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Lidocaine Turns the Surface Charge of Biological Membranes More Positive and Changes the Permeability of Blood-Brain Barrier Culture Models

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Lidocaine Turns the Surface Charge of Biological Membranes More Positive and Changes the Permeability of Blood-Brain Barrier Culture Models The role of brain endothelial surface charge and glycocalyx in the function and integrity of the blood-brain barrier Ph.D. Thesis Ana Raquel Pato Santa Maria Supervisor: Prof. Dr. Mária A. Deli, scientific adviser Co-supervisor: Dr. Fruzsina R. Walter, research associate Biological Barriers Research Group, Institute of Biophysics Biological Research Centre, Szeged Doctoral School of Biology Faculty of Science and Informatics University of Szeged 2020 Szeged Table of contents List of Publications ....................................................................................................... IV List of Abbreviations .................................................................................................... VI 1. Introduction ............................................................................................................... 1 1.1.Blood-brain barrier .................................................................................................. 1 1.2.Negative surface charge of brain endothelial cells: a defense system and a regulator of BBB permeability ................................................................................ 4 1.3.Blood-brain barrier modeling .................................................................................. 7 1.3.1. Type of cell models ....................................................................................... 8 1.3.2. Type of cell culture setups ............................................................................. 9 1.4.Techniques to assess blood-brain barrier integrity ................................................ 11 1.4.1. Transendothelial electrical resistance .......................................................... 11 1.4.2. Permeability assay for marker molecules .................................................... 13 2. Aims .......................................................................................................................... 14 3. Materials and Methods ........................................................................................... 15 3.1.Animals ................................................................................................................. 15 3.2.Materials ................................................................................................................ 15 3.3.Cell cultures .......................................................................................................... 15 3.3.1. BBB models on culture inserts .................................................................... 15 3.3.2. hCMEC/D3 human brain endothelial cell line ............................................ 15 3.3.3. Primary cell cultures and rat BBB co-culture model ................................... 16 3.3.4. Human BBB co-culture model .................................................................... 17 3.4.Lab-on-a-chip device ............................................................................................ 18 3.4.1. Device fabrication ....................................................................................... 18 3.4.2. Static and dynamic condition in the chip device ......................................... 19 3.5.Cell culture treatments .......................................................................................... 20 3.5.1. Lidocaine treatment ..................................................................................... 20 3.5.2. Neuraminidase treatment ............................................................................. 20 3.6.Cell viability assays............................................................................................... 20 3.6.1. Impedance measurements ............................................................................ 20 3.6.2. MTT and lactate dehydrogenase release assays .......................................... 21 3.7.Evaluation of barrier function and integrity .......................................................... 21 3.7.1. Transendothelial electrical resistance .......................................................... 21 3.7.2. Permeability measurement .......................................................................... 22 3.7.3. Measurement of efflux pump activity ......................................................... 23 3.7.4. Immunocytochemistry for tight junction proteins and image analysis ....... 24 3.8.Staining and visualization of cell surface glycocalyx ........................................... 25 3.9.Zeta potential measurements ................................................................................. 25 3.10. Gene sequencing ................................................................................................ 26 3.10.1. Total RNA isolation .................................................................................... 26 3.10.2. Massive analysis of cDNA ends library preparation and RNA sequencing 26 3.10.3. Bioinformatic analysis of MACE-seq data .................................................. 27 3.11. Statistics ............................................................................................................. 27 | II 4. Results ...................................................................................................................... 28 4.1.Characterization of the different blood-brain barrier models ............................... 28 4.2.Modulation of the brain endothelial glycocalyx and surface charge using the neuraminidase enzyme .......................................................................................... 32 4.2.1. Effect of neuraminidase on the cell viability of primary brain endothelial cells .............................................................................................................. 32 4.2.2. Neuraminidase as a modulator of the glycocalyx and surface charge of brain endothelial cells ........................................................................................... 33 4.2.3. Integrity of the BBB models after neuraminidase treatment ....................... 35 4.3.Modulation of the brain endothelial surface charge by lidocaine ......................... 36 4.3.1. Effect of lidocaine on brain endothelial cell viability ................................. 36 4.3.2. Lidocaine as a modulator of the surface charge of brain endothelial cells . 38 4.3.3. Integrity of the BBB models after lidocaine treatment ............................... 38 4.4.Characterization of a human BBB model in a lab-on-a-chip device .................... 42 4.4.1. Effect of flow on barrier properties of the human BBB model ................... 42 4.4.2. Effect of flow on the global gene expression profile .................................. 44 4.4.3. Effect of flow on endothelial cell markers .................................................. 45 4.4.4. Effect of flow on BBB-related genes .......................................................... 47 4.4.5. The effect of fluid flow on the endothelial surface charge and glycocalyx of the human BBB model cultured in the lab-on-a-chip device ...................... 51 5. Discussion ................................................................................................................ 54 5.1.BBB models in cell culture inserts and lab-on-a-chip device ............................... 54 5.2.Modulation of the brain endothelial surface charge by neuraminidase and lidocaine ................................................................................................................ 55 5.3.Fluid flow makes brain endothelial surface charge more negative and promotes glycocalyx expression on the human BBB model in the lab-on-a-chip device .... 60 6. Conclusion ............................................................................................................... 65 Acknowledgements ....................................................................................................... 67 References ...................................................................................................................... 68 Summary ........................................................................................................................ 74 Összefoglaló ................................................................................................................... 77 Appendices ...................................................................................................................... A Publication I .............................................................................................................. A1 Publication II ............................................................................................................. A2 Publication III ........................................................................................................... A3 Publication IV ........................................................................................................... A4 | III List of Publications MTMT identification number: 10055709 Cumulative Impact Factor: 19.21 *Authors contributed equally to the publication Publication related to the dissertation: I. Santa-Maria AR, Walter FR, Valkai S, Brás AR, Mészáros M, Kincses A, Klepe A, Gaspar D, Castanho MARB, Zimányi L, Dér A, Deli MA. Lidocaine turns the surface charge of biological membranes more positive and changes the permeability of blood-brain barrier culture models. Biochimica et Biophysica Acta - Biomembranes 1861: 1579-1591. (2019) IF: 3.411 II. Kincses
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