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Epilepsy: From Molecular Basis to Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 20 November 2024 | Viewed by 10325

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Dr. Henry Hing Cheong Lee

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Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA 02115, USA
Interests: epilepsy

Special Issue Information

Dear Colleagues,

Epilepsy is a generalizable neuropathology arising from a wide range of etiologies, including genetic malfunctions, metabolic disorders, and brain trauma. Regardless of the underlying cause, an imbalance between excitatory and inhibitory neurotransmission is often associated with epilepsy. A better understanding of the molecular mechanisms governing proper excitatory and inhibitory neurotransmission is therefore important for identifying relevant therapeutic targets. In this Special Issue, we aim to cover the latest research on the molecular mechanisms underlying epileptogenesis, as well as rational therapeutic design based on our latest knowledge. We will focus specifically on three areas of research: (1) ion channels or transporters that underlie excitatory and inhibitory neurotransmissions, (2) reversibility of excitatory and inhibitory neurotransmissions during epileptogenesis, and (3) epilepsy models that allow systematic investigations of rational approaches for therapeutic design, including molecularly based targeted therapies such as gene therapy and chaperone therapies.

Dr. Henry Hing Cheong Lee
Guest Editor

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Keywords

genetic epilepsy
post-traumatic epilepsy
neurodevelopmental disorder
glutamate
GABA
ionic homeostasis
disease-modifying therapy
in vitro
in vivo
animal model
gene replacement therapy
gene editing
protein misfolding
small molecule
pharmacokinetics
pharmacodynamics
translational research
biomarker
clinical trial

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Published Papers (10 papers)

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Research

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24 pages, 4908 KiB

Open AccessArticle

PPARβ/δ Agonist GW0742 Modulates Microglial and Astroglial Gene Expression in a Rat Model of Temporal Lobe Epilepsy

by Olga E. Zubareva, Adeliya R. Kharisova, Anna I. Roginskaya, Anna A. Kovalenko, Maria V. Zakharova, Alexander P. Schwarz, Denis S. Sinyak and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2024, 25(18), 10015; https://doi.org/10.3390/ijms251810015 - 17 Sep 2024

Viewed by 264

Abstract

The role of astroglial and microglial cells in the pathogenesis of epilepsy is currently under active investigation. It has been proposed that the activity of these cells may be regulated by the agonists of peroxisome proliferator-activated nuclear receptors (PPARs). This study investigated the effects of a seven-day treatment with the PPAR β/δ agonist GW0742 (Fitorine, 5 mg/kg/day) on the behavior and gene expression of the astroglial and microglial proteins involved in the regulation of epileptogenesis in the rat brain within a lithium–pilocarpine model of temporal lobe epilepsy (TLE). TLE resulted in decreased social and increased locomotor activity in the rats, increased expression of astro- and microglial activation marker genes (Gfap, Aif1), pro- and anti-inflammatory cytokine genes (Tnfa, Il1b, Il1rn), and altered expression of other microglial (Nlrp3, Arg1) and astroglial (Lcn2, S100a10) genes in the dorsal hippocampus and cerebral cortex. GW0742 attenuated, but did not completely block, some of these impairments. Specifically, the treatment affected Gfap gene expression in the dorsal hippocampus and Aif1 gene expression in the cortex. The GW0742 injections attenuated the TLE-specific enhancement of Nlrp3 and Il1rn gene expression in the cortex. These results suggest that GW0742 may affect the expression of some genes involved in the regulation of epileptogenesis. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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12 pages, 3497 KiB

Open AccessArticle

Automatic Detection of the EEG Spike–Wave Patterns in Epilepsy: Evaluation of the Effects of Transcranial Current Stimulation Therapy

by Elzbieta Olejarczyk, Aleksander Sobieszek and Giovanni Assenza

Int. J. Mol. Sci. 2024, 25(16), 9122; https://doi.org/10.3390/ijms25169122 - 22 Aug 2024

Viewed by 481

Abstract

This study aims to develop a detection method based on morphological features of spike–wave (SW) patterns in the EEG of epilepsy patients and evaluate the effect of cathodal transcranial direct current stimulation (ctDCS) treatment. The proposed method is based on several simple features describing the shape of SW patterns and their synchronous occurrence on at least two EEG channels. High sensitivity, specificity and selectivity values were achieved for each patient and condition. ctDCS resulted in a significant reduction in the number of detected patterns, a decrease in spike duration and amplitude, and an increased spike mobility. The proposed method allows efficient identification of SW patterns regardless of brain condition, although the recruitment of patterns may be modified by ctDCS. This method can be useful in the clinical evaluation of ctDCS effects. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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25 pages, 3323 KiB

Open AccessArticle

Phase-Dependent Response to Electrical Stimulation of Cortical Networks during Recurrent Epileptiform Short Discharge Generation In Vitro

by Anton V. Chizhov, Vasilii S. Tiselko, Tatyana Yu. Postnikova and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2024, 25(15), 8287; https://doi.org/10.3390/ijms25158287 - 29 Jul 2024

Viewed by 531

Abstract

The closed-loop control of pathological brain activity is a challenging task. In this study, we investigated the sensitivity of continuous epileptiform short discharge generation to electrical stimulation applied at different phases between the discharges using an in vitro 4-AP-based model of epilepsy in rat hippocampal slices. As a measure of stimulation effectiveness, we introduced a sensitivity function, which we then measured in experiments and analyzed with different biophysical and abstract mathematical models, namely, (i) the two-order subsystem of our previous Epileptor-2 model, describing short discharge generation governed by synaptic resource dynamics; (ii) a similar model governed by shunting conductance dynamics (Epileptor-2B); (iii) the stochastic leaky integrate-and-fire (LIF)-like model applied for the network; (iv) the LIF model with potassium M-channels (LIF+KM), belonging to Class II of excitability; and (v) the Epileptor-2B model with after-spike depolarization. A semi-analytic method was proposed for calculating the interspike interval (ISI) distribution and the sensitivity function in LIF and LIF+KM models, which provided parametric analysis. Sensitivity was found to increase with phase for all models except the last one. The Epileptor-2B model is favored over other models for subthreshold oscillations in the presence of large noise, based on the comparison of ISI statistics and sensitivity functions with experimental data. This study also emphasizes the stochastic nature of epileptiform discharge generation and the greater effectiveness of closed-loop stimulation in later phases of ISIs. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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15 pages, 3947 KiB

Open AccessArticle

Comparative Proteomic Profiling of Blood Plasma Revealed Marker Proteins Involved in Temporal Lobe Epilepsy

by Yury E. Glazyrin, Dmitry V. Veprintsev, Elena E. Timechko, Zoran Minic, Tatiana N. Zamay, Diana V. Dmitrenko, Maxim V. Berezovski and Anna S. Kichkailo

Int. J. Mol. Sci. 2024, 25(14), 7935; https://doi.org/10.3390/ijms25147935 - 20 Jul 2024

Cited by 1 | Viewed by 773

Abstract

Temporal lobe epilepsy has various origins, involving or not involving structural changes in brain tissue. The mechanisms of epileptogenesis are associated with cell regulation and signaling disruptions expressed in varied levels of proteins. The blood plasma proteomic profiling of temporal lobe epilepsy patients (including magnetic resonance imaging (MRI)-positive and MRI-negative ones) and healthy volunteers using mass spectrometry and label-free quantification revealed a list of differently expressed proteins. Several apolipoproteins (APOA1, APOD, and APOA4), serpin protease inhibitors (SERPINA3, SERPINF1, etc.), complement components (C9, C8, and C1R), and a total of 42 proteins were found to be significantly upregulated in the temporal lobe epilepsy group. A classification analysis of these proteins according to their biological functions, as well as a review of the published sources, disclosed the predominant involvement of the processes mostly affected during epilepsy such as neuroinflammation, intracellular signaling, lipid metabolism, and oxidative stress. The presence of several proteins related to the corresponding compensatory mechanisms has been noted. After further validation, the newly identified temporal lobe epilepsy biomarker candidates may be used as epilepsy diagnostic tools, in addition to other less specific methods such as electroencephalography or MRI. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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0 pages, 7214 KiB

Open AccessArticle

Modulating Endoplasmic Reticulum Chaperones and Mutant Protein Degradation in GABRG2(Q390X) Associated with Genetic Epilepsy with Febrile Seizures Plus and Dravet Syndrome

by Sarah Poliquin, Gerald Nwosu, Karishma Randhave, Wangzhen Shen, Carson Flamm and Jing-Qiong Kang

Int. J. Mol. Sci. 2024, 25(9), 4601; https://doi.org/10.3390/ijms25094601 - 23 Apr 2024

Viewed by 1397

Abstract

A significant number of patients with genetic epilepsy do not obtain seizure freedom, despite developments in new antiseizure drugs, suggesting a need for novel therapeutic approaches. Many genetic epilepsies are associated with misfolded mutant proteins, including GABRG2(Q390X)-associated Dravet syndrome, which we have previously shown to result in intracellular accumulation of mutant GABA_A receptor γ2(Q390X) subunit protein. Thus, a potentially promising therapeutic approach is modulation of proteostasis, such as increasing endoplasmic reticulum (ER)-associated degradation (ERAD). To that end, we have here identified an ERAD-associated E3 ubiquitin ligase, HRD1, among other ubiquitin ligases, as a strong modulator of wildtype and mutant γ2 subunit expression. Overexpressing HRD1 dose-dependently reduced the γ2(Q390X) subunit. Additionally, we show that zonisamide (ZNS)—an antiseizure drug reported to upregulate HRD1—reduces seizures in the Gabrg2^+/Q390X mouse. We propose that a possible mechanism for this effect is a partial rescue of surface trafficking of GABA_A receptors, which are otherwise sequestered in the ER due to the dominant-negative effect of the γ2(Q390X) subunit. Furthermore, this partial rescue was not due to changes in ER chaperones BiP and calnexin, as total expression of these chaperones was unchanged in γ2(Q390X) models. Our results here suggest that leveraging the endogenous ERAD pathway may present a potential method to degrade neurotoxic mutant proteins like the γ2(Q390X) subunit. We also demonstrate a pharmacological means of regulating proteostasis, as ZNS alters protein trafficking, providing further support for the use of proteostasis regulators for the treatment of genetic epilepsies. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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17 pages, 3513 KiB

Open AccessArticle

Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes

by Grzegorz Witkowski, Bartlomiej Szulczyk, Ewa Nurowska, Marta Jurek, Michal Pasierski, Agata Lipiec, Agnieszka Charzewska, Mateusz Dawidziuk, Michal Milewski, Szymon Owsiak, Rafal Rola, Halina Sienkiewicz Jarosz and Dorota Hoffman-Zacharska

Int. J. Mol. Sci. 2024, 25(3), 1745; https://doi.org/10.3390/ijms25031745 - 1 Feb 2024

Cited by 1 | Viewed by 1261

Abstract

Mutations of the SCN1A gene, which encodes the voltage-dependent Na⁺ channel’s α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes’ variability in the family of five SCN1A gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing SCN1A-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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28 pages, 9500 KiB

Open AccessArticle

Changes in the Dentate Gyrus Gene Expression Profile Induced by Levetiracetam Treatment in Rats with Mesial Temporal Lobe Epilepsy

by Veronica Diaz-Villegas, Luz Adriana Pichardo-Macías, Sergio Juárez-Méndez, Iván Ignacio-Mejía, Noemí Cárdenas-Rodríguez, Marco Antonio Vargas-Hernández, Julieta Griselda Mendoza-Torreblanca and Sergio R. Zamudio

Int. J. Mol. Sci. 2024, 25(3), 1690; https://doi.org/10.3390/ijms25031690 - 30 Jan 2024

Viewed by 1207

Abstract

Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy. Levetiracetam (LEV) is an antiepileptic drug whose mechanism of action at the genetic level has not been fully described. Therefore, the aim of the present work was to evaluate the relevant gene expression changes in the dentate gyrus (DG) of LEV-treated rats with pilocarpine-induced TLE. Whole-transcriptome microarrays were used to obtain the differential genetic profiles of control (CTRL), epileptic (EPI), and EPI rats treated for one week with LEV (EPI + LEV). Quantitative RT–qPCR was used to evaluate the RNA levels of the genes of interest. According to the results of the EPI vs. CTRL analysis, 685 genes were differentially expressed, 355 of which were underexpressed and 330 of which were overexpressed. According to the analysis of the EPI + LEV vs. EPI groups, 675 genes were differentially expressed, 477 of which were downregulated and 198 of which were upregulated. A total of 94 genes whose expression was altered by epilepsy and modified by LEV were identified. The RT–qPCR confirmed that LEV treatment reversed the increased expression of Hgf mRNA and decreased the expression of the Efcab1, Adam8, Slc24a1, and Serpinb1a genes in the DG. These results indicate that LEV could be involved in nonclassical mechanisms involved in Ca²⁺ homeostasis and the regulation of the mTOR pathway through Efcab1, Hgf, SLC24a1, Adam8, and Serpinb1a, contributing to reduced hyperexcitability in TLE patients. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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20 pages, 5745 KiB

Open AccessArticle

Effect of Vagus Nerve Stimulation on the GASH/Sal Audiogenic-Seizure-Prone Hamster

by Jaime Gonçalves-Sánchez, Consuelo Sancho, Dolores E. López, Orlando Castellano, Begoña García-Cenador, Gabriel Servilha-Menezes, Juan M. Corchado, Norberto García-Cairasco and Jesús M. Gonçalves-Estella

Int. J. Mol. Sci. 2024, 25(1), 91; https://doi.org/10.3390/ijms25010091 - 20 Dec 2023

Cited by 1 | Viewed by 1157

Abstract

Vagus nerve stimulation (VNS) is an adjuvant neuromodulation therapy for the treatment of refractory epilepsy. However, the mechanisms behind its effectiveness are not fully understood. Our aim was to develop a VNS protocol for the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) in order to evaluate the mechanisms of action of the therapy. The rodents were subject to VNS for 14 days using clinical stimulation parameters by implanting a clinically available neurostimulation device or our own prototype for laboratory animals. The neuroethological assessment of seizures and general behavior were performed before surgery, and after 7, 10, and 14 days of VNS. Moreover, potential side effects were examined. Finally, the expression of 23 inflammatory markers in plasma and the left-brain hemisphere was evaluated. VNS significantly reduced seizure severity in GASH/Sal without side effects. No differences were observed between the neurostimulation devices. GASH/Sal treated with VNS showed statistically significant reduced levels of interleukin IL-1β, monocyte chemoattractant protein MCP-1, matrix metalloproteinases (MMP-2, MMP-3), and tumor necrosis factor TNF-α in the brain. The described experimental design allows for the study of VNS effects and mechanisms of action using an implantable device. This was achieved in a model of convulsive seizures in which VNS is effective and shows an anti-inflammatory effect. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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17 pages, 6392 KiB

Open AccessArticle

Enhanced Membrane Incorporation of H289Y Mutant GluK1 Receptors from the Audiogenic Seizure-Prone GASH/Sal Model: Functional and Morphological Impacts on Xenopus Oocytes

by Sandra M. Díaz-Rodríguez, Isabel Ivorra, Javier Espinosa, Celia Vegar, M. Javier Herrero-Turrión, Dolores E. López, Ricardo Gómez-Nieto and Armando Alberola-Die

Int. J. Mol. Sci. 2023, 24(23), 16852; https://doi.org/10.3390/ijms242316852 - 28 Nov 2023

Cited by 1 | Viewed by 1733

Abstract

Epilepsy is a neurological disorder characterized by abnormal neuronal excitability, with glutamate playing a key role as the predominant excitatory neurotransmitter involved in seizures. Animal models of epilepsy are crucial in advancing epilepsy research by faithfully replicating the diverse symptoms of this disorder. In particular, the GASH/Sal (genetically audiogenic seizure-prone hamster from Salamanca) model exhibits seizures resembling human generalized tonic-clonic convulsions. A single nucleotide polymorphism (SNP; C9586732T, p.His289Tyr) in the Grik1 gene (which encodes the kainate receptor GluK1) has been previously identified in this strain. The H289Y mutation affects the amino-terminal domain of GluK1, which is related to the subunit assembly and trafficking. We used confocal microscopy in Xenopus oocytes to investigate how the H289Y mutation, compared to the wild type (WT), affects the expression and cell-surface trafficking of GluK1 receptors. Additionally, we employed the two-electrode voltage-clamp technique to examine the functional effects of the H289Y mutation. Our results indicate that this mutation increases the expression and incorporation of GluK1 receptors into an oocyte’s membrane, enhancing kainate-evoked currents, without affecting their functional properties. Although further research is needed to fully understand the molecular mechanisms responsible for this epilepsy, the H289Y mutation in GluK1 may be part of the molecular basis underlying the seizure-prone circuitry in the GASH/Sal model. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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Review

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25 pages, 856 KiB

Open AccessReview

Molecular Mechanisms Underlying the Generation of Absence Seizures: Identification of Potential Targets for Therapeutic Intervention

by Beulah Leitch

Int. J. Mol. Sci. 2024, 25(18), 9821; https://doi.org/10.3390/ijms25189821 - 11 Sep 2024

Viewed by 357

Abstract

Understanding the molecular mechanisms underlying the generation of absence seizures is crucial for developing effective, patient-specific treatments for childhood absence epilepsy (CAE). Currently, one-third of patients remain refractive to the antiseizure medications (ASMs), previously called antiepileptic drugs (AEDs), available to treat CAE. Additionally, these ASMs often produce serious side effects and can even exacerbate symptoms in some patients. Determining the precise cellular and molecular mechanisms directly responsible for causing this type of epilepsy has proven challenging as they appear to be complex and multifactorial in patients with different genetic backgrounds. Aberrant neuronal activity in CAE may be caused by several mechanisms that are not fully understood. Thus, dissecting the causal factors that could be targeted in the development of precision medicines without side effects remains a high priority and the ultimate goal in this field of epilepsy research. The aim of this review is to highlight our current understanding of potential causative mechanisms for absence seizure generation, based on the latest research using cutting-edge technologies. This information will be important for identifying potential targets for future therapeutic intervention. Full article

(This article belongs to the Special Issue Epilepsy: From Molecular Basis to Therapy)

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