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Novel Neuroprotective Compunds for Use in Parkinson's Disease Novel neuroprotective compounds for use in Parkinson’s disease A thesis submitted to Kent State University in partial Fulfillment of the requirements for the Degree of Master of Science By Ahmed Shubbar December, 2013 Thesis written by Ahmed Shubbar B.S., University of Kufa, 2009 M.S., Kent State University, 2013 Approved by ______________________Werner Geldenhuys ____, Chair, Master’s Thesis Committee __________________________,Altaf Darvesh Member, Master’s Thesis Committee __________________________,Richard Carroll Member, Master’s Thesis Committee ___Eric_______________________ Mintz , Director, School of Biomedical Sciences ___Janis_______________________ Crowther , Dean, College of Arts and Sciences ii Table of Contents List of figures…………………………………………………………………………………..v List of tables……………………………………………………………………………………vi Acknowledgments.…………………………………………………………………………….vii Chapter 1: Introduction ..................................................................................... 1 1.1 Parkinson’s disease .............................................................................................. 1 1.2 Monoamine Oxidases ........................................................................................... 3 1.3 Monoamine Oxidase-B structure ........................................................................... 8 1.4 Structural differences between MAO-B and MAO-A .............................................13 1.5 Mechanism of oxidative deamination catalyzed by Monoamine Oxidases ............15 1 .6 Neuroprotective effects of Monoamine oxidase-B inhibitors ................................19 Chapter 2: Materials and Methods ..............................................................22 2.1 Monoamine Oxidase Inhibition assay ...................................................................26 2.2 Determination of Monoamine Oxidase-B binding reversibility ...............................28 2.3 Measuring the effects of test compounds on Km and Vmax of MAO-B .....................29 2.4 Oxygen radical absorbance capacity assay .........................................................30 2.5 Acetylcholinesterase Inhibition Assay ..................................................................31 2.6 Measuring IC50 of test compounds against acetylcholinesterase enzyme .............33 2.7 Bovine Serum Albumin Binding Assay .................................................................33 2.8 Parallel Artificial Membrane Permeability Assay ...................................................34 Curve fitting and graphs .............................................................................................36 Docking Studies .........................................................................................................37 iii Chapter 3: Results ..............................................................................................38 3.1 Monoamine Oxidase Inhibition assay ...................................................................38 3.2 Acetylcholinesterase Inhibition Assay ..................................................................44 3.3 Parallel Artificial Membrane Permeability Assay ...................................................46 3.4 Bovine Serum Albumin Binding Assay .................................................................48 3.5 Oxygen radical absorbance capacity assay .........................................................52 3.6 Effect of 5223890 and 7691778 on Km and Vmax of MAO-B ...................................54 3.7 Determination of Monoamine Oxidase-B binding reversibility ...............................56 3.8 Docking of test compounds in MAO-B crystal.......................................................58 Chapter 4: Discussion and Conclusions .................................................69 Bibliography…………………………………………………………..…………………………………………………78 iv List of figures Figure 1: Three dimensional structure of human MAO-B. .............................................10 Figure 2: Three dimensional structure of human MAO-A ..............................................14 Figure 3: Oxidative deamination of monoamines catalyzed by MAO-A and MAO-B. .....17 Figure 4: Proposed polar nucleophilic attack mechanism and single electron transfer. 18 Figure 5: Structures of test compounds. .......................................................................24 Figure 6: Conversion of kynuramine to 4-hydroxyquinoline catalyzed by MAO .............28 Figure 7: Effect of test compounds on enzymatic activity of MAO-B. ............................40 Figure 8: Effect of test compounds on enzymatic activity of MAO-A .............................41 Figure 9: Inhibition curves of MAO-B by test compounds..............................................42 Figure 10: Effect of test compounds on acetylcholinesterase activity ............................45 Figure 11: Percentage of free BSA after treatment with test compounds.. ....................49 Figure 12: BSA-binding curves for test compounds ......................................................50 Figure 13: Effect of test compounds on fluorescein level.. ............................................53 Figure 14: Effect of test compounds on Km and Vmax of MAO reaction ...........................55 Figure 15: Effects of test compounds on MAO-B activity at different time points. ..........57 Figure 16: Docking of 5223890 in MAO-B crystal .........................................................59 Figure 17: Docking of 7691778 in MAO-B crystal. ........................................................61 Figure 18: Docking of 7704954 in MAO-B crystal. ........................................................63 Figure 19: Docking of 7738820 in MAO-B crystal. ........................................................65 Figure 20: Docking of F5123-0122 in MAO-B crystal. ...................................................67 v List of tables Table 1: Selectivity, binding reversibility and therapeutic uses of MAO-inhibitors ........... 4 Table 2: Compounds’ ID and their molecular weights. .................................................23 Table 3: IC50 of test compounds against MAO-B and MAO-A. .......................................39 Table 4: IC50 of test compounds against acetylcholinesterase.......................................46 Table 5: log Pe and Pe of test compounds measured by PAMPA ..................................47 Table 6: EC50 of test compound towards BSA ...............................................................48 Table 7: EC50 of test compounds as anti-oxidants. ........................................................53 Table 8: Effect of test compounds on Vmax and Km of MAO-B reaction ...........................54 vi Acknowledgments First and foremost I would like to express heartfelt gratefulness to my family. Without the support and encouragement of my parents, sister and brother, I could not have finished my study. I am grateful for all encouragement and reassurance they gave me. I would like to thank my advisor and mentor Dr. Werner Geldenhuys for giving me the opportunity to work in his laboratory and his invaluable guidance with my research and thesis. Without his guidance and persistent support, this thesis would not have been possible. I would also like to thank Dr. Altaf Darvesh and Dr. Richard Carroll for serving on my thesis committee and providing valuable insights and expert advice on my project. Besides my advisor, I would like to express my sincere gratitude to my previous mentor Dr. Thomas Jones for all his support and guidance. Finally, I would like to express my gratitude to Dr. Eric Mintz and Mrs. Judith Wearden for their help and support. vii Chapter 1: Introduction 1.1 Parkinson’s disease Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease affecting about 1% of people aged more than 65 years old (29). Parkinson’s disease is a chronic progressive motor disorder that is caused by irreversible damage to dopaminergic neurons located in substantia nigra pars compacta of the midbrain (30). Motor symptoms of Parkinson’s disease include tremor, rigidity and bradykinesia. Parkinson’s disease is characterized by the presence of Lewy bodies which are intracytoplasmic inclusions from protein aggregates (31). Dopaminergic neuronal death is caused by several factors and the most important factor is oxidative stress. Oxidative stress is a powerful stimulator of microglial activation with subsequent release of reactive oxygen species (ROS) (32). Dopaminergic neurons located in substantia nigra have a greater sensitivity to oxidative stress due to reduced levels of glutathione, an important endogenous antioxidant, and increased level of iron in substantia nigra (33)(37). α-synuclein is the major constituent of Lewy bodies and it has been reported to be produced by dying dopaminergic neurons in Parkinson’s disease (34). Both oxidized and nitrated α- synuclein have a detrimental effect on dopaminergic neurons which is mediated 1 2 by microglial activation and subsequent induction of oxidative stress and inflammation (35)(36). There is no permanent cure for Parkinson’s disease, but there are several pharmacological interventions that can help to alleviate motor and non-motor symptoms of the disease. Levodopa, a precursor for dopamine synthesis, is the most important drug that is used in the treatment of for Parkinson’s disease; however it has no effect on non-motor symptoms of the disease (38). Levodopa is usually administered with a decaroboxylase inhibitor such
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