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Tetrahydroisoquinoline Neurotoxins in Parkinson Disease Michael G University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 5-2010 Tetrahydroisoquinoline Neurotoxins in Parkinson Disease Michael G. DeCuypere University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Nervous System Diseases Commons, and the Neurosciences Commons Recommended Citation DeCuypere, Michael G. , "Tetrahydroisoquinoline Neurotoxins in Parkinson Disease" (2010). Theses and Dissertations (ETD). Paper 55. http://dx.doi.org/10.21007/etd.cghs.2010.0067. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. Tetrahydroisoquinoline Neurotoxins in Parkinson Disease Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Biomedical Sciences Track Neuroscience Research Advisor Mark S. LeDoux, M.D., Ph.D. Committee Joseph C. Callaway, Ph.D. Angela R. Cantrell, Ph.D. Duane D. Miller, Ph.D. Lawrence T. Reiter, Ph.D. DOI 10.21007/etd.cghs.2010.0067 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/55 TETRAHYDROISOQUINOLINE NEUROTOXINS AND PARKINSON DISEASE A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Michael G. DeCuypere May 2010 Chapter 2 © 2008 by Wiley-Liss, Inc. Chapter 3 © 2008 by International Society for Neurochemistry. All other material © 2010 by Michael G. DeCuypere. All rights reserved. ii DEDICATION To my loving wife, best friend and eternal companion Norma. With love and thanks for supporting me in all my endeavors into neuroscience and neurosurgery. You make my journey worthwhile. iii ACKNOWLEDGEMENTS First and foremost, I would like to thank my research advisor and mentor, Dr. Mark LeDoux, for the training I received in his laboratory. His encouragement, advice and supervision in my research and medical endeavors are much appreciated. Of utmost importance to my career, I appreciate his time, effort and motivation in my education on scientific writing. I would like to thank the members of my graduate committee, Drs. Angela Cantrell, Lawrence Reiter, Joseph Callaway and Duane Miller, for their valuable comments and advice on my qualifying exam, research proposal and dissertation formulation. I would also like to sincerely thank all the current and former members in Dr. LeDoux’s laboratory: Dr. Jianfeng Xiao, Dr. Suzhen Gong and Dr. Yu Zhao, for their technical assistance, suggestions and camaraderie. In particular, I would like to thank Dr. Yu Zhao for her extensive training and assistance in cell culture techniques and valuable input regarding my experiments. Her scientific knowledge and friendship were welcoming and valued in the often-times rough seas of graduate school. During my graduate school training I have had the privilege to learn from several faculty members in the Department of Anatomy and Neurobiology. My sincere thanks to: Drs. Robert Foehring, William Armstrong and Robert Waters for their instruction in neuronal physiology; to Dr. Matt Ennis for instruction in neuroanatomy; to Drs. Melburn Park and Lawrence Reiter for instruction on techniques in microscopy; to Drs. Angela Cantrell and Thomas Schikorski for their instruction on critical review of literature. I am especially grateful to Dr. Pat Ryan, IPBS program director, and Dr. Joseph Callaway, neuroscience graduate program director, who provided me with direction and support from the very beginning of my foray in neuroscience. Many thanks to the staff in the Departments of Neurology and Anatomy and Neurobiology, including Brenda Smith for her administrative help in graduate school and Mary Reed, Bobbie Scott, and Frances Grigsby for their help in reagent purchasing and administrative work. I would especially thank my wife and my extended family for their incredible love and support throughout my graduate training. Finally, I would like to thank the National Institute of Neurological Disorders and Stroke for financial support (R03-NS049123 to MSL). iv ABSTRACT The goal of this dissertation work was to (1) determine the distribution of several tetrahydroisoquinoline (TIQ) derivatives in rodent, normal human and Parkinson disease (PD) brain, (2) quantify the levels of these TIQ derivatives in common food sources in an effort to link specific food intake patterns with the development of PD and (3) examine the neurotoxicity of select TIQ derivatives in human dopaminergic cell culture. The TIQs are a family of monoamine alkaloids that share structural homology with 1-methyl-4- phenyl-1,2,3,6-tetrahyrdropyridine (MPTP), can be formed from dopamine or its oxidized metabolites and may be involved in the pathogenesis of monoaminergic cell death. In our studies, we utilize enantiomeric-selective high-performance liquid chromatography with electrochemical detection (HPLC-EC) and liquid chromatography with tandem mass spectroscopy (LC-MS/MS) to determine the concentrations of TIQ derivatives in brain, as well as in common dietary plants in the United States. The dopaminergic SH-SY5Y human neuroblastoma cell line was utilized to document the neurotoxicity of N-methylated salsolinol derivatives. Several TIQ derivatives were detected in all regions subjected to analysis. In general, salsolinols were present at higher concentrations than TIQ and its benzyl and methyl derivatives, especially in human brain. Moreover, salsolinols were concentrated in areas with increased dopamine synthesis and turnover such as the ventral midbrain and striatum, respectively. Significantly lower levels of (R)salsolinol, (S)salsolinol, N- methyl-(R)salsolinol and N-methyl-(S)salsolinol were found in the caudate nuclei of PD in comparison with normal human brain. N-methyl-norsalsolinol was detected in all regions of rodent and human brain subjected to analysis. In comparison to normal human controls, N-methyl-norsalsolinol levels were significantly lower in the substantia nigra and caudate nuclei from PD patients. N-methyl-norsalsolinol-immunoreactivity co- localized with a general neuronal marker and a monoaminergic cell marker. N-methyl- norsalsolinol-immunoreactivity was not observed in glia. Our analysis of common foods revealed high concentrations of TIQ derivatives in banana, cherry, peach, grapefruit, avocado, button mushroom, leaf lettuce and celery. Enantiomeric salsolinol derivatives were detected as racemic mixtures, without evidence of stereoselective synthesis. Utilizing a lifetime food-item intake questionnaire, we identified trends for increased intake of several plants products in PD patients. Members of the rue (Rutaceae), banana (Musaceae), gourd (Cucurbitaceae), carrot (Apiaceae) and nightshade (Solanaceae) families were found to be highly consumed in both normal human and PD groups, and to concentrate several potentially neurotoxic TIQ derivatives. We correlated indices of cellular energy production and cell viability in dopaminergic SH-SY5Y cells after exposure to N-methyl-norsalsolinol and N-methyl- (R/S)salsolinol. Both toxins induce dose-dependent decreases in cell survival with LC50 values of 0.305 mM and 0.377 mM after 24 hrs, respectively. These results suggest that cell death induced by these N-methylated salsolinols is due to impairment of cellular energy supply, caused in particular by inhibition of mitochondrial complex I. Their concentration in dopaminergic regions of human brain and relatively potent cytotoxicity among TIQs makes these compounds strong candidates for both an endogenous and exogenous link to cell death in PD. v TABLE OF CONTENTS CHAPTER 1. INTRODUCTION ........................................................................................ 1 1.1 PARKINSON DISEASE ................................................................................... 1 1.1.1 Clinical Features .................................................................................. 1 1.1.1.1 Tremor .................................................................................... 1 1.1.1.2 Rigidity .................................................................................... 2 1.1.1.3 Bradykinesia ........................................................................... 2 1.1.1.4 Parkinsonian Gait ................................................................... 3 1.1.1.5 Secondary Manifestations ...................................................... 3 1.1.2 Natural History ..................................................................................... 5 1.1.3 Epidemiology ....................................................................................... 7 1.1.3.1 Incidence ................................................................................ 7 1.1.3.2 Prevalence .............................................................................. 8 1.1.3.3 Geographic Environments ...................................................... 9 1.1.3.4 Genetic Risk Factors .............................................................. 9 1.1.4 Cellular and Molecular Pathology ...................................................... 10 1.2 THE TETRAHYDROISOQUINOLINES ........................................................
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