Pharmacoresistance in Epilepsy. From Genes and Molecules to Promising Therapies.

Preface
Contents
Contributors
Chapter 1: Why Study Drug-Resistant Epilepsy?
	References
Chapter 2: Pharmacoresistance in Epilepsy
	2.1 Epilepsy
	2.2 Epilepsy as Stigma
	2.3 Epilepsy and Pharmacoresistance
	2.4 Epilepsy as Health Problem
	2.5 Burden of Pharmacoresistant Epilepsy
	2.6 Epilepsy Care
	2.7 Conclusion
	References
Chapter 3: Experimental Models for the Study of Drug-Resistant Epilepsy
	3.1 Introduction
	3.2 In Vitro Models
		3.2.1 Cell Cultures
		3.2.2 Brain Slices with Cortical Dysplasia Exposed to 4-Aminopyridine
		3.2.3 In Vitro Study of Brain Tissue from Patients with Drug-Resistant Epilepsy
	3.3 In Vivo Models of Drug-Resistant Seizures
		3.3.1 Caenorhabditis Elegans
		3.3.2 Zebrafish
	3.4 Induction of Drug-Resistant Seizures by Repeated Administration of Proconvulsant Drugs
	3.5 Chemical Kindling and Drug Resistance
	3.6 Electrical Kindling and Drug Resistance
	3.7 Corneal Electric Kindling
	3.8 Models of Drug-Resistant Epilepsy
		3.8.1 Drug-Resistant Epilepsy Secondary to Status Epilepticus Due to Lithium-Pilocarpine
		3.8.2 Kainic Acid and Drug-Resistant Epilepsy
		3.8.3 Models of Drug-Resistant Posttraumatic Epilepsy
		3.8.4 Canines with Drug-Resistant Epilepsy
	3.9 Models of Drug-Resistant Epilepsy Due to Genetic Alterations
	3.10 Novel Approaches to Assess Drug-Resistant epilepsy in Animal Models
	3.11 Epilepsy Therapy Screening Program: Advantages and Limitations for the Detection of Therapies for Drug-Resistant Epilepsy
	3.12 Conclusions
	References
Chapter 4: On Complexity and Emergence: Linking the Hypotheses of Pharmacoresistance in Epilepsy
	4.1 Introduction
	4.2 Emergence: Linking Multiple Hypotheses of DRE
	4.3 The Role of Comorbidities in DRE
	4.4 Systems Biology: Dealing with the Multiple Mechanisms of DRE
	4.5 The Advent of Systems Pharmacology for the Treatment of Epilepsy
	4.6 Conclusion
	References
Chapter 5: The Role of High-Frequency Oscillation Networks in Managing Pharmacoresistant Epilepsy
	5.1 Introduction
	5.2 Different Types of HFO in Normal Brain and the Brain with Focal Epilepsy
	5.3 Mechanisms Generating Normal and Pathological HFO and the Contributions of Inhibitory and Excitatory Cells
	5.4 Fast Ripples as Biomarkers of Epileptogenic Tissue
	5.5 Proposed Roles of FR in Surgical Planning
	5.6 Utilizing FR Graph Theoretical Metrics to Assess the Epileptogenic Network for Surgical Planning
	5.7 Stimulation Therapy of the Epileptogenic Network
	5.8 Summary
	References
Chapter 6: Transporter Hypothesis in Pharmacoresistant Epilepsies: Is it at the Central or Peripheral Level?
	6.1 Introduction
	6.2 The Multidrug Resistance (MDR) Phenotype
	6.3 Role of ABC-t in the “LADME System” as the Peripheral Mechanism of Drug Resistance in Epilepsy
	6.4 ABC-t in the Central Mechanism of Drug-Resistant Epilepsy
		6.4.1 Does the Expression of P-gp in Neuronal Membranes Play an Epileptogenic Role?
		6.4.2 ABC Transporters and Phosphatidylserine Translocation to the Outer Face of the Cell Plasmatic Membrane. A Potential Mechanism of Epileptogenesis
	6.5 Brain Inflammation, ABC-t, and Blood-Brain Barrier Dysfunction
	6.6 Interconnection of Central and Peripheral Role of ABC Transporters in Refractory Epilepsy and SUDEP
		6.6.1 Expression of P-Glycoprotein in Cardiomyocytes and Its Potential Role in SUDEP Development
	6.7 Conclusions and Remarks
	References
Chapter 7: Changes in Targets as an Explanation for Drug Resistance in Epilepsy
	7.1 Introduction
	7.2 Voltage-Gated Sodium Channels
	7.3 GABAA Receptors
	7.4 Other Receptors Involved in Drug-Resistant Epilepsy
	7.5 Conditions that Reduce ASMs Effectiveness
		7.5.1 Desensitization
		7.5.2 Receptor Downregulation
		7.5.3 Internalization
	7.6 Changes in Receptor Signaling
		7.6.1 PIP2 Modifies the Response to ASMs
		7.6.2 Lipid Rafts Modify ASMs Effects
		7.6.3 Oligomer Receptor Complexes in Drug-Resistant Epilepsy
	7.7 Epigenetic Changes in ASM Targets
	7.8 Conclusions
	References
Chapter 8: Cellular and Molecular Mechanisms of Neuroinflammation in Drug-Resistant Epilepsy
	8.1 Introduction
		8.1.1 The Immune Response in the CNS
		8.1.2 The Blood-Brain Barrier and the Inflammatory Response During Epilepsy
	8.2 Molecular Mechanisms Related to Inflammation in Drug-Resistant Epilepsy
		8.2.1 Toll-Like Receptors
		8.2.2 Receptor for Advanced Glycation End Products (RAGE) in Epilepsy
	8.3 Cytokines and Chemokines in the Pathogenesis of Epilepsy
	8.4 Reactive Oxygen Species and Epilepsy
	8.5 Conclusion
	References
Chapter 9: Contribution of the Antiepileptic Drug Administration Regime to Avoid the Development and/or Establishment of Pharmacoresistant Epilepsy
	9.1 Refreshing Last Edition of the Chapter and Scope of the Present Update
	9.2 The Effect of Cardiac Output Distribution on Tissue Drug Concentration
		9.2.1 Body Water Distribution
		9.2.2 Tissue Metabolic Rate and Tissue Blood Flow
		9.2.3 Kinetics of Solute Exchange Between Blood and Tissues
		9.2.4 Blood Flow Fraction and Efflux Transporter Expression
		9.2.5 Circadian Rhythms of Blood Flow Fraction and Efflux Transporter Activity
	9.3 Epilepsy and Its Refractoriness
		9.3.1 Seizure Cause
		9.3.2 Seizure Consequence
		9.3.3 Refractoriness
	9.4 Role of Physical Activity in Attenuating Seizure Occurrence and Its Refractoriness
	9.5 Combined Strategy with ASMs, Dietary Supplement, and Physical Exercise
	9.6 Conclusions
	References
Chapter 10: Pharmacogenetics in Epilepsy and Refractory Epilepsy
	10.1 Introduction
	10.2 Pharmacogenetics of Antiseizure Medications and Their Relationship with Pharmacoresistant Epilepsy
		10.2.1 Pharmacogenetics of Drugs (Absorption-Biodistribution-Metabolism-Excretion)
		10.2.2 Pharmacogenetics of Cannabidiol
		10.2.3 Pharmacogenetics of Antiepileptic Drugs Adverse Drug Reactions
	10.3 Gene Mutations Related to Epilepsy and Potential Pharmacogenetic Therapeutic Targets
		10.3.1 Mutations in Neurotransmitter Receptors
		10.3.2 Drug-Responsive Epileptic Syndromes Associated with Specific Mutations
			Pyridoxine (Vitamin B6)-Dependent Epilepsy
			Folinic Acid Responsive Seizures
		10.3.3 Glucose Type 1 Transporter Deficiency
		10.3.4 Pharmacogenetics of Epileptic mTORopathies
			Tuberous Sclerosis Complex
			Polyhydramnios, Megalencephaly, and Symptomatic Epilepsy Syndrome
			Neurofibromatosis Type 1 and Seizures
			Fragile X Syndrome and mTOR Signaling
			MECP2 Gene Mutations (Rett Syndrome), Seizures, and mTOR
			DEPDC5 Gene Mutations, mTOR, and Epilepsy
			mTOR and Epileptogenesis
	10.4 Conclusions
	References
Chapter 11: Seizures Induce Hypoxia, and Hypoxia Induces Seizures: A Perverse Relationship That Increases the Risk of Sudden Unexpected Death in Epilepsy (SUDEP)
	11.1 Introduction
	11.2 Hypoxia and Seizures: A Mutual Relationship of Cause and Effect
		11.2.1 Hypoxia Induces Seizures and Epilepsy
		11.2.2 Seizures Induce Hypoxia
		11.2.3 Epilepsy Induces Hypoxia and Inflammation
	11.3 Hypoxia, Free Radicals, Iron, and Ferroptosis
		11.3.1 Free Radicals and Glutathione Peroxidase System
		11.3.2 Hypoxia, Free Radicals, and Induction of ABC Transporters
	11.4 Refractory Epilepsy, Systemic Hypoxia, Epileptic Heart, and Sudden Unexpected Death in Epilepsy
		11.4.1 Cardiac Effects of Refractory Epilepsy
		11.4.2 Heart Ferroptosis and SUDEP
	11.5 Conclusions
	References
Chapter 12: Neonatal Excitotoxicity Triggers Degenerative Processes Related to Seizure Susceptibility and Pharmacoresistance
	12.1 Introduction: The Relationship Between Excitotoxicity and Seizure Susceptibility Through Amino Acid Neurotransmitters
	12.2 Glutamate-Mediated Excitotoxicity and Neuronal Death in Neurological Illnesses
		12.2.1 Glutamate Receptors
		12.2.2 Mechanisms Implicated in the Neuronal Death Produced by Glutamate
		12.2.3 Glutamate-Mediated Excitotoxicity and Neurological Illnesses
	12.3 Systemic Administration of Monosodium Glutamate as Excitotoxicity Model
		12.3.1 Changes Induced by Systemically Administered MSG in Neonatal Rats
	12.4 Changes in Adulthood Seizure Susceptibility After MSG Neonatal Treatment and Its Possible Relationship with the Pharmacoresistance
	12.5 Concluding Remarks and Perspectives
	References
Chapter 13: Cerebrovascular Remodeling and the Role of Vascular Endothelial Growth Factor in the Epileptic Brain and Pharmacoresistance
	13.1 Introduction
	13.2 Vascular Remodeling
	13.3 BBB Dysfunction
	13.4 Aberrant Angiogenesis and Barriergenesis
	13.5 VEGF Signaling in Epilepsy
	13.6 Conclusions
	References
Chapter 14: The Role of JNK3 in Epilepsy and Neurodegeneration
	14.1 Introduction
	14.2 JNK Pathway Signaling
		14.2.1 JNKs and Neuronal Death
	14.3 JNK Inhibitors
		14.3.1 Characterization of JNK Inhibitors
	14.4 JNK3 and Neurodegenerative Diseases
		14.4.1 Epilepsy
			Jnk Knockout Mice Have Neuroprotection Against Seizure Induction
			Therapeutic Epileptic Treatments Are Correlated with JNK Activity Modulation
			The Transport Activity of ABCG2 Protein, That Is Modulated by JNK Activity, Is Related to Epileptic Pharmacoresistance
			TLR4 and JNK Activity to Be Considered in Epilepsy Pharmacoresistance
		14.4.2 Alzheimer’s Disease
		14.4.3 Parkinson’s Disease
		14.4.4 Huntington’s Disease
		14.4.5 Ischemia
	14.5 Future Perspectives of Inhibiting the c-JNKs Pathway in the Treatment of Neurological Disorders
	References
Chapter 15: Application of Proteomics in the Study of Molecular Markers in Epilepsy
	15.1 Introduction
		15.1.1 Techniques Used in Proteomics
		15.1.2 Proteomics and Epilepsy
			Proteomics Profile of Epilepsy Models
			Proteomics Profile of the Patients with Epilepsy
	15.2 Conclusions
	References
Chapter 16: GABAergic Neurotransmission Abnormalities in Pharmacoresistant Epilepsy: Experimental and Human Studies
	16.1 Introduction
	16.2 GABAergic Neurotransmission
	16.3 Involvement of GABAARs in Seizure, Epilepsy, and Pharmacoresistance
		16.3.1 GABAARs Expression in Experimental Models of Epilepsy
		16.3.2 GABAARs Functional Expression in Pharmacoresistant Epilepsy
	16.4 Genetic Abnormalities in the GABAergic System Associated with Refractory Human Epilepsy
		16.4.1 Genetic Alterations of GABAARs Involved in Epilepsy
			Gamma-Aminobutyric Acid A Receptor-α1 Gene or GABRA1, NCBI RefSeqGene NG_011548.1
			Gamma-Aminobutyric Acid A Receptor-α2 Gene or GABRA2, NCBI RefSeq NG_012835.2
			Gamma-Aminobutyric Acid A Receptor-α5 Gene or GABRA5, NCBI RefSeq NG_032883.1
			Gamma-Aminobutyric Acid A Receptor-β2 Gene or GABRB2, NCBI RefSeq NG_047050.1
			Gamma-Aminobutyric Acid A Receptor-β3 Gene or GABRB3, NCBI RefSeq NG_047050.1
			Gamma-Aminobutyric Acid A Receptor-δ Gene or GABRD, NCBI RefSeq NG_008168.1
			Gamma-Aminobutyric Acid a Receptor-γ2 or GABRG2, NCBI RefSeq NM_000806.5
		16.4.2 Genetic Alterations in Gamma-Aminobutyric Acid B Receptor 2 or GABBR2, NCBI RefSeq NM_005458.7
		16.4.3 Genetic Alterations in Solute Carrier Family 6 Member 1 or SLC6A1, NCBI RefSeq NM_005458.7
	16.5 GABAergic Agents as Treatment to Refractory Human Epilepsy
	16.6 Concluding Remarks
	References
Chapter 17: Genes Involved in Pharmacoresistant Epilepsy
	17.1 Genetics of Target Hypothesis
		17.1.1 Genetic Variants of Voltage-Gated Ion Channels
			Voltage-Dependent Alterations of Sodium (Na+) Channels
			Voltage-Dependent Alterations of Calcium (Ca+) Channels
		17.1.2 Genetic Variants of Neurotransmitters Receptors
			Alterations of Gamma Aminobutyric Acid (GABA) Channels
			Glutamate Channel Alterations
	17.2 Genetics of Transporter Hypothesis in Drug-Resistant Epilepsy (See Fig. 17.1)
		17.2.1 The ABC Transporters (ATP Binding Cassette)
	17.3 Genetics of Neural Networks Hypothesis
	17.4 Gene Variant Hypothesis
	17.5 Genetics of Pharmacokinetic Hypothesis
	17.6 Pharmacogenetics of DRE in Children
	17.7 Genetic Epilepsies “Difficult to Treat”
	17.8 Conclusions
		17.8.1 Limitations of the Gene Hypothesis
		17.8.2 How to Define Genetic Drug-Resistant Epilepsies?
		17.8.3 Future Directions
	References
Chapter 18: Drug-Resistant Epilepsy and the Influence of Age, Gender, and Comorbid Disorders
	18.1 Introduction
	18.2 Role of Age on DRE
	18.3 Impact of DRE Throughout Life
	18.4 Age and DRE Treatment
	18.5 Involvement of Gender and Hormones on DRE
	18.6 Evidence of the Coexistence of Comorbidities and DRE
	18.7 Pathogenic Mechanisms Associated with DRE and Its Comorbidities
	18.8 Localization of Epileptic Foci as a Link Between DRE and Psychiatric Comorbidities
	18.9 Adenosine Hypothesis of Comorbidities
	18.10 Perspectives and Opportunities
	18.11 Conclusions
	References
Chapter 19: Indications for Intracerebral Recording in Candidates for Epilepsy Surgery
	19.1 Introduction
	19.2 Noninvasive Phase
	19.3 Invasive Phase, SEEG
		19.3.1 Criteria for Indication of SEEG
		19.3.2 Methodology: Acquisition, Recording, and Analysis
	19.4 Experience of Argentine Epilepsy Surgery Program and SEEG
		19.4.1 Electrical Stimulation During SEEG
		19.4.2 MRI CT Acquisition and PET
		19.4.3 Neuropsychological Evaluation
		19.4.4 Psychiatric Assessment
		19.4.5 Surgery and Follow-up Evaluation
	19.5 Basic Anatomo Functional Organization EZ Hypothesis Located in Patients with Temporal Lobe Epilepsy
	19.6 Results of Our Experience
	19.7 Conclussion
	References
Chapter 20: On the Development of New Drugs for the Treatment of Drug-Resistant Epilepsy: An Update on Different Approaches to Different Hypotheses
	20.1 Drug-Resistant Epilepsy: Possible Explanations
	20.2 Possible Therapeutic Answers to the Transporter and Pharmacokinetic Hypothesis
	20.3 Possible Therapeutic Answers to the Target Hypothesis
	20.4 Conclusions
	References
Chapter 21: Physical Exercise as a Strategy to Reduce Seizure Susceptibility
	21.1 General View of the Influence of Physical Exercise in the Healthy Brain and in Neurological Diseases
	21.2 Non-pharmacological Treatments for Epilepsy
	21.3 Physical Fitness in PWE
	21.4 Effect of Physical Exercise on Seizure Discharges in the EEG (Electroencephalogram)
	21.5 Effects of Physical Exercise on Seizure Occurrence
	21.6 Antiepileptogenic Effects of Exercise
	21.7 Neurobiological Mechanisms by Which Exercise Can Reduce Seizures
		21.7.1 Proposed Mechanisms of the Antiepileptogenic Effects of Exercise
		21.7.2 Proposed Mechanisms of the Favourable Effects of Exercise in Chronic Epilepsy
	21.8 Risks of Exercise in Terms of Inducing Seizures?
		21.8.1 Seizure-Precipitating Factors
			Stress
			Fatigue
			Hyperthermia
			Hypoxia
			Hyperventilation
			Hypoglycaemia
			Hyponatraemia
		21.8.2 Seizures Induced by Exercise
	21.9 Physical Exercise Minimising Comorbidities Associated with Epilepsy
	21.10 Physical Exercise and ASMs
	21.11 ILAE Task Force on Sports and Epilepsy
	21.12 Final Considerations
	References
Chapter 22: Ketogenic Diet and Drug-Resistant Epilepsy
	22.1 Introduction
	22.2 Ketogenic Dietary Therapies
	22.3 Mechanisms of Action
	22.4 Indications: Inclusion and Exclusion Criteria
	22.5 Ketogenic Dietary Therapy in Epileptic Syndromes
	22.6 Ketogenic Dietary Therapies and Etiology
	22.7 The Use of the Diet in Status Epilepticus
	22.8 Management of Ketogenic Diet Therapies
	22.9 Adverse Effects
	22.10 Neuroprotective and Epigenetic Effects of KDT
	22.11 Conclusion
	References
Chapter 23: Modulating P-glycoprotein Regulation as a Therapeutic Strategy for Pharmacoresistant Epilepsy
	23.1 Introduction
	23.2 Strategies to Overcome P-glycoprotein-Mediated Efflux Transport
	23.3 Regulation of P-glycoprotein Expression
	23.4 Targeting Signaling Pathways of P-glycoprotein
	23.5 Biomarkers of P-glycoprotein-Associated Drug Resistance
	23.6 Future Perspectives
	References
Chapter 24: Vagus Nerve Stimulation for Intractable Seizures
	24.1 Introduction
	24.2 Mechanisms of Action (MOA)
	24.3 Patient Selection and Indications
	24.4 Technology
	24.5 Surgical Procedure
	24.6 Magnet Use
	24.7 Stimulation Protocols
	24.8 Complications and Adverse Effects
	24.9 Device Revisions and Removals
	24.10 Results
		24.10.1 Seizure Reduction
		24.10.2 Quality of Life (QoL) and Other Neuropsychological Variables
		24.10.3 ASMs
	24.11 Cost-Effectiveness
	24.12 Prognostic Factors and Future Directions
	24.13 Conclusion
	References
Chapter 25: Noninvasive Brain Stimulation as a Potential Therapeutic Procedure in Drug-Resistant Epilepsy
	25.1 Introduction
	25.2 Non-invasive Brain Stimulation: Basic Principles and Protocols
		25.2.1 Repetitive Transcranial Magnetic Stimulation
		25.2.2 Transcranial Direct Current Stimulation (tDCS)
	25.3 Safety and Tolerability of Noninvasive Brain Stimulation in Patients with Drug-Resistant Epilepsy
	25.4 Noninvasive Brain Stimulation as Therapeutic Procedure: Effects on Seizures and Interictal Epileptiform Discharges in Drug-Resistant Epilepsy
	25.5 Evaluation of Non-invasive Brain Stimulation Effects on Electroencephalogram Functional Connectivity
	25.6 Conclusions
	References
Chapter 26: Effects of Transcranial Focal Electrical Stimulation Via Concentric Ring Electrodes on Seizure Activity
	26.1 Introduction
		26.1.1 Medically Intractable Epilepsy and Its Consequences
		26.1.2 Brain Stimulation for Pharmacoresistant Epilepsy
			Invasive Approaches
			Noninvasive Approaches
	26.2 TCREs and TFS
		26.2.1 Innovation
			Innovative Electrode Design
			Focal Stimulation
			Common Instrumentation for Focal Stimulation and Focal Transcranial Recordings from the Same Electrodes
	26.3 Results from Animal Models
		26.3.1 Penicillin
		26.3.2 Pilocarpine
			Effects of Transcranial Focal Electrical Stimulation Alone and Associated with a Subeffective Dose of Diazepam on Pilocarpine-Induced Status Epilepticus and Subsequent Neuronal Damage in Rats
			Transcranial Focal Electrical Stimulation Reduces the Convulsive Expression and Amino Acid Release in the Hippocampus During Pilocarpine-Induced Status Epilepticus in Rats
		26.3.3 Pentylenetetrazol
			TSF Reduced PTZ-Induced Hypersynchrony
			TSF Reduced Two-Dose PTZ-Induced Behavioral Activity
			Automated Seizure Detection Triggers TSF and Reduces PTZ-Induced Electrographic Activity
			Effects of Transcranial Focal Electrical Stimulation Via Tripolar Concentric Ring Electrodes on Pentylenetetrazole-Induced Seizures in Rats
		26.3.4 3-Mercaptopropionic Acid (MPA)
			Noninvasive Transcranial Focal Stimulation Affects the Convulsive Seizure-Induced P-Glycoprotein Expression and Function in Rats
		26.3.5 Amygdala Kindling
			Transcranial Focal Electrical Stimulation via Concentric Ring Electrodes in Freely Moving Cats: Antiepileptogenic and Postictal Effects
	26.4 Tissue Safety
		26.4.1 Scalp
		26.4.2 Cortex and Hippocampus
		26.4.3 Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats
		26.4.4 Transcranial Focal Electrical Stimulation Via Tripolar Concentric Ring Electrodes Does Not Modify the Short- and Long-Term Memory Formation in Rats Evaluated in the Novel Object Recognition Test
		26.4.5 Transcranial Focal Electrical Stimulation (TFS) via Tripolar Concentric Ring Electrodes (TCREs) Safety in Humans
	26.5 Concluding Remarks
	References
Index