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