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Mechanism of Carbamathione As a Therapeutic Agent For MECHANISM OF CARBAMATHIONE AS A THERAPEUTIC AGENT FOR STROKE by Jigar Modi A Dissertation Submitted to the Faculty of The Charles E. Schmidt College of Science In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Florida Atlantic University Boca Raton, FL December 2017 Copyright by Jigar Modi 2017 ii ACKNOWLEDGEMENTS I want to express my sincerest gratitude to my supervisor, Dr. Jang-Yen Wu, for his great patience, advice, and guidance, as well as giving me extraordinary experiences throughout the work. He provided me unflinching encouragement and support for allowing me the room to work in my own way. Without his mentoring, this dissertation would not have been possible. One simply could not wish for a better or friendlier supervisor. The author wishes to express his sincere thanks and love appreciation to Dr. Jang Yen Wu for his assistance and guidance in preparation of this thesis. Many thanks to my committee members, Dr. Howard Prentice, Dr. Jianning Wei and Dr. Rui Tao, for their contribution on finalizing this thesis. I would like to thank Hongyuan Chou, Dr. Janet Menzie, and Dr. Payam Gharibani for helpfulness on this thesis. At last but not the least, I want to thank my family. My wife Dr. Bhumika Tandel and my sister’s family, Dr. Dipali Mevawala and Dr.Dharmesh Mevawala are always there to encourage and support me. A special thought is devoted to my parents, Nishaben Modi, Pravinchandra Modi and Dr. Binaben Tandel for their unconditional love and endless support. iv ABSTRACT Author: Jigar Modi Title: Mechanism of Carbamathione as a therapeutic agent for Stroke. Institution: Florida Atlantic University Dissertation Advisor: Jang-Yen Wu, Ph.D. Degree: Doctor of Philosophy. Year: 2017 Stroke is the third leading cause of mortality in the United States, and so far, no clinical interventions have been shown completely effective in stroke treatment. Stroke may result in hypoxia, glutamate release and oxidative stress. One approach for protecting neurons from excitotoxic damage in stroke is to attenuate receptor activity with specific antagonists. Disulfiram requires bio-activation to S-methyl N, N-diethylthiolcarbamate sulfoxide (DETC-MeSO). In vivo, DETC-MeSO is further oxidized to the sulfone which is carbamoylated forming Carbamathione, a glutathione adducts. Carbamathione proved to be useful as a pharmacological agent in the treatment of cocaine dependence with the advantage that it lacks ALDH2 inhibitory activity. Carbamathione is a partial NMDA glutamate antagonist. The purpose of this dissertation study is to evaluate the neuroprotective effects of Carbamathione drug on PC-12 cell line and to understand the protective mechanisms underlying in three stroke-related models: excessive glutamate, hypoxia/reoxygenation and bilateral carotid artery occlusion (BCAO). Carbamathione was v administered 14 mg/kg subcutaneously for 4 days with the first injection occurring 30 min after occlusion in the mouse BCAO stroke model. Mice were subjected to the locomotor test, and the brain was analyzed for infarct size. Heat shock proteins, key proteins involved in apoptosis and endoplasmic reticulum (ER) stress, were analyzed by immunoblotting. Carbamathione reduced both cell death following hypoxia/reoxygenation and brain infarct size. It improved performance on the locomotor test. The level of pro-apoptotic proteins declined, and anti-apoptotic, P-AKT and HSP27 protein expressions were markedly increased. We found that Carbamathione suppresses the up- regulation of Caspase-12, Caspase-3 and significantly declined ER stress protein markers GRP 78, ATF4, XBP-1, and CHOP. Carbamathione can down- regulate ATF 4 and XBP1 expression, indicating that Carbamathione inhibits the ER stress induced by hypoxia/reoxygenation through suppressing PERK and IRE1 pathways. Carbamathione elicits neuroprotection through the preservation of ER resulting in reduction of apoptosis by increase of anti-apoptotic proteins and decrease of pro-apoptotic proteins. Carbamathione can suppress the activation of both PERK and IRE1 pathways in PC-12 cell cultures and has no inhibitory effect on ATF6 pathway. These findings provide promising and rational strategies for stroke therapy. vi DEDICATION This dissertation is dedicated to my beloved guru Param pujya Pramukh Swami Maharaj and Pragat guru Mahant Swami Maharaj, and my family, particularly my mother, Nishaben Modi, and my father, though no longer with me, Pravinchandra Modi, who have put up with these many years of research. These two people are/ have been the most supportive and caring parents I am/was blessed to have in my life. I also dedicate this work to my father in law, though no longer with us, Dr. Mahesh Tandel all of whom believed in the pursuit of dreams. And finally, to my present BAPS family (Miami Temple), who prayed for me constantly, especially when the going was tough. MECHANISM OF CARBAMATHIONE AS A THERAPEUTIC AGENT FOR STROKE LIST OF FIGURES ........................................................................................................... xi LIST OF ABBREVIATIONS .......................................................................................... xiv 1 INTRODUCTION .......................................................................................................1 1.1 Stroke ............................................................................................................................1 1.2 Model of stroke ............................................................................................................4 1.3 Endoplasmic reticulum (ER) stress. .............................................................................6 1.3.1 The unfolded protein response (UPR): ................................................................... 7 1.4 Carbamathione ............................................................................................................10 1.5 Summary of My Research Project ..............................................................................12 2 MATERIALS AND METHODS ...............................................................................13 2.1 Materials .....................................................................................................................13 2.2 In Vitro Study .............................................................................................................13 2.2.1 PC-12 cell line culture .......................................................................................... 13 2.2.2 Glutamate toxicity ................................................................................................. 14 2.2.3 Hypoxia/reoxygenation ......................................................................................... 14 2.2.4 Carbamathione concentration ............................................................................... 14 2.2.5 Measurement of cell viability by ATP assay ........................................................ 15 2.3 In Vivo Study .............................................................................................................15 2.3.1 Animal preparation ............................................................................................... 16 viii 2.3.2 Bilateral common carotid artery occlusion (BCAO) ............................................ 16 2.3.3 Corner tests ........................................................................................................... 17 2.3.4 Locomotion (Force-plate actometer) test .............................................................. 17 2.3.5 Mice Groups and Treatment Schedules ................................................................ 18 2.3.6 2, 3, 5-Triphenyltetrazolium chloride (TTC) assessment of lesion size ............... 19 2.4 Sample collection for western blot analysis ...............................................................19 2.5 Data and Statistical analysis .......................................................................................20 3 EXPERIMENTAL RESULTS ...................................................................................22 3.1 Glutamate excitotoxicity is dose-dependent in PC-12 cell culture ............................22 3.2 Carbamathione protects PC-12 cells against glutamate-induced excitotoxicity ........23 3.2.1 Carbamathione modulates expression of Heat shock protein (Hsp) and AKT induced by glutamate toxicity ............................................................................... 25 3.2.2 Carbamathione can decrease apoptosis by down-regulation of apoptotic markers .................................................................................................................. 28 3.2.3 Carbamathione protects neuronal cells against glutamate excitotoxicity by suppressing the expression of GRP 78, CHOP ..................................................... 31 3.3 Carbamathione demonstrates robust protective activity against hypoxia/reoxygenation on PC-12 cell cultures ..........................................................35 3.3.1 Effect of Carbamathione on expression of Heat shock protein and AKT induced by hypoxia/reoxygenation ..................................................................................... 37 3.3.2 Carbamathione inhibits the expression of GRP 78, CHOP and Caspase-12 induced by hypoxia/reoxygenation ....................................................................... 41 3.3.3 PERK and IRE1 pathways were inhibited by Carbamathione under ix hypoxia/reoxygenation,
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