Underlying Mechanisms of Epilepsy Edited by Fatima Shad Kaneez UNDERLYING MECHANISMS OF EPILEPSY Edited by Fatima Shad Kaneez INTECHOPEN.COM Underlying Mechanisms of Epilepsy http://dx.doi.org/10.5772/1825 Edited by Fatima Shad Kaneez Contributors Jesús Pastor, Rafael G Sola, Sang Pil Yoon, Logan Voss, Jamie Sleigh, Gregory Michael Jacobson, Ayse Kutlu, Halil Unalan, Keiko Kato, Tessy Lopez, Emma Ortiz, Anna Kozina, Karla Espinoza, Richard Gonzalez, Alfonso Alfaro-Rodrí- guez, Emilio Arch-Tirado, Rigoberto Gonzalez-Pina, Pedro Castanheira, Susana Moreira, Miguel Gama, Carlos Faro, Margarida Casal, Yau-Huei Wei, Yu-Ting Wu, Shi-Bei Wu, Wan-Yu Lee, Bruno Dallapiccola, Sofia Douzgou, Maria Jose Fernandes, Daniele Persike, Joao P. Leite, Esper Abrão Cavalheiro, Joao Paulo Viana Leite, Ilgaz Akdogan, Nilufer Yonguc, Fawaz Assaad, Raydeh Al Khani, Ara Sahaki Bazyan, Flavia Prodam, Simonetta Bellone, Roberta Ricotti, Giulia Genoni, Marina Caputo, Gianni Bona, Mahyar Janahmadi, Sahar Farajnia, Zahra Ghasemi, Ali Rastqar, Zhang, Guang-Yi Zhang, Antonio-Carlos Almeida, Antonio Rodrigues, Mario Duarte, Esper Cavalheiro, Gilcelio Silveira, Ricardo Mario Arida, Fulvio Scorza, Jane Roskams, Stacey Beth Foti, Jai Jai Shiva Shankar © The Editor(s) and the Author(s) 2011 The moral rights of the and the author(s) have been asserted. All rights to the book as a whole are reserved by INTECH. The book as a whole (compilation) cannot be reproduced, distributed or used for commercial or non-commercial purposes without INTECH’s written permission. Enquiries concerning the use of the book should be directed to INTECH rights and permissions department (permissions@intechopen.com). 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The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. First published in Croatia, 2011 by INTECH d.o.o. eBook (PDF) Published by IN TECH d.o.o. Place and year of publication of eBook (PDF): Rijeka, 2019. IntechOpen is the global imprint of IN TECH d.o.o. Printed in Croatia Legal deposit, Croatia: National and University Library in Zagreb Additional hard and PDF copies can be obtained from orders@intechopen.com Underlying Mechanisms of Epilepsy Edited by Fatima Shad Kaneez p. cm. ISBN 978-953-307-765-9 eBook (PDF) ISBN 978-953-51-6504-0 Selection of our books indexed in the Book Citation Index in Web of Science™ Core Collection (BKCI) Interested in publishing with us? Contact book.department@intechopen.com Numbers displayed above are based on latest data collected. For more information visit www.intechopen.com 4,100+ Open access books available 151 Countries delivered to 12.2% Contributors from top 500 universities Our authors are among the Top 1% most cited scientists 116,000+ International authors and editors 120M+ Downloads We are IntechOpen, the world’s leading publisher of Open Access books Built by scientists, for scientists Meet the editor Dr. Fatima Shad Kaneez is currently working as Profes- sor of Neurophysiology at the PAP RSB IHS, University Brunei Darussalam. She completed her PhD in 1994 in Neurosciences from the Faculty of Medicine, University of New South Wales, Sydney Australia. She has been teaching Neurosciences, General and Medical Sciences, and other Biological Sciences for the last thirty years to Science, Medical and Paramedical graduates and post-graduates in Aus- tralia, USA, UAE, Bahrain, Pakistan and Brunei Darussalam. She has also been involved in developing, writing, interacting and getting General and Medical Research grants around the world. She completed her first post doc in Prof White’s lab at Allegheny Uni- versity of Health Sciences, Philadelphia, USA. There she was involved in mutating serotonin type 3 channel lumen and identifying the amino acids responsible for ionic selectivity of the channel by using site directed mutagenesis in conjunction with patch clamping. During her PhD she was the first to exhibit the presence of glycine receptor channels in postnatal hippocampal neurons. She has experience in multiple techniques includ- ing: Patch Clamp, Tissue culture, Single Cell RT PCR, Proteomics and Bioinformatics. She is a member of 14 learned societies including her role as regional representative of Women in World Neurosciences (WWN) and coordinator of the Neuroscience Program Network, IBRO (NPN). She has achieved many awards and scholarships, is the author of 20 full refereed papers published in International Tier 1 and 2 journals and 66 refereed conference and short communications. She is the editor of 3 books and 4 journals and has contributed a number of book chapters and reviews. Contents Preface X III Part 1 Causes and Types of Epilepsy 1 Chapter 1 Histopathological Changes in Temporal Epilepsy 3 Assaad Fawaz and Al Khani Raydeh Chapter 2 The Role of Astrocytes in Epileptogenesis 19 Jesús Pastor and Rafael G. Sola Chapter 3 START Proteins in Epilepsy 45 Sang Pil Yoon Chapter 4 Introduction of a Novel Molecular Mechanism of Epilepsy Progression: Roles of Growth Hormone Signaling in a Mouse Model of Temporal Lobe Epilepsy 63 Keiko Kato Chapter 5 Bridging the Gap – Understanding the Role of Gap Junctions in Seizures 77 Logan J. Voss, Gregory Jacobson and Jamie W. Sleigh Part 2 Underlying Mechanisms 99 Chapter 6 Recombinant Laforin for Structural Studies 101 Pedro Castanheira, Susana Moreira, Margarida Casal, Miguel Gama and Carlos Faro Chapter 7 Temporal Lobe Epilepsy: Cell Death and Molecular Targets 117 Maria José da Silva Fernandes, Esper Abrão Cavalheiro, João Pereira Leite and Daniele Suzete Persike X Contents Chapter 8 The Cross-Talk Between Mitochondria and the Nucleus in the Response to Oxidative Stress Associated with Mitochondrial Dysfunction in Mitochondrial Encephalomyopathies 135 Yu-Ting Wu, Wan-Yu Lee, Shi-Bei Wu and Yau-Huei Wei Chapter 9 Ghrelin Regulation in Epilepsy 151 Flavia Prodam, Simonetta Bellone, Roberta Ricotti, Giulia Genoni, Marina Caputo and Gianni Bona Chapter 10 Regulation of GluR6-PSD95-MLK3 Signaling in KA-Induced Epilepsy 181 Chong Li and Guang-Yi Zhang Chapter 11 Biophysical Aspects of the Nonsynaptic Epileptiform Activity 189 Antônio-Carlos G. Almeida, Antônio M. Rodrigues, Mário A. Duarte, Gilcélio da Silveira, Fulvio A. Scorza, Ricardo M. Arida, Jaderson C. Costa and Esper A. Cavalheiro Chapter 12 A Tale of Two Epiphenomena: The Complex Interplay of Epigenetics and Epilepsy 219 Stacey Beth Foti and A. Jane Roskams Chapter 13 Multimodal MRI Evaluation in Intractable Epilepsy with Pathologically Confirmed Mesial Temporal Sclerosis 241 Jai Jai Shiva Shankar Part 3 Therapeutic Regimes and Side Effects 249 Chapter 14 The Gingival Fibromatoses 251 Sofia Douzgou and Bruno Dallapiccola Chapter 15 Experimental Epilepsy Models and Morphologic Alterations of Experimental Epilepsy Models in Brain and Hippocampus 268 Ilgaz Akdogan and Nilufer Goksin Yonguc Chapter 16 Two Types of Epilepsy Models and Processes of Cognition: Pentylenetetrazole Kindling and Absence Epilepsy of WAG/Rij Rats Strain 283 A. S. Bazyan Chapter 17 Monoamines and Sleep: Effects of Oxcarbazepine 303 Alfonso Alfaro-Rodríguez, Emilio Arch-Tirado and Rigoberto González-Piña Chapter 18 Medicinal Herbs and Epilepsy: A Two Edged Sword 317 Mahyar Janahmadi, Sahar Farajnia, Zahra Ghasemi and Ali Rastqar Contents X I Chapter 19 In-situ Release of Antiepileptic Drugs from Nanostructured Reservoirs 333 Tessy Lopez, Anna Kozina, Emma Ortiz-Islas, Karla A. Espinoza and Richard Gonzalez Chapter 20 Quality of Life and Psychiatric Aspects in Epilepsy 347 Ayşe Kutlu and Halil Ünalan Preface Approximately 1 out of 120 people have epilepsy and 2 out of every 3 new cases are found in developing countries. Young children and people over the age of 65 are more susceptible to epilepsy; however, it can occur to any one at any time in life. Although around 5% of the total world population have seizures, only 0.9% are diagnosed with epilepsy so it is very important to understand the differences between seizures and epilepsy and also to identify the factors responsible for its etiology in order to have more effective therapeutic regime. This book presents twenty chapters ranging from causes and underlying mechanisms to treatment and side effects of epilepsy. This introductory part offers merely a brief skim through some of these quite interesting multidisciplinary chapters. The chapter entitled “Histopathological Changes in Temporal Epilepsy” is an interesting review on the etiology of drug resistant epilepsy. In this paper, authors discuss the dual pathology of epilepsy in association with other alterations due to neuronal injury and loss. Authors offer a hypothesis that the presence of an epileptogenic foci provokes a process of progressive damage of the nervous tissue and result in drug resistant epilepsy. Next chapter, entitled “The Role of Astrocytes in Epileptogenesis” is a review about how astrocytes modulate different types of partial seizure. Authors discuss the pivotal role of astrocytes in epilepsy and their involvement in: managing the trafficking of substances between capillary vessels and neurons, homeostasis of ions, principally potassium (K+), and their role in the metabolism of the brain through the degradation of both glucose and glutamate. In addition, they discuss the release of gliotransmitters, and multiple contacts of cortical astrocytes. They also debate on how astrocytic integration can affect the function of several groups of neurons or synapses, thus working in a more coherent model. Any change in astrocytic physiology changes the equilibrium between neuronal excitation and inhibition leading to epileptogenesis. Further on, the chapter “START proteins in Epilepsy” is based on the observations that the release of neuroactive steroids impairs neuronal survival in the hippocampus. In this chapter, various molecules including steroidogenic acute regulatory protein (StAR)-related lipid transfer domain-containing proteins (START proteins) and their relationship with neurosteroidogenesis were reviewed for further understanding of X Preface their role in epilepsy. The START domain that operates as a lipid exchange unit is suggested for further studies as to elucidate the exact nuclear roles of StarD6 on neurosteroidogenesis with StAR in the nervous system. “Introduction of a novel molecular mechanism on epilepsy progression: roles of growth hormone signaling in a mouse model of temporal lobe epilepsy” is a chapter on epilepsy with foci and the candidate molecules involved in refractory epilepsy. Up- regulation of growth hormones found to have occurred during the process, and metabolic regulation by GH-signaling appears to be responsible for initiating the after discharge threshold during epileptogenesis. “Role of gap junctions and connexion proteins in the mechanism of seizures” is a paper with reference to the connexion proteins, resultant hemichannels, and the association of two hemichannels on neighboring cells to form a gap junction. Literature suggested a deep and multifaceted relationship between gap junction regulation and seizure susceptibility. In this chapter authors have sought to bring together research from a wide range of disciplines encompassing electrophysiology, molecular biology and mathematical modeling, with the aim of addressing the role of gap junctions in the mechanism of seizures. Chapter “Recombinant Laforin for Structural Studies” is about autosomal recessive Lafora disease, also known as progressive myoclonic epilepsy. This type of epilepsy is caused by the mutations in two genes: EPM2A gene, coding for the protein laforin, and NHLRC1 gene, for the protein malin. Focusing on Laforin and its involvement in Lafora disease, authors reported it as therapeutic contender for myoclonic epilepsy as well as a novel candidate for biotechnological applications of carbohydrate binding proteins. “The Cross-talk between Mitochondria and the Nucleus in the Response to Oxidative Stress Associated with Mitochondrial Dysfunction in Mitochondrial Encephalomyopathies” is an interesting review combined with author’s own work. In this review authors discussed the biochemical consequences of mitochondrial dysfunction-elicited oxidative stress, mitochondrial retrograde signaling and regulation of Ca 2+ homoeostasis in neuronal excitability and resultant epileptic seizures. They also discussed the role of stress responsive gene, Sirt1, in the signaling pathway of the cross-talk between mitochondria and the nucleus. “Temporal Lobe Epilepsy (TLE): molecular targets and cell death” is about TLE and other molecular mechanisms involved in the process of cell death. Authors also explored Bcl-2 gene family and their levels in the hippocampus of patients with intractable seizures. In this paper authors have nicely demonstrated that Caspase- mediated inflammatory process could be a potential mechanism for the pathogenesis of TLE and Caspase inhibitors may act as novel therapeutic agents. “Ghrelin regulation in epilepsy” is a review discussing whether hormonal changes in relation to epilepsy are due to seizures activity per se or to consequential effects of Preface XI antiepileptic drugs. Authors re-evaluate the hormones involved in epilepsy focusing on ghrelin, a 28 amino acid peptide produced by stomach. Increasing evidence indicated that ghrelin plays a role in anxiety and stress, though in vitro and in vivo experiments are still controversial. However, it is confirmed that ghrelin has anticonvulsant properties and blood ghrelin levels were shown to be decreased both in experimental epileptic rodents and in humans. Literature indicated that ghrelin can act as a neuroprotective agent due to its antiepileptic and anti-inflammatory effects on neuronal brain cells. A better understanding of ghrelin’s activities may help to develop new therapeutic approaches to epilepsy. “Regulation of GluR6-PSD95-MLK3 signalling in KA-induced rat seizure models” is a short review about the beneficial effects of the co-application of muscimol and baclofen against Kainic acid induced seizures. An experimental model based on Kainic acid (KA) injections replicates many phenomenological features of human temporal lobe epilepsy Moreover some details are present in the article explaining how both ionotropic and metabotropic GABA agonists can inhibit the assembly of the GluR6- PSD95-MLK3 signaling responsible for KA-induced seizures. “Biophysical Aspects of the non synaptic epileptiform Activity” is a very nicely written chapter, which demonstrates the conjoint actuation of non-synaptic mechanisms and connections, able to induce and sustain seizures. Focusing on different regions of the hippocampus, and their ability to generate or sustain non- synaptic epileptiform activities authors found them to be directly related with the reduced levels of calcium and increased level of potassium in the extracellular fluid. Authors postulated that these epileptiform activities of non-synaptic origin could be mediated by gap-junctions, ionic fluctuations, or field effect. They described the cellular mechanisms regarding epilepsy using computational simulations for membrane ionic currents, Na + /K +-ATPase, co-transporters, and exchangers. “The Complex Interplay Of Epigenetics And Epilepsy” is a very well written and interesting review about the pharmacological manipulation of epigenetic factors and development of subtype-specific HDAC (Histone deacetylases) inhibitors. Evidence is emerging that epileptogenesis involves changes in the expression patterns of several classes of functionally or genomically-grouped genes that coordinate neural development, homeostasis and stress responses, and neural network formation. Abnormal activity of epigenetic mediators including DNMTs, MBDs, HDACs and repressor complexes could result in altered neuro- and gliogenesis, aberrant migration of newly born cells, and improper integration of these cells into circuits, thereby causing hyper-excitable circuits and seizures. “Mechanisms Involved in the Pathophysiological Progression of Epilepsy” is a review about pharmacological and genetic importance in molecular signaling mechanisms underlying epileptogenesis. Authors discuss a number of ionotropic and metabotropic glutamate receptors, neurotrophin receptors, calcium regulated enzymes and non- receptor tyrosine kinases which are involved in orchestrating various biochemical XII Preface events in brain, finally leading to precipitation of a multitude of severe epileptic condition. The chapter is designed to contribute novel concepts for antiepileptic drug. “The Gingival Fibromatoses (GF)” is a review with personal observations in which authors suggested that GF can be apparent within a systemic disease, and anticonvulsant drug therapy is one of the most common causes of isolated GF. They discuss the prevalence of GF secondary to drug treatment following long term phenytoin therapy. They talk about the clinical heterogeneity and reflected genetic heterogeneity. Then they discuss different conditions which extends from the association of GF with hypertrichosis up to the multi-systemic syndromes of Zimmermann-Laband and Ramon. In addition to reviewing the literature they discuss patients with GH, tonic clonic seizures and GF unrelated to antiepileptic treatment. “Experimental Epilepsy Models and Morphological Alterations” is a review about the different chemically and electrically induced epilepsy models. Authors conclude that there is no model for answering all questions regarding epilepsy and the studies performed by using experimental models can only explore the basic mechanisms of that particular type of epilepsy. Some chemicals can induce more than one type of epilepsy model. For example crystallized penicillin can induce simple partial, generalized myoclonic, generalized tonic-clonic and generalized absence epilepsy when given using different routes of administration. Therefore, EEG and behavioral studies should be used for analyzing the induced model. “Two types of epilepsy models and processes of cognition” is a review in which author presents literature and her own data for the comparison of two types of epileptic activities that is the convulsive epilepsy induced by pentilenetetrazole (PTZ) kindling in Wister rats and non-convulsive absence epilepsy in WAG/Rij rats. The main difference between these two types of epilepsy was described. Oxcarbazepine (OXC) is an antiepileptic drug (AED) of the second generation, with a chemical structure similar to carbamazepine, but with different metabolism OXC is used for the treatment of partial seizures as monotherapy or adjunctive therapy in adults, and in children aged 4 to 16 years. OXC is also sometimes used to treat acute mania in adults, bipolar disorder, and manic-depressive disorder. The neurobiological interaction between epilepsy and sleep is receiving enhanced attention. A key role for limbic monoamines in epilepsy has been established and recently some studies showed the importance of hippocampal monoamines in limbic seizures control Medicinal herbs are a two edged sword, as discussed in the following chapter. Some herbs are often used in the treatment of the disease, including epilepsy; however, they could also induce or worsen epileptic activity. Effects of an Ethanolic extract and essential oil of Artemisia dracunculus L. (Tarragon) were explored before and after the induction of epileptiform activity in snail neurons, using intracellular recording technique. Ethanolic extract and essential oil of Tarragon produce different electrophysiological changes in Pentylenetetrazole (PTZ)-induced epilepsy model. Preface XIII Tarragon extract results in the complete disappearance of paroxysmal depolarization shift (PDS)-induced by PTZ, while its essential oil potentiate the epileptic activities in the presence of PTZ. Based on their electrophysiological findings, authors suggested that a certain caution is needed when medicinal herbs are used for treating patients suffering from epilepsy. “In situ release of anti epileptic drugs from nanostructure reservoirs” is a very informative chapter about novel drug delivery system. Author’s exhibited how anticonvulsant drug phenytoin encapsulated into the sol-gel biocompatible Titania and can be successfully implanted into the temporal lobe of the brain by low invasion stereotactic surgery. The implantation process is such that the damage of the surrounding tissue is minimal. The drug release from the implants is controlled by the parameters of the matrix such as its morphology, drug-matrix interaction strength, etc. Depending on the parameters of the synthesis, the release profile may be designed according to the necessities in terms of release rate and the amount of the released drug. One of the main prospects of the study is to achieve better protection ’in vivo’ for longer time. Also, one needs to find a correlation between the drug release ’in vitro’ and its effect and release profile ’in vivo’. In short, this book contains a range of proposals regarding causes mechanisms and treatment options of epilepsy which will be of interest to a number of scientists and scholars from different disciplines. Prof. Dr. Fatima Shad Kaneez Human Physiology, PAP RSB Institute of Health Sciences University Brunei Darussalam The State of Brunei Darussalam Part 1 Causes and Types of Epilepsy