ReviewDrug-resistant epilepsy: From multiple hypotheses to an integral explanation using preclinical resources
Section snippets
Drug-resistant epilepsy
Epilepsy is a neurological disease characterized by the presence of spontaneous and recurrent seizures [1], which affects approximately 50 million people worldwide [2], [3]. Approximately 30% of these patients show drug-resistant epilepsy [4], [5], which is defined as the persistence of epileptic seizures despite an adequate and well-tolerated anticonvulsant pharmacological treatment [6]. Regardless of the advances in the field of epilepsy and the acquisition of new antiepileptic drugs, the
Experimental models of drug-resistant epilepsy
Several animal models are used to reproduce pharmacological resistance in epilepsy, which allows to investigate their mechanisms and test drugs to modify this condition [7], [8], [9]. Three experimental approaches of pharmacoresistant epilepsy are commonly used: animal models with recurrent and spontaneous epileptic seizures, animal models in which chemical or electrical stimulations induce epileptic seizures, and in vitro models of brain slices with epileptiform activity (Table 1).
Only some of
Hypotheses for drug resistance in epilepsy
Experimental findings from animal models and brain tissue from patients with drug-resistant epilepsy have helped to propose different hypotheses for the mechanisms underlying this disease (see Fig. 1) [24]. However, currently, no advances in the effective therapeutic control of drug-resistant epilepsy have been achieved [4], [25]. This lack of progress could be explained because of the significant limitations in several hypotheses that attempt to explain the mechanisms of drug resistance in
Future directions in the study of drug-resistant epilepsy
Although a wide variety of experimental models of drug-resistant epilepsy currently exists [8], some populations are not represented, for which the prediction of their results is partial. The female population is not considered in the models of drug-resistant epilepsy. The influence of sex hormones on epileptic activity is a complex phenomenon [135]. Recently, efforts have been made to encourage the inclusion of female individuals in clinical and preclinical biomedical research [136], [137],
Conclusions
Drug resistance in epilepsy is a current scientific dilemma that demands attention. The lack of accessibility to human tissue limits the progression in the study of the mechanisms associated with resistance, for which experimental models are of high relevance. At present, experimental models of drug resistance in epilepsy include a broad spectrum ranging from in vitro models to animals with spontaneous drug-resistant seizures. These models have helped to design hypotheses allowing a better
Acknowledgments
We thank Mrs. Julia Segura for their assistance in improving the English of the manuscript. This study was supported by the National Council for Science and Technology (CONACyT) grants A3-S-26782 and 261481 and scholarships 622940 (DPP) and 704471 (CLFS).
References (163)
Animal models of drug-refractory epilepsy
- et al.
Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy
Neuroscience
(2002) - et al.
Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy
Epilepsy Res
(2001) - et al.
New model of pharmacoresistant seizures induced by 3-mercaptopropionic acid in mice
Epilepsy Res
(2017) - et al.
Drug development for refractory epilepsy: the past 25 years and beyond
Seizure
(2017) - et al.
A new hypothesis of drug refractory epilepsy: neural network hypothesis
Med Hypotheses
(2011) - et al.
Neuropsychological performance before and after partial or complete insulectomy in patients with epilepsy
Epilepsy Behav
(2015) - et al.
Factors predicting the outcome following medical treatment of mesial temporal epilepsy with hippocampal sclerosis
Seizure
(2014) - et al.
Predicting drug resistance in adult patients with generalized epilepsy: a case–control study
Epilepsy Behav
(2015) - et al.
Seizure related elevations of extracellular amino acids in human focal epilepsy
Neurosci Lett
(1992)
Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain
Lancet
Effects of high-frequency electrical stimulation and R-verapamil on seizure susceptibility and glutamate and GABA release in a model of phenytoin-resistant seizures
Neuropharmacology
Glutamate is critically involved in seizure-induced overexpression of P-glycoprotein in the brain
Neuropharmacology
The genetic variant “C588T” of GABARG2 is linked to childhood idiopathic generalized epilepsy and resistance to antiepileptic drugs
Seizure
Association study between polymorphisms in the CACNA1A, CACNA1C, and CACNA1H genes and drug-resistant epilepsy in the Chinese Han population
Seizure
The potential implication of SCN1A and CYP3A5 genetic variants on antiepileptic drug resistance among Egyptian epileptic children
Seizure
Association between SCN1A gene polymorphisms and drug resistant epilepsy in pediatric patients
Seizure
Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy
Pharmacol Rep
Epigenetic mechanisms in epilepsy
Prog Brain Res
Expression of microRNA-129-2-3p and microRNA-935 in plasma and brain tissue of human refractory epilepsy
Epilepsy Res
Overexpression of miRNA-137 in the brain suppresses seizure activity and neuronal excitability: a new potential therapeutic strategy for epilepsy
Neuropharmacology
The molecular hallmarks of epigenetic effects mediated by antiepileptic drugs
Epilepsy Res
A functional polymorphism of the microRNA-146a gene is associated with susceptibility to drug-resistant epilepsy and seizures frequency
Seizure
Association of the genetic polymorphisms in pre-microRNAs with risk of childhood epilepsy in a Chinese population
Seizure
GABA(A) receptor subunits in the rat hippocampus II: altered distribution in kainic acid-induced temporal lobe epilepsy
Neuroscience
mRNA coding for voltage-gated sodium channel beta2 subunit in rat central nervous system: cellular distribution and changes following kainate-induced seizures
Neurosci Lett
Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense
Toxicol Appl Pharmacol
Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy
Pediatr Neurol
ILAE official report: a practical clinical definition of epilepsy
Epilepsia
Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015
Lancet Neurol
Epilepsia. OMS
Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study
JAMA Neurol
The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis
Epilepsia
Definition of drug-resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies
Epilepsia
Animal models in epilepsy research: legacies and new directions
Nat Neurosci
Animal models of seizures and epilepsy: past, present, and future role for the discovery of antiseizure drugs
Neurochem Res
The search for new screening models of pharmacoresistant epilepsy: is induction of acute seizures in epileptic rodents a suitable approach?
Neurochem Res
Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma
Epilepsia
Assessment of seizure susceptibility in pilocarpine epileptic and nonepileptic Wistar rats and of seizure reinduction with pentylenetetrazole and electroshock models
Epilepsia
Lamotrigine treatment during amygdala-kindled seizure development fails to inhibit seizures and diminishes subsequent anticonvulsant efficacy
Epilepsia
Validation of a preclinical drug screening platform for pharmacoresistant epilepsy
Neurochem Res
Neuronal and glial expression of the multidrug resistance gene product in an experimental epilepsy model
Cell Mol Neurobiol
P-glycoprotein contributes to cell membrane depolarization of hippocampus and neocortex in a model of repetitive seizures induced by pentylenetetrazole in rats
Curr Pharm Des
Phenytoin carried by silica core iron oxide nanoparticles reduces the expression of pharmacoresistant seizures in rats
Nanomedicine (Lond)
Inhibition of glutamate decarboxylase (GAD) by ethyl ketopentenoate (EKP) induces treatment-resistant epileptic seizures in zebrafish
Sci Rep
The National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP)
Neurochem Res
Drug-resistant epilepsy: multiple hypotheses, few answers
Front Neurol
Physiologic and morphologic characteristics of granule cell circuitry in human epileptic hippocampus
Epilepsia
Immunohistochemical characterization of mossy fiber sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy
Brain
Cited by (30)
Drug-resistant epilepsy: Definition, pathophysiology, and management
2023, Journal of the Neurological SciencesDrug resistance in epilepsy
2023, The Lancet NeurologyMedical perspectives on pediatric sports medicine–Selective topics
2022, Disease-a-MonthCitation Excerpt :Utilization of appropriate head and neck protective equipment is recommended for all athletes in sports activities with increased risks for such injuries. Approximately 25% to 33% of persons with epilepsy are not fully controlled and an unstable neurological pattern for persons with refractory epilepsy provides considerable difficulties for these individuals in their lives including sports participation.489,490 There are many mechanisms for such refractory epilepsy including abnormality of the P-glycoprotein (P-gp) with inadequate transport of anticonvulsant medications into the brain parenchyma due to defects of P-gp transport.489
Protein expression of P-glycoprotein in neocortex from patients with frontal lobe epilepsy
2022, Epilepsy ResearchCitation Excerpt :At the BBB, the P-gp is localized in the brain endothelial cells (BECs) (Beaulieu et al., 1997; Cordon-Cardo et al., 1989), astrocytes (Golden and Pardridge, 1999), and the choroid plexus (Rao et al., 1999). The “transporter hypothesis” of DRE originates from P-gp overexpression at the BBB which has been associated with an increased ASM extrusion and thus, ineffective intraparenchymal ASM concentration (Pérez-Pérez et al., 2019; Potschka et al., 2002, 2004; Tishler et al., 1995). However, P-gp overexpression was not restricted to BBB, P-gp stained neurons were described in brain tissue from patients with drug-resistant temporal lobe epilepsy (Marchi et al., 2004) and tuberous sclerosis (Lazarowski et al., 1999).
The role of P-glycoprotein (P-gp) and inwardly rectifying potassium (Kir) channels in sudden unexpected death in epilepsy (SUDEP)
2021, Epilepsy and BehaviorCitation Excerpt :Other risk factors, such as the early onset of epilepsy, the use of specific antiepileptic drugs (AEDs), polytherapy, duration of epilepsy, and symptomatic etiology, are actually under discussion [4–7]. In addition to these risk factors, several clinical features, such as frequent changes in the dosage of AEDs, persistent low plasma levels of AEDs, or poor adherence to pharmacotherapy, are not only defined as the main risk factors for SUDEP [8–10], but also commonly observed in patients with refractory epilepsy (RE) [11]. It is known that the risk of SUDEP increases with the severity and frequency of uncontrolled epileptic seizures, which is a common feature in patients with RE.
- 1
These authors contributed equally to this study.