Across the Blood-Brain Barrier : Implications for Therapy of Neurodegenerative Diseases
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- Mihajlica, Nebojsa, 1983- (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Translational PKPD
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- Hammarlund-Udenaes, Margareta, Professor (thesis advisor)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Betsholtz, Christer, Professor (thesis advisor)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- (creator_code:org_t)
- ISBN 9789151302713
- Uppsala : Acta Universitatis Upsaliensis, 2018
- English 61 s.
- Series: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 250
- Doctoral thesis (other academic/artistic)
Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- Blood-brain barrier
- pericytes
- pericyte-deficiency
- pharmacokinetics
- small-molecular drugs
- drug distribution
- transporters
- P-glycoprotein
- tyrosine kinase inhibitors
- Farmakokinetik och läkemedelsterapi
- Pharmacokinetics and Drug Therapy
Publication and Content Type
- vet (subject category)
- dok (subject category)
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