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Targeting Maladaptive Plasticity After Spinal Cord Injury to Prevent the Development of Autonomic Dysreflexia

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Targeting Maladaptive Plasticity After Spinal Cord Injury to Prevent the Development of Autonomic Dysreflexia University of Kentucky UKnowledge Theses and Dissertations--Physiology Physiology 2019 TARGETING MALADAPTIVE PLASTICITY AFTER SPINAL CORD INJURY TO PREVENT THE DEVELOPMENT OF AUTONOMIC DYSREFLEXIA Khalid C. Eldahan University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0003-1674-2386 Digital Object Identifier: https://doi.org/10.13023/etd.2019.064 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Eldahan, Khalid C., "TARGETING MALADAPTIVE PLASTICITY AFTER SPINAL CORD INJURY TO PREVENT THE DEVELOPMENT OF AUTONOMIC DYSREFLEXIA" (2019). Theses and Dissertations--Physiology. 41. https://uknowledge.uky.edu/physiology_etds/41 This Doctoral Dissertation is brought to you for free and open access by the Physiology at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Physiology by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Khalid C. Eldahan, Student Dr. Alexander G. Rabchevsky, Major Professor Dr. Kenneth S. Campbell, Director of Graduate Studies TARGETING MALADAPTIVE PLASTICITY AFTER SPINAL CORD INJURY TO PREVENT THE DEVELOPMENT OF AUTONOMIC DYSREFLEXIA DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Medicine at the University of Kentucky By Khalid Charles Eldahan Lexington, Kentucky, United States of America Director: Dr. Alexander G. Rabchevsky, Professor of Physiology Lexington, Kentucky 2019 Copyright © Khalid C. Eldahan 2019 ABSTRACT OF DISSERTATION TARGETING MALADAPTIVE PLASTICITY AFTER SPINAL CORD INJURY TO PREVENT THE DEVELOPMENT OF AUTONOMIC DYSREFLEXIA Vital autonomic and cardiovascular functions are susceptible to dysfunction after spinal cord injury (SCI), with cardiovascular dysregulation contributing to morbidity and mortality in the SCI population. Autonomic dysreflexia (AD) is a condition that develops after injury to the sixth thoracic spinal segment or higher and is characterized by potentially dangerous and volatile surges in arterial pressure often accompanied with irregular heart rate, headache, sweating, flushing of the skin, and nasal congestion. These symptoms occur in response to abnormal outflow of sympathetic activity from the decentralized spinal cord typically triggered by noxious, yet unperceived nociceptive stimulation beneath the level of lesion. Maladaptive plasticity of primary afferents and spinal interneurons influencing sympathetic preganglionic neurons is known to contribute to the development of AD. However, there are currently no treatments capable of targeting this underlying pathophysiology. The goal of this work was to test pharmacological agents for their potential to modify intraspinal plasticity associated with AD in order to prophylactically prevent the development of this condition altogether. We first tested whether the drug rapamycin (RAP), a well-studied inhibitor of the growth promoting kinase “mammalian target of rapamycin” (mTOR), could prevent aberrant sprouting of primary c-fiber afferents in association with reduced indices of AD severity. Naïve and T4-transected rats undergoing 24/7 cardiovascular monitoring were treated with rapamycin (i.p.) for 4 weeks before tissue collection. RAP attenuated intraspinal mTOR activity after injury, however it also caused toxic weight loss. RAP treated SCI rats developed abnormally high blood pressure both at rest and during colorectal distension (CRD) induced AD, as well as more frequent bouts of spontaneous AD (sAD). These cardiovascular alterations occurred without altered intraspinal c-fiber sprouting. Our finding that rapamycin exacerbates cardiovascular dysfunction after SCI underscores the importance of screening potential pharmacological agents for cardiovascular side effects and suggests that the mTOR pathway plays a limited or dispensable role in c-fiber sprouting after SCI. We next examined the effects of the antinociceptive drug gabapentin (GBP) on AD development. Our previous work demonstrated that a single acute administration of GBP can reduce the severity of AD. The mechanism of action, however, remains unclear. Emerging evidence suggests that GBP may act by blocking de novo synaptogenesis. We investigated whether continuous GBP treatment could attenuate the development of AD by modifying synaptic connectivity between primary afferents and ascending propriospinal neurons. SCI rats were treated with GBP every six hours for four weeks. We found that GBP reduced blood pressure during CRD stimulation and prevented bradycardia typically observed during AD. However, GBP treated rats also had a higher sAD frequency and failed to return to pre-injury body weight. Moreover, SCI reduced the density of putative excitatory (VGLUT2+) and inhibitory (VGAT+) synaptic puncta in the lumbosacral cord, although GBP did not alter these parameters. Our results suggest that continuous GBP treatment alters hemodynamic control after SCI and that decreased synaptic connectivity may contribute to the development of AD. These studies demonstrate the need for further research to better understand the cellular signaling driving maladaptive plasticity after SCI as well as the complex and dynamic changes in intraspinal synaptic connectivity contributing to the development of AD. Moreover, GBP treatment may offer clinical benefit by reducing blood pressure during AD, however the optimal dosage must be identified to avoid undesired side-effects. KEYWORDS: Spinal cord injury, autonomic, rapamycin, gabapentin, synapse, plasticity Khalid C. Eldahan January 11, 2019 TARGETING MALADAPTIVE PLASTICITY AFTER SPINAL CORD INJURY TO PREVENT THE DEVELOPMENT OF AUTONOMIC DYSREFLEXIA By Khalid C. Eldahan Dr. Alexander G. Rabchevsky Director of Dissertation Dr. Kenneth S. Campbell Director of Graduate Studies This dissertation is dedicated to my parents, Ismail and Cathy Eldahan. ACKNOWLEDGEMENTS First, I would like to extend gratitude to my advisor, Dr. Alexander Rabchevsky, for my experiences in his lab both as Technician/Lab Manager and later as a graduate student. I admire his unrelenting dedication to the scientific method and experimental rigor which are essential for the pursuit of new knowledge. I look forward to discovering how these experiences and lessons will continue to serve me and my career in the future. To my committee members, Dr. Steve Estus, Dr. Bret Smith, Dr. Ai-Ling Lin and Dr. Jose Abisambra, as well as my Director of Graduate Studies, Dr. Kenneth Campbell: I am grateful for all of your advice, scientific discussion and encouragement over the years. You have each contributed positively to my scientific, professional and personal growth. Next, thank you to all of the lab members that I have had the pleasure of working alongside over the years, especially Dr. Samir Patel, Dr. Jenna Gollihue, David Cox and Hannah Williams. I appreciate the comradery which made even the most grueling long experimental days fun and positive. Moreover, I most certainly appreciate all of your help with the early-morning and late-night animal care. I would also like to thank all of the faculty and staff in the Department of Physiology and Spinal Cord and Brain Injury Research Center. I feel fortunate to have had such great educators and support staff that made this dissertation possible. Last, but not least: thank you to all my family and friends who have been a constant source of support and advocacy. Your support has taken many forms over the years and kept me going when changing course would have been much easier. iii TABLE OF CONTENTS Acknowledgements iii List of Figures vii 1 Chapter 1: Introduction 1.1 Introduction to the Autonomic Nervous System 1 1.1.1 Evolution and History of the Autonomic Nervous System 1 1.1.2 Anatomical Organization of the Autonomic Nervous System 3 1.1.3 Autonomic Control of the Heart 7 1.1.4 Autonomic Control of the Vascular System 11 1.2 Introduction and Overview
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