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Molecular Research in Epilepsy and Epileptogenesis

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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 February 2025 | Viewed by 10333

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Prof. Dr. Stanisław Jerzy Czuczwar

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Guest Editor

Department of Pathophysiology, Medical University of Lublin, 20-090 Lublin, Poland
Interests: Alzheimer; epilepsy; stroke

Special Issue Information

Dear Colleauges,

Epilepsy is a neurological disorder affecting approximately 65 million people worldwide. In about 30% of patients with epilepsy, seizures are poorly controlled with antiseizure (antiepileptic) drugs, and drug-resistant epilepsy poses a significant therapeutic problem. Thus, there is a need for more efficient treatments of epilepsy in order to obtain freedom from seizures in a more significant proportion of patients. The molecular targets for available antiseizure drugs have been recognized, and the identification of novel targets and their ligands should result in the development of innovative drugs sharing additional mechanisms of action.

Antiseizure drugs are generally not effective against epileptogenesis that is triggered by an initial insult (e.g., status epilepticus, head trauma or stroke). The durable process of epileptogenesis has been proven to convert a normally functioning mammalian brain into one generating seizure activity. A possibility arises that stopping or slowing down the progress of epileptogenesis may prevent the occurrence of epilepsy. Certainly, anti-epileptogenic drugs would be most effective prior to seizure activity, so markers for epileptogenesis are required.

Considering what was stated above, this Special Issue on "Molecular Research in Epilepsy and Epileptogenesis" is open to research dealing with molecular mechanisms of seizure activity or epileptogenesis and focused on possible targets for antiseizure and anti-epileptogenic drugs. Original and review papers based on in vitro experiments, animal models of seizures also aimed at the process of epileptogenesis, and clinical studies are invited.

Prof. Dr. Stanisław Jerzy Czuczwar
Guest Editor

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Keywords

epilepsy
antiseizure
anti-epileptogenic drugs
biomarkers

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Published Papers (7 papers)

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Research

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16 pages, 3858 KiB

Open AccessArticle

Identification of Reliable Reference Genes for Use in Gene Expression Studies in Rat Febrile Seizure Model

by Anna A. Kovalenko, Maria V. Zakharova, Alexander P. Schwarz, Olga E. Zubareva and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2024, 25(20), 11125; https://doi.org/10.3390/ijms252011125 - 16 Oct 2024

Viewed by 589

Abstract

The study of the pathogenesis of febrile seizures and their consequences frequently necessitates gene expression analysis. The primary methodology employed for such analysis is reverse transcription with quantitative polymerase chain reaction (RT-qPCR). To ensure the accuracy of data obtained by RT-qPCR, it is crucial to utilize stably expressed reference genes. The objective of this study was to identify the most suitable reference genes for use in the analysis of mRNA production in various brain regions of rats following prolonged neonatal febrile seizures. The expression stability of eight housekeeping genes was evaluated using the online tool RefFinder in the dorsal and ventral hippocampal regions and in the temporal and medial prefrontal cortex of the brain. The Ppia gene exhibited the greatest stability of expression. Conversely, the genes with the least stable expression levels were Actb and Ywhaz; thus, it is not recommended to use them for normalization in a febrile seizure model. Additionally, the majority of housekeeping genes demonstrate age-related, region-specific fluctuations. Therefore, it is crucial to employ the appropriate housekeeping genes for each brain structure under investigation when examining the expression dynamics of genes of interest in a febrile seizure model. Full article

(This article belongs to the Special Issue Molecular Research in Epilepsy and Epileptogenesis)

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24 pages, 1956 KiB

Open AccessArticle

Development of Novel Alaninamide Derivatives with Anticonvulsant Activity and Favorable Safety Profiles in Animal Models

by Michał Abram, Marcin Jakubiec, Paulina Koczurkiewicz-Adamczyk, Agata Doroz-Płonka, Anna Rapacz and Krzysztof Kamiński

Int. J. Mol. Sci. 2024, 25(18), 9861; https://doi.org/10.3390/ijms25189861 - 12 Sep 2024

Viewed by 576

Abstract

In our current study, we developed a focused series of original ((benzyloxy)benzyl)propanamide derivatives that demonstrated potent activity across in vivo mouse seizure models, specifically, maximal electroshock (MES) and 6 Hz (32 mA) seizures. Among these derivatives, compound 5 emerged as a lead molecule, exhibiting robust protection following intraperitoneal (i.p.) injection, as follows: ED₅₀ = 48.0 mg/kg in the MES test, ED₅₀ = 45.2 mg/kg in the 6 Hz (32 mA) test, and ED₅₀ = 201.3 mg/kg in the 6 Hz (44 mA) model. Additionally, compound 5 displayed low potential for inducing motor impairment in the rotarod test (TD₅₀ > 300 mg/kg), indicating a potentially favorable therapeutic window. In vitro toxicity assays further supported its promising safety profile. We also attempted to identify a plausible mechanism of action of compound 5 by applying both binding and functional in vitro studies. Overall, the data obtained for this lead molecule justifies the more comprehensive preclinical development of compound 5 as a candidate for a potentially broad-spectrum and safe anticonvulsant. Full article

(This article belongs to the Special Issue Molecular Research in Epilepsy and Epileptogenesis)

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16 pages, 3855 KiB

Open AccessArticle

Oral Administration of Probiotic Bifidobacterium breve Ameliorates Tonic–Clonic Seizure in a Pentylenetetrazole-Induced Kindling Mouse Model via Integrin-Linked Kinase Signaling

by Toshiaki Ishii, Motohiro Kaya and Yoshikage Muroi

Int. J. Mol. Sci. 2024, 25(17), 9259; https://doi.org/10.3390/ijms25179259 - 27 Aug 2024

Viewed by 708

Abstract

Epilepsy is a chronic neurological disorder characterized by recurrent seizures that affects over 70 million people worldwide. Although many antiepileptic drugs that block seizures are available, they have little effect on preventing and curing epilepsy, and their side effects sometimes lead to serious morbidity. Therefore, prophylactic agents with anticonvulsant properties and no adverse effects need to be identified. Recent studies on probiotic administration have reported a variety of beneficial effects on the central nervous system via the microbiota–gut–brain axis. In this study, we investigated the effects of the oral administration of Bifidobacterium breve strain A1 [MCC1274] (B. breve A1) on tonic–clonic seizure in a pentylenetetrazole (PTZ)-induced kindling mouse (KD mouse) model. We found that the oral administration of B. breve A1 every other day for 15 days significantly reduced the seizure score, which gradually increased with repetitive injections of PTZ in KD mice. The administration of B. breve A1, but not saline, to KD mice significantly increased the level of Akt Ser⁴⁷³ phosphorylation (p-Akt) in the hippocampus; this increase was maintained for a minimum of 24 h after PTZ administration. Treatment of B. breve A1-administered KD mice with the selective inhibitor of integrin-linked kinase (ILK) Cpd22 significantly increased the seizure score and blocked the antiepileptic effect of B. breve A1. Moreover, Cpd22 blocked the B. breve A1-induced increase in hippocampal p-Akt levels. These results suggest that the ILK-induced phosphorylation of Akt Ser⁴⁷³ in the hippocampus might be involved in the antiepileptic effect of B. breve A1. Full article

(This article belongs to the Special Issue Molecular Research in Epilepsy and Epileptogenesis)

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18 pages, 2716 KiB

Open AccessArticle

Age-Dependent Activation of Pannexin1 Function Contributes to the Development of Epileptogenesis in Autosomal Dominant Sleep-related Hypermotor Epilepsy Model Rats

by Kouji Fukuyama, Eishi Motomura and Motohiro Okada

Int. J. Mol. Sci. 2024, 25(3), 1619; https://doi.org/10.3390/ijms25031619 - 28 Jan 2024

Cited by 1 | Viewed by 1213

Abstract

To explore the processes of epileptogenesis/ictogenesis, this study determined the age-dependent development of the functional abnormalities in astroglial transmission associated with pannexin1-hemichannel using a genetic rat model of autosomal dominant sleep-related hypermotor epilepsy (ADSHE) named ‘S286L-TG’. Pannexin1 expression in the plasma membrane of primary cultured cortical astrocytes and the orbitofrontal cortex (OFC), which is an ADSHE focus region, were determined using capillary immunoblotting. Astroglial D-serine releases induced by artificial high-frequency oscillation (HFO)-evoked stimulation, the removal of extracellular Ca²⁺, and the P2X7 receptor agonist (BzATP) were determined using ultra-high performance liquid chromatography (UHPLC). The expressions of pannexin1 in the plasma membrane fraction of the OFC in S286L-TG at four weeks old were almost equivalent when compared to the wild type. The pannexin1 expression in the OFC of the wild type non-statistically decreased age-dependently, whereas that in S286L-TG significantly increased age-dependently, resulting in relatively increasing pannexin1 expression from the 7- (at the onset of interictal discharge) and 10-week-old (after the ADSHE seizure onset) S286L-TG compared to the wild type. However, no functional abnormalities of astroglial pannexin1 expression or D-serine release through the pannexin1-hemichannels from the cultured astrocytes of S286L-TG could be detected. Acutely HFO-evoked stimulation, such as physiological ripple burst (200 Hz) and epileptogenic fast ripple burst (500 Hz), frequency-dependently increased both pannexin1 expression in the astroglial plasma membrane and astroglial D-serine release. Neither the selective inhibitors of pannexin1-hemichannel (10PANX) nor connexin43-hemichannel (Gap19) affected astroglial D-serine release during the resting stage, whereas HFO-evoked D-serine release was suppressed by both inhibitors. The inhibitory effect of 10PANX on the ripple burst-evoked D-serine release was more predominant than that of Gap19, whereas fast ripple burst-evoked D-serine release was predominantly suppressed by Gap19 rather than 10PANX. Astroglial D-serine release induced by acute exposure to BzATP was suppressed by 10PANX but not by Gap19. These results suggest that physiological ripple burst during the sleep spindle plays important roles in the organization of some components of cognition in healthy individuals, but conversely, it contributes to the initial development of epileptogenesis/ictogenesis in individuals who have ADSHE vulnerability via activation of the astroglial excitatory transmission associated with pannexin1-hemichannels. Full article

(This article belongs to the Special Issue Molecular Research in Epilepsy and Epileptogenesis)

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Review

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18 pages, 1173 KiB

Open AccessReview

A Systematic Review of the Predictive and Diagnostic Uses of Neuroinflammation Biomarkers for Epileptogenesis

by Maria Jose Aguilar-Castillo, Pablo Cabezudo-García, Guillermina García-Martín, Yolanda Lopez-Moreno, Guillermo Estivill-Torrús, Nicolas Lundahl Ciano-Petersen, Begoña Oliver-Martos, Manuel Narváez-Pelaez and Pedro Jesús Serrano-Castro

Int. J. Mol. Sci. 2024, 25(12), 6488; https://doi.org/10.3390/ijms25126488 - 12 Jun 2024

Viewed by 2339

Abstract

A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). The study analysed articles published in JCR journals from 2019 to 2024. The search strategy comprised the MESH, free terms of “Neuroinflammation”, and selective searches for the following single biomarkers that had previously been selected from the relevant literature: “High mobility group box 1/HMGB1”, “Toll-Like-Receptor 4/TLR-4”, “Interleukin-1/IL-1”, “Interleukin-6/IL-6”, “Transforming growth factor beta/TGF-β”, and “Tumour necrosis factor-alpha/TNF-α”. These queries were all combined with the MESH terms “Epileptogenesis” and “Epilepsy”. We found 243 articles related to epileptogenesis and neuroinflammation, with 356 articles from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 55 evaluated by the authors. A total of 21 articles were included in the qualitative evaluation, including 18 case–control studies, 2 case series, and 1 prospective study. As conclusion, this systematic review provides acceptable support for five biomarkers, including TNF-α and some of its soluble receptors (sTNFr2), HMGB1, TLR-4, CCL2 and IL-33. Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control of epileptic seizures. Their value will be better defined by future studies. Full article

(This article belongs to the Special Issue Molecular Research in Epilepsy and Epileptogenesis)

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20 pages, 334 KiB

Open AccessReview

Genetic Background of Epilepsy and Antiepileptic Treatments

by Kinga Borowicz-Reutt, Julia Czernia and Marlena Krawczyk

Int. J. Mol. Sci. 2023, 24(22), 16280; https://doi.org/10.3390/ijms242216280 - 14 Nov 2023

Cited by 6 | Viewed by 3088

Abstract

Advanced identification of the gene mutations causing epilepsy syndromes is expected to translate into faster diagnosis and more effective treatment of these conditions. Over the last 5 years, approximately 40 clinical trials on the treatment of genetic epilepsies have been conducted. As a result, some medications that are not regular antiseizure drugs (e.g., soticlestat, fenfluramine, or ganaxolone) have been introduced to the treatment of drug-resistant seizures in Dravet, Lennox-Gastaut, maternally inherited chromosome 15q11.2-q13.1 duplication (Dup 15q) syndromes, and protocadherin 19 (PCDH 19)-clusterig epilepsy. And although the effects of soticlestat, fenfluramine, and ganaxolone are described as promising, they do not significantly affect the course of the mentioned epilepsy syndromes. Importantly, each of these syndromes is related to mutations in several genes. On the other hand, several mutations can occur within one gene, and different gene variants may be manifested in different disease phenotypes. This complex pattern of inheritance contributes to rather poor genotype–phenotype correlations. Hence, the detection of a specific mutation is not synonymous with a precise diagnosis of a specific syndrome. Bearing in mind that seizures develop as a consequence of the predominance of excitatory over inhibitory processes, it seems reasonable that mutations in genes encoding sodium and potassium channels, as well as glutamatergic and gamma-aminobutyric (GABA) receptors, play a role in the pathogenesis of epilepsy. In some cases, different pathogenic variants of the same gene can result in opposite functional effects, determining the effectiveness of therapy with certain medications. For instance, seizures related to gain-of-function (GoF) mutations in genes encoding sodium channels can be successfully treated with sodium channel blockers. On the contrary, the same drugs may aggravate seizures related to loss-of-function (LoF) variants of the same genes. Hence, knowledge of gene mutation–treatment response relationships facilitates more favorable selection of drugs for anticonvulsant therapy. Full article

(This article belongs to the Special Issue Molecular Research in Epilepsy and Epileptogenesis)

Other

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11 pages, 1789 KiB

Open AccessCase Report

The Aggravation of Neuropsychiatric Symptoms in the Offspring of a Korean Family with Intellectual Disability and Developmental Delay Caused by a Novel ARX p.Lys385Ter Variant

by Ji Yoon Han, Tae Yun Kim, Jin Gwack and Joonhong Park

Int. J. Mol. Sci. 2024, 25(19), 10327; https://doi.org/10.3390/ijms251910327 - 25 Sep 2024

Viewed by 686

Abstract

The ARX mutations encompass a nearly continuous spectrum of neurodevelopmental disorders (NDDs), ranging from lissencephaly to Proud syndrome, as well as infantile spasms without brain malformations, and including both syndromic and non-syndromic intellectual disabilities (IDs). We describe worsening neuropsychiatric symptoms in the offspring of a Korean family with ID/developmental delay (DD) caused by a novel ARX p.Lys385Ter variant. Sequential genetic testing was performed to investigate the ID, DD, agenesis of the corpus callosum (ACC), and developmental epileptic encephalopathy (DEE) observed in the proband. A comprehensive trio clinical exome sequencing approach using a Celemics G-Mendeliome Clinical Exome Sequencing Panel was employed. Given the clinical manifestations observed in the proband, gene panel sequencing identified a heterozygous ARX variant, c.1153A>T/p.Lys385Ter (Reference transcript ID: NM_139058.3), as the most likely cause of ID, DD, ACC, and DEE in the proband. Sanger sequencing confirmed the segregation of the ARX variant, c.1153A>T/p.Lys385Ter, with the phenotype and established the maternally inherited dominant status of the heterozygous variant in the patient, as well as in her grandmother, mother, and aunt. Our case report adds to the understanding of the female phenotype in ARX-related disorders caused by loss-of-function variants in the ARX gene. Genetic counseling for ARX families should proceed with caution, as female carriers can exhibit a wide range of phenotypes, from normal cognitive development to ID/DD, ACC, and DEE. Full article

(This article belongs to the Special Issue Molecular Research in Epilepsy and Epileptogenesis)

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