| 1. |
- Luptáková, Dominika, et al.
(författare)
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Neuropharmacokinetic visualization of regional and subregional unbound antipsychotic drug transport across the blood-brain barrier.
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26, s. 7732-7745
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Tidskriftsartikel (refereegranskat)abstract
- Comprehensive determination of the extent of drug transport across the region-specific blood-brain barrier (BBB) is a major challenge in preclinical studies. Multiple approaches are needed to determine the regional free (unbound) drug concentration at which a drug engages with its therapeutic target. We present an approach that merges in vivo and in vitro neuropharmacokinetic investigations with mass spectrometry imaging to quantify and visualize both the extent of unbound drug BBB transport and the post-BBB cerebral distribution of drugs at regional and subregional levels. Direct imaging of the antipsychotic drugs risperidone, clozapine, and olanzapine using this approach enabled differentiation of regional and subregional BBB transport characteristics at 20-µm resolution in small brain regions, which could not be achieved by other means. Our approach allows investigation of heterogeneity in BBB transport and presents new possibilities for molecular psychiatrists by facilitating interpretation of regional target-site exposure results and decision-making.
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| 2. |
- Balayssac, David, et al.
(författare)
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Neurofilament light chain in plasma as a sensitive diagnostic biomarker of peripheral neurotoxicity : In Vivo mouse studies with oxaliplatin and paclitaxel - NeuroDeRisk project
- 2023
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Ingår i: Biomedicine and Pharmacotherapy. - : Elsevier. - 0753-3322 .- 1950-6007. ; 167
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Tidskriftsartikel (refereegranskat)abstract
- Identifying compounds that are neurotoxic either toward the central or the peripheral nervous systems (CNS or PNS) would greatly benefit early stages of drug development by derisking liabilities and selecting safe compounds. Unfortunately, so far assays mostly rely on histopathology findings often identified after repeated-dose toxicity studies in animals. The European NeuroDeRisk project aimed to provide comprehensive tools to identify compounds likely inducing neurotoxicity. As part of this project, the present work aimed to identify diagnostic non-invasive biomarkers of PNS toxicity in mice. We used two neurotoxic drugs in vivo to correlate functional, histopathological and biological findings. CD1 male mice received repeated injections of oxaliplatin or paclitaxel followed by an assessment of drug exposure in CNS/PNS tissues. Functional signs of PNS toxicity were assessed using electronic von Frey and cold paw immersion tests (oxaliplatin), and functional observational battery, rotarod and cold plate tests (paclitaxel). Plasma concentrations of neurofilament light chain (NF-L) and vascular endothelial growth factor A (VEGF-A) were measured, and histopathological evaluations were performed on a comprehensive list of CNS and PNS tissues. Functional PNS toxicity was observed only in oxaliplatin-treated mice. Histopathological findings were observed dose-dependently only in paclitaxel groups. While no changes of VEGF-A concentrations was recorded, NF-L concentrations were increased only in paclitaxel-treated animals as early as 7 days after the onset of drug administration. These results show that plasma NF-L changes correlated with microscopic changes in the PNS, thus strongly suggesting that NF-L could be a sensitive and specific biomarker of PNS toxicity in mice.
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| 3. |
- Bällgren, Frida, et al.
(författare)
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Active Uptake of Oxycodone at Both the Blood-Cerebrospinal Fluid Barrier and The Blood-Brain Barrier without Sex Differences : A Rat Microdialysis Study
- 2023
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Ingår i: Pharmaceutical research. - : Springer Nature. - 0724-8741 .- 1573-904X. ; 40, s. 2715-2730
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Tidskriftsartikel (refereegranskat)abstract
- Background: Oxycodone active uptake across the blood-brain barrier (BBB) is associated with the putative proton-coupled organic cation (H+/OC) antiporter system. Yet, the activity of this system at the blood-cerebrospinal fluid barrier (BCSFB) is not fully understood. Additionally, sex differences in systemic pharmacokinetics and pharmacodynamics of oxycodone has been reported, but whether the previous observations involve sex differences in the function of the H+/OC antiporter system remain unknown. The objective of this study was, therefore, to investigate the extent of oxycodone transport across the BBB and the BCSFB in female and male Sprague-Dawley rats using microdialysis.Methods: Microdialysis probes were implanted in the blood and two of the following brain locations: striatum and lateral ventricle or cisterna magna. Oxycodone was administered as an intravenous infusion, and dialysate, blood and brain were collected. Unbound partition coefficients (Kp,uu) were calculated to understand the extent of oxycodone transport across the blood-brain barriers. Non-compartmental analysis was conducted using Phoenix 64 WinNonlin. GraphPad Prism version 9.0.0 was used to perform t-tests, one-way and two-way analysis of variance followed by Tukey's or Sidak's multiple comparison tests. Differences were considered significant at p < 0.05.Results: The extent of transport at the BBB measured in striatum was 4.44 ± 1.02 (Kp,uu,STR), in the lateral ventricle 3.41 ± 0.74 (K-p,K-uu,K-LV) and in cisterna magna 2.68 ± 1.01 (Kp,Kuu,KCM). These Kp,uu values indicate that the extent of oxycodone transport is significantly lower at the BCSFB compared with that at the BBB, but still confirm the presence of active uptake at both blood-brain interfaces. No significant sex differences were observed in neither the extent of oxycodone delivery to the brain, nor in the systemic pharmacokinetics of oxycodone.Conclusions: The findings clearly show that active uptake is present at both the BCSFB and the BBB. Despite some underestimation of the extent of oxycodone delivery to the brain, CSF may be an acceptable surrogate of brain ISF for oxycodone, and potentially also other drugs actively transported into the brain via the H+/OC antiporter system.
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| 4. |
- Holder, Brianna M., et al.
(författare)
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Brain barriers virtual : an interim solution or future opportunity?
- 2022
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Ingår i: Fluids and Barriers of the CNS. - : Springer Nature. - 2045-8118. ; 19:1
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Tidskriftsartikel (refereegranskat)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.
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| 5. |
- Hu, Yang, 1989-, et al.
(författare)
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Analysis of the contributing role of drug transport across biological barriers in the development and treatment of chemotherapy-induced peripheral neuropathy
- 2024
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Ingår i: Fluids and Barriers of the CNS. - : Springer Nature. - 2045-8118. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Chemotherapy-induced peripheral neuropathy (CIPN) represents a major unmet medical need that currently has no preventive and/or curative treatment. This is, among others, driven by a poor understanding of the contributive role of drug transport across biological barriers to target-site exposure. Methods Here, we systematically investigated the transport of 11 small-molecule drugs, both, associated and not with CIPN development, at conventional (dorsal root ganglia, sciatic nerve) and non-conventional (brain, spinal cord, skeletal muscle) CIPN sites. We developed a Combinatory Mapping Approach for CIPN, CMA-CIPN, combining in vivo and in vitro elements. Results Using CMA-CIPN, we determined the unbound tissue-to-plasma concentration ratio (K-p,K-uu) and the unbound intracellular-to-extracellular concentration ratio (K-p,K-uu,K-cell), to quantitatively assess the extent of unbound drug transport across endothelial interfaces and parenchymal cellular barriers of investigated CIPN-sites, respectively, in a rat model. The analysis revealed that unique pharmacokinetic characteristics underly time-dependent accumulation of the CIPN-positive drugs paclitaxel and vincristine at conventional (dorsal root ganglia and sciatic nerve) and non-conventional (skeletal muscle) CIPN sites. Investigated CIPN-positive drugs displayed intracellular accumulation contrary to CIPN-negative drugs nilotinib and methotrexate, which lacked this feature in all investigated tissues. Conclusions Hence, high unbound drug intracellular and extracellular exposure at target sites, driven by an interplay of drug transport across the endothelial and parenchymal cellular barriers, is a predisposing factor to CIPN development for CIPN-positive drugs. Critical drug-specific features of unbound drug disposition at various CIPN- sites provide invaluable insights into understanding the pharmacological/toxicological effects at the target-sites which will inform new strategies for monitoring and treatment of CIPN.
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| 6. |
- Kurtyka, Magdalena, et al.
(författare)
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The solute carrier SLC7A1 may act as a protein transporter at the blood-brain barrier
- 2024
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Ingår i: European Journal of Cell Biology. - : Elsevier. - 0171-9335 .- 1618-1298. ; 103:2
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Tidskriftsartikel (refereegranskat)abstract
- Despite extensive research, targeted delivery of substances to the brain still poses a great challenge due to the selectivity of the blood -brain barrier (BBB). Most molecules require either carrier- or receptor -mediated transport systems to reach the central nervous system (CNS). These transport systems form attractive routes for the delivery of therapeutics into the CNS, yet the number of known brain endothelium -enriched receptors allowing the transport of large molecules into the brain is scarce. Therefore, to identify novel BBB targets, we combined transcriptomic analysis of human and murine brain endothelium and performed a complex screening of BBBenriched genes according to established selection criteria. As a result, we propose the high -affinity cationic amino acid transporter 1 (SLC7A1) as a novel candidate for transport of large molecules across the BBB. Using RNA sequencing and in situ hybridization assays, we demonstrated elevated SLC7A1 gene expression in both human and mouse brain endothelium. Moreover, we confirmed SLC7A1 protein expression in brain vasculature of both young and aged mice. To assess the potential of SLC7A1 as a transporter for larger proteins, we performed internalization and transcytosis studies using a radiolabelled or fluorophore-labelled anti-SLC7A1 antibody. Our results showed that SLC7A1 internalised a SLC7A1-specific antibody in human colorectal carcinoma (HCT116) cells. Moreover, transcytosis studies in both immortalised human brain endothelial (hCMEC/D3) cells and primary mouse brain endothelial cells clearly demonstrated that SLC7A1 effectively transported the SLC7A1specific antibody from luminal to abluminal side. Therefore, here in this study, we present for the first time the SLC7A1 as a novel candidate for transport of larger molecules across the BBB.
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| 7. |
- Loryan, Irena, Associate Professor (Docent), 1977-, et al.
(författare)
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Brain Distribution of Drugs: : Pharmacokinetic Considerations
- 2020
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Ingår i: Handbook of Experimental Pharmacology. - Cham : Springer Berlin/Heidelberg.
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Bokkapitel (refereegranskat)abstract
- It is crucial to understand the basic principles of drug transport, from the site of delivery to the site of action within the CNS, in order to evaluate the possible utility of a new drug candidate for CNS action, or possible CNS side effects of non-CNS targeting drugs. This includes pharmacokinetic aspects of drug concentration-time profiles in plasma and brain, blood–brain barrier transport and drug distribution within the brain parenchyma as well as elimination processes from the brain. Knowledge of anatomical and physiological aspects connected with drug delivery is crucial in this context. The chapter is intended for professionals working in the field of CNS drug development and summarizes key pharmacokinetic principles and state-of-the-art experimental methodologies to assess brain drug disposition. Key parameters, describing the extent of unbound (free) drug across brain barriers, in particular blood–brain and blood–cerebrospinal fluid barriers, are presented along with their application in drug development. Special emphasis is given to brain intracellular pharmacokinetics and its role in evaluating target engagement. Fundamental neuropharmacokinetic differences between small molecular drugs and biologicals are discussed and critical knowledge gaps are outlined.
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| 8. |
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| 9. |
- Loryan, Irena, Associate Professor (Docent), 1977-, et al.
(författare)
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Unbound Brain-to-Plasma Partition Coefficient, K-p,K-uu,K-brain-a Game Changing Parameter for CNS Drug Discovery and Development
- 2022
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Ingår i: Pharmaceutical research. - : Springer Nature. - 0724-8741 .- 1573-904X. ; 39:7, s. 1321-1341
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Tidskriftsartikel (refereegranskat)abstract
- Purpose More than 15 years have passed since the first description of the unbound brain-to-plasma partition coefficient (K-p,K-uu,K-brain) by Prof. Margareta Hammarlund-Udenaes, which was enabled by advancements in experimental methodologies including cerebral microdialysis. Since then, growing knowledge and data continue to support the notion that the unbound (free) concentration of a drug at the site of action, such as the brain, is the driving force for pharmacological responses. Towards this end, K-p,K-uu,K-brain is the key parameter to obtain unbound brain concentrations from unbound plasma concentrations. Methods To understand the importance and impact of the K-p,K-uu,K-brain concept in contemporary drug discovery and development, a survey has been conducted amongst major pharmaceutical companies based in Europe and the USA. Here, we present the results from this survey which consisted of 47 questions addressing: 1) Background information of the companies, 2) Implementation, 3) Application areas, 4) Methodology, 5) Impact and 6) Future perspectives. Results and conclusions From the responses, it is clear that the majority of the companies (93%) has established a common understanding across disciplines of the concept and utility of K-p,K-uu,K-brain as compared to other parameters related to brain exposure. Adoption of the K-p,K-uu,K-brain concept has been mainly driven by individual scientists advocating its application in the various companies rather than by a top-down approach. Remarkably, 79% of all responders describe the portfolio impact of K-p,K-uu,K-brain implementation in their companies as 'game-changing'. Although most companies (74%) consider the current toolbox for K-p,K-uu,K-brain assessment and its validation satisfactory for drug discovery and early development, areas of improvement and future research to better understand human brain pharmacokinetics/pharmacodynamics translation have been identified.
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| 10. |
- Melander, Erik, et al.
(författare)
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Differential Blood-Brain Barrier Transport and Cell Uptake of Cyclic Peptides In Vivo and In Vitro
- 2023
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- The blood-brain barrier (BBB) poses major challenges to drug delivery to the CNS. SFTI-1 and kalata B1 are cyclic cell-penetrating peptides (cCPPs) with high potential to be used as scaffolds for drug delivery. We here studied their transport across the BBB and distribution within the brain to gauge the potential of these two cCPPs as scaffolds for CNS drugs. In a rat model, SFTI-1 exhibited, for a peptide, high extent of BBB transport with a partitioning of unbound SFTI-1 across the BBB, K-p,K-uu,K-brain, of 13%, while only 0.5% of kalata B1 equilibrated across the BBB. By contrast, kalata B1, but not SFTI-1, readily entered neural cells. SFTI-1, but not kalata B1, could be a potential CNS delivery scaffold for drugs directed to extracellular targets. These findings indicate that differences between the BBB transport and cellular uptake abilities of CPPs are crucial in the development of peptide scaffolds.
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