| 1. |
- Mihajlica, Nebojsa, 1983-
(author)
-
Pericyte Influence on Drug Delivery Across the Blood-Brain Barrier : Implications for Therapy of Neurodegenerative Diseases
- 2018
-
Doctoral thesis (other academic/artistic)abstract
- 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.
|
|
| 2. |
- Holder, Brianna M., et al.
(author)
-
Brain barriers virtual : an interim solution or future opportunity?
- 2022
-
In: Fluids and Barriers of the CNS. - : Springer Nature. - 2045-8118. ; 19:1
-
Journal article (peer-reviewed)abstract
- BackgroundScientific conferences are vital communication events for scientists in academia, industry, and government agencies. In the brain barriers research field, several international conferences exist that allow researchers to present data, share knowledge, and discuss novel ideas and concepts. These meetings are critical platforms for researchers to connect and exchange breakthrough findings on a regular basis. Due to the worldwide COVID-19 pandemic, all in-person meetings were canceled in 2020. In response, we launched the Brain Barriers Virtual 2020 (BBV2020) seminar series, the first stand-in virtual event for the brain barriers field, to offer scientists a virtual platform to present their work. Here we report the aggregate attendance information on two in-person meetings compared with BBV2020 and comment on the utility of the virtual platform.MethodsThe BBV2020 seminar series was hosted on a Zoom webinar platform and was free of cost for participants. Using registration- and Zoom-based data from the BBV2020 virtual seminar series and survey data collected from BBV2020 participants, we analyzed attendance trends, global reach, participation based on career stage, and engagement of BBV2020. We compared these data with those from two previous in-person conferences, a BBB meeting held in 2018 and CVB 2019.ResultsWe found that BBV2020 seminar participation steadily decreased over the course of the series. In contrast, live participation was consistently above 100 attendees and recording views were above 200 views per seminar. We also found that participants valued BBV2020 as a supplement during the COVID-19 pandemic in 2020. Based on one post-BBV2020 survey, the majority of participants indicated that they would prefer in-person meetings but would welcome a virtual component to future in-person meetings. Compared to in-person meetings, BBV2020 enabled participation from a broad range of career stages and was attended by scientists in academic, industry, and government agencies from a wide range of countries worldwide.ConclusionsOur findings suggest that a virtual event such as the BBV2020 seminar series provides easy access to science for researchers across all career stages around the globe. However, we recognize that limitations exist. Regardless, such a virtual event could be a valuable tool for the brain barriers community to reach and engage scientists worldwide to further grow the brain barriers research field in the future.
|
|
| 3. |
- Lindqvist, Annika, 1983-
(author)
-
Quantitative Aspects of Nanodelivery Across the Blood-Brain Barrier : Exemplified with the Opioid Peptide DAMGO
- 2015
-
Doctoral thesis (other academic/artistic)abstract
- The use of nanocarriers is an intriguing approach in the development of efficacious treatment for brain disorders. The aim of the conducted research was to evaluate and quantify the impact of a liposomal nanocarrier formulation on the brain drug delivery. A novel approach for investigating the blood-brain barrier transport of liposomal DAMGO is presented, including in vivo microdialysis in rat, a high quality LC-MS/MS bioanalytical method and pharmacokinetic model analysis of the data. Factors limiting the brain distribution of the free peptide DAMGO were also investigated. Microdialysis, in combination with plasma sampling, made it possible to separate the released drug from the encapsulated and to quantify the active substance in both blood and brain interstitial fluid over time.The opioid peptide DAMGO entered the brain to a limited extent, with a clearance out of the brain 13 times higher than the clearance into the brain. The brain to blood ratio of unbound drug was not affected when the efflux transporter inhibitors cyclosporine A and elacridar were co-administered with DAMGO. Nor was the transport affected in the in vitro Caco-2 assay using the same inhibitors. This indicates that DAMGO is not transported by P-glycoprotein (Pgp) or breast cancer resistant protein (Bcrp). The blood-brain barrier transport was significantly increased for DAMGO when formulated in liposomes, resulting in 2-3 fold higher brain to blood ratio of unbound DAMGO. The increased brain delivery was seen both for glutathione tagged PEGylated liposomes, as well as for PEGyalted liposomes without specific brain targeting. The improvement in brain delivery was observed only when DAMGO was encapsulated into the liposomes, thus excluding any effect of the liposomes themselves on the integrity of the blood-brain barrier. Modeling of the data provided additional mechanistic understanding of the brain uptake, showing that endocytosis or transcytosis of intact liposomes across the endothelial cell membranes were unlikely. A model describing fusion of the liposomes with the luminal membrane described the experimental data the best.In conclusion, the studies presented in this thesis all contribute to an increased understanding of how to evaluate and improve brain delivery of CNS active drugs and contribute with important insights to the nanocarrier field.
|
|
