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The Effect of Aging on the Blood Brain Barrier Permeability and Response to Fluoxetine Enantiomers

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The Effect of Aging on the Blood Brain Barrier Permeability and Response to Fluoxetine Enantiomers Wright State University CORE Scholar Browse all Theses and Dissertations Theses and Dissertations 2017 The Effect of Aging on the Blood Brain Barrier Permeability and Response to Fluoxetine Enantiomers Ethar Arkan Wright State University Follow this and additional works at: https://corescholar.libraries.wright.edu/etd_all Part of the Neuroscience and Neurobiology Commons, and the Physiology Commons Repository Citation Arkan, Ethar, "The Effect of Aging on the Blood Brain Barrier Permeability and Response to Fluoxetine Enantiomers" (2017). Browse all Theses and Dissertations. 1844. https://corescholar.libraries.wright.edu/etd_all/1844 This Thesis is brought to you for free and open access by the Theses and Dissertations at CORE Scholar. It has been accepted for inclusion in Browse all Theses and Dissertations by an authorized administrator of CORE Scholar. For more information, please contact [email protected]. THE EFFECT OF AGING ON THE BLOOD BRAIN BARRIER PERMEABILITY AND RESPONSE TO FLUOXETINE ENANTIOMERS A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By ETHAR ARKAN B.S., Wright State University, 2012 2017 Wright State University WRIGHT STATE UNIVERSITY GRADUATE SCHOOL July 31, 2017 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY Ethar Arkan ENTITILED The Effect of Aging On The Blood Brain Barrier Permeability And Response To Fluoxetine To Fluoxetine Enantiomers BE ACCEPTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science. Adrian Corbett, Ph.D. Thesis Director Eric Bennett, Ph.D. Depart ment Chair Department of Neuroscience, Cell Biology, and Physiology Committee on Final Examination Adrian Corbett, Ph.D. Debra Mayes, Ph.D. Kathrin Engisch, Ph.D. Robert E.W. Fyffe, Ph.D. Vice President for Research and Dean of the Graduate School ABSTRACT Arkan, Ethar. M.S., Physiology and Neuroscience, Wright State University, 2017. The effect of aging on the blood brain barrier permeability and response to fluoxetine enantiomers. We tested the effect of the fluoxetine enantiomers (S-fluoxetine and R-fluoxetine) versus Prozac (50:50 ratio of R- and S- fluoxetine enantiomers) and/or control on blood brain barrier (BBB) permeability in different brain regions in both male and female rats. The rats consumed orally the drug (5 mg/kg) or vehicle for a total of three days, then were injected with sterile Evans blue dye ip, at least 12 hours before euthanasia.. We see significant regional brain differences in BBB permeability (hippocampus has tighter BBB), significant differences based on the age of the animals (young rats show enhanced permeability in lower brain region), and significant differences based on the sex of animals interacting with specific regional differences in BBB permeability (female rats have enhanced permeability in cerebellum). We also see some effect of the fluoxetine enantiomers, with S-fluoxetine enhancing permeability, and R fluoxetine reducing permeability. iii TABLE OF CONTENTS BACKGROUND ........................................................................................................... 1 I.INTRODUCTION ....................................................................................................... 3 1.1 The Blood Brain Barrier ..................................................................................... 3 1.2 Neurovascular Unit ............................................................................................. 5 1.2.1 Microglia ....................................................................................................... 6 1.2.2 The Basement Membrane .............................................................................. 7 1.2.3 Endothelial Cells (ECs) ................................................................................. 7 1.2.4 Astrocytes ...................................................................................................... 8 1.3 Tight Junction ..................................................................................................... 9 1.4 Transport across the BBB ................................................................................. 14 1.5 BBB Disruption ................................................................................................ 15 1.6 Fluoxetine ......................................................................................................... 21 1.6.1 Fluoxetine Metabolism ................................................................................ 21 1.6.2 Fluoxetine Effect on Microglial cells .......................................................... 23 1.7 HYPOTHESIS .................................................................................................. 23 1.7.1 Specific Aims .............................................................................................. 24 II. MATERIALS AND METHODS ............................................................................ 26 iv 2.1 Voluntary Drug Administration ......................................................................... 26 2.2 Euthanization ...................................................................................................... 27 2.3 Cardioperfusion .................................................................................................. 27 2.4 Pellet Homogenization ....................................................................................... 31 2.5 Bradford Protein Assay ...................................................................................... 32 2.6 Animal Model ................................................................................................... 33 2.7 Statistical Analysis ............................................................................................ 34 III. Results .................................................................................................................... 35 3.1 Young Male Rats .............................................................................................. 36 3.2 Old Male Rats ................................................................................................... 43 3.3 Old Female Rats ................................................................................................ 48 3.4 Young Male Rats versus Old Male Rats ........................................................... 54 3.5 Comparison among the Young Males Groups .................................................. 63 3.6 Comparisons among the Old Males Groups ..................................................... 82 3.7 Old Male Rats versus Old Female Rats ............................................................ 89 3.8 Comparison of All treatment groups across a Brain Regions ........................... 99 3.8.1 Cortex ......................................................................................................... 99 3.8.2 Hippocampus ............................................................................................ 102 3.8.3 Brain ......................................................................................................... 106 3.8.4 Cerebellum ............................................................................................... 110 v IV. Discussion ............................................................................................................ 116 4.1 The results of the total ng EB/mg protein of young versus old male rats (Age difference) .................................................................................................................. 116 4.2 The results of the total ng EB/mg protein in male versus female (Gender difference) .................................................................................................................. 117 4.3 Comparison of All treatment groups across a Brain Regions ......................... 118 4.4 The Treatment Effect among the Different Animal Groups………………...122 ….4.5 The Activity of the Fluoxetine Metabolites .................................................... 123 4.6 Previous Research Studies .............................................................................. 125 V. Future Directions................................................................................................... 127 VI. Conclusion………………………………………………………………………………………………………………128 VII. References .......................................................................................................... 130 vi LIST OF FIGURES Figure 1 .......................................................................................................................... 4 Figure 2 .......................................................................................................................... 5 Figure 3 ........................................................................................................................ 10 Figure 4 ........................................................................................................................ 11 Figure 5 ........................................................................................................................ 12 Figure 6 ........................................................................................................................ 14 Figure 7 ........................................................................................................................ 14 Figure 8 .......................................................................................................................
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