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Robrecht Raedt Cell Therapy for Temporal Lobe Epilepsy: Feasibility of Neurotransplantation versus Modulation of Endogenous Neurogenesis Robrecht Raedt Thesis submitted to fulfil the requirements for the degree of Doctor in Medical Sciences August 2007 Onderzoek gefinanicierd met een specialisatiebeurs van het instituut voor de aanmoediging van Innovatie door Wetenschap en Technolgie in Vlaanderen (IWT-Vlaanderen, beurs nummer 23363) Reseach funded by a PhD grant of the Institute for the promotion of Innovation through Science and Technology in Flanders (IWT Vlaanderen, grant number 23363) Promotor Prof. Dr. Paul Boon Universiteit Gent, Belgium Copromotor Prof. Dr. J. Plum Universiteit Gent, Belgium Members of the examination committee Prof. Dr. Marleen Temmerman Universiteit Gent, Belgium Prof. Dr. Robert Rubens Universiteit Gent, Belgium Prof. Dr. Catherine Verfaillie Katholieke Univeristeit Leuven, Belgium Prof. Dr. Elinor Ben-Menachem Goteborg University, Sweden Prof. Dr. Wytse Wadman Universiteit van Amsterdam, The Netherlands Prof. Dr. Bart Vandekerckhove Universiteit Gent, Belgium Prof. Dr. Kristl Vonck Universiteit Gent, Belgium TABLE OF CONTENTS CHAPTER 1: INTRODUCTION ON TEMPORAL LOBE EPILEPSY 9 EPILEPSY .................................................................................................................................................................. 11 TEMPORAL LOBE EPILEPSY ..................................................................................................................................................... 12 ANIMAL MODELS FOR EPILEPSY ............................................................................................................................................. 16 CHAPTER 2: CELL THERAPY IN NEUROLOGY 27 MANUSCRIPT 1: RAEDT R. & BOON P., CELL THERAPY FOR NEUROLOGICAL DISORDERS: A COMPREHENSIVE REVIEW ...... 29 ACTA NEUROL BELG. 2005,105,158-170 ADDENDUM TO MANUSCRIPT 1 ............................................................................................................................................ 51 MANUSCRIPT 2: RAEDT R. ET AL., CELL THERAPY IN MODELS FOR TEMPORAL LOBE EPILEPSY ............................................ 71 SEIZURE. JUNE 11 2007, ONLINE EARLY ARTICLE CHAPTER 3: ADULT NEUROGENESIS 97 INTRODUCTION ON ADULT NEUROGENESIS .......................................................................................................................... 99 ADULT NEUROGENESIS AND NEURAL DAMAGE .................................................................................................................. 103 NEUROGENESIS IN EPILEPSY ................................................................................................................................................ 107 CHAPTER 4: RATIONALE, AIMS AND OUTLINE OF THE THESIS 115 RATIONALE ................................................................................................................................................................ 117 AIMS ................................................................................................................................................................ 121 OUTLINE OF THE THESIS ....................................................................................................................................................... 123 CHAPTER 5: CELL TRANSPLANTATION FOR TLE 127 MANUSCRIPT 3: RAEDT R. ET AL., DIFFERENTIATION ASSAYS OF BONE MARROW DERIVED MAPC-LIKE CELLS ................ 129 TOWARDS NEURAL CELLS CANNOT DEPEND ON MORPHOLOGY AND A LIMITED SET OF NEURAL MARKERS EXPERIMENTAL NEUROLOGY. 2007,203,542-554 MANUSCRIPT 4: RAEDT R. ET AL.,SEIZURES IN THE INTRAHIPPOCAMPAL KAINIC ACID EPILEPSY MODEL: ......................... 155 CHARACTERIZATION USING LONG TERM VIDEO-EEG MONITORING IN THE RAT ACTA NEUROLOGICA SCANDINAVICA. 2007,SUBMITTED MANUSCRIPT 5: RAEDT R. ET AL., TRANSPLANTATION OF ADULT SUBVENTRICULAR ZONE-DERIVED NEURAL ................ 175 STEM CELLS IN THE KAINIC ACID LESIONED HIPPOCAMPUS OF THE RAT EXPERIMENTAL NEUROLOGY. 2007,SUBMITTED CHAPTER 6: MODULATION OF ENDOGENOUS NEUROGENESIS IN TLE 199 MANUSCRIPT 6: RAEDT R. ET AL., RADIATION OF THE RAT BRAIN SUPPRESSES SEIZURE-INDUCED NEUROGENESIS......... 201 AND TRANSIENTLY ENHANCES EXCITABILITY DURING KINDLING ACQUISITION EPILEPSIA. JUNE 6 2007,ONLINE EARLY ARTICLE CHAPTER 7: GENERAL DISCUSSION 229 CELL THERAPY FOR TLE THROUGH CELL TRANSPLANTATION .............................................................................................. 231 CELL THERAPY FOR TLE TRHOUGH MODULATION OF ENDOGENOUS NEUROGENESIS ....................................................... 249 CHAPTER 8: GENERAL CONCLUSION 261 CHAPTER 9: FUTURE PERSPECTIVES 271 CELL TRANSPLANTATION FOR TLE ........................................................................................................................................ 273 MODULATION OF ENDOGENOUS NEUROGENESIS IN CASE OF TLE ..................................................................................... 276 SUMMARY; SAMENVATTING; RÉSUMÉ 283 DANKWOORD 295 LIST OF ABBREVIATIONS 4-VO four vessel occlusion DCX doublecortin 6-OHDA 6-hydroxydopamine DMEM dulbecco's modified eagle's medium ABI applied biosystems DMSO dimethylsulfoxide AchE acetylcholine DNA deoxyribonucleic acid AD afterdischarge DPBS dulbecco's phospate buffered saline ADD afterdischarge duration DV dorsoventral ADK adenosine kinase EC embryonic carcinoma ADT afterdischarge threshold EEG electro-encephalogram AED antiepileptic drugs EG embryonic germ ALS amyotrophic lateral sclerosis EGF epidermal growth factor ang angiopoietin EPSP exitatory postsynaptic potentials ANOVA analysis of variance ESC embryonic stem cells AP anteroposterior ESGP embryonic stem cell-derived glial araC cytosine-b-D-arabinofuranoside precursors ESN embryonic stem cell-derived neurons azaC 5-azacytidine FBS fetal bovine serum β-3 tub β-3 tubulin FCS fetal calf serum BDNF brain-derived neurotrophic factor FF fimbria fornix bFGF basic fibroblast growth factor FGF fibroblast growth factor BHA butylated hydroxyanisol FSG fish skin gelatin BLA basolateral amygdala GABA gamma-aminobutyric acid BLAST basic local alignment search tool GAD glutamic acid decarboxylase BM bone marrow GalC galactocerebrosidase BMMNC bone marrow mononucleated cells GCL granule cell layer BMP bone morphogenic protein GDNF glial-derived neurotrophic factor BMSC bone marrow-derived multipotent cells GFAP glial fibrillary acidic protein BrdU 5-bromo-2 deoxyuridine GFP green fluorescent protein CA cornu ammonis GKS gamma knife surgery cDNA copy deoxyribonucleic acid Gy gray CFW california fine wire HD Huntington's disease CNS central nervous system HFO high frequency oscillation CNTF ciliary neurotrophic factor HPLC high pressure liquid chromatography CPS complex partial seizures HPRT hypoxanthine phosphoribosyl DAPI 4,6-diamidino-2-phenylindole transferase HS hippocampal sclerosis db-cAMP dibutyril cyclic adenosine monophosphate HSC hematopoietic stem cells DBS deep brain stimulation HUVEC human umbilical vein endothelial cells List of abbreviations 7 HYP hypersynchronous type NT-3 neurotrophin-3 ICC immunocytochemistry PB phosphate buffer IGF insulin growth factor PBS phosphate buffered saline IgG immunoglobulin PC pyriform cortex ILAE international league against epilepsy PD Parkinson's disease IR immunoreactive PDGF platelet-derived growth factor ITS insulin-transferrin-selenium PFA paraformaldehyde KA kainic acid PGC primordial germ cells LA-BSA linoleic acid-bovine serum albumin PILO pilocarpine LC locus coeruleus PLD postlesion delay LTLE lateral temporal lobe epilepsy PPV posterior periventricular region LVF low-voltage fast type PSA- polysialylated neural cell adhesion MACS magnetic beads cell sorting NCAM molecule PTZ pentylenetetrazol MAP microtubule associated protein RA retinoic acid MAPC multipotent adult progenitor cells RFA radiofrequency ablation MBP myelin basic protein RMS rostral migratory stream MES maximal electroshock RNA ribonucleic acid MHC major histocompatibility complex RT-PCR real-time polymerase chain reaction MIAMI marrow-isolated adult multilineage inducible SCG superior cervical ganglion ML mediolateral SE status epilepticus mLIF mouse leukemia inhibitory factor SEM standard error of the mean MOSFET Metal-Oxide-Semiconductor Field- SGZ subgranular zone Effect Transistor SG secondary generalization MRI magnetic resonance imaging SHH sonic hedgehog mRNA messenger ribonucleic acid SNr substantia nigra MS medial septum SPS simple partial seizures MSC mesenchymal stem cells SSSE self-sustaining stauts epilepticus MTLE mesial temporal lobe epilepsy SVZ subventricular zone NA noradrenaline TBS tris-buffered saline NCBI national centre for biotechnology information TH tyrosine hydrolase NeuN neuronal nuclei TLE temporal lobe epilepsy NF neurofilament TX100 Triton X-100 NGF nerve growth factor USSCs unrestricted somatic stem cells NMDA N-methyl-D-aspartate VEGF vascular endothelial growth factor NSC neural stem cells VNS vagus nerve stimulation NSE neuron specific enolase 8 List of abbreviations Chapter 1 Introduction on Temporal Lobe Epilepsy EPILEPSY Epilepsy affects 0.5-1% of the general population and is the second most common chronic neurological disease following cerebrovascular disorders. It is a central nervous system (CNS) disorder characterized by recurring epileptic seizures and by the neurobiological, cognitive and psycho-social consequences for individual patients. The definition of epilepsy requires the occurrence of
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