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New Insights into Epilepsy: From Molecular Physiology to Pathology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 September 2026 | Viewed by 3184

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Guest Editor
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16126 Genoa, Italy
Interests: epilepsy

Special Issue Information

Dear Colleagues,

In 2002, Vezzani et al. wrote that brain inflammation is the pathophysiological cause of epileptic seizures, not a simple predisposing factor, and in 2004 Riazi et al. highlight the role of peripheral inflammation capable of migrating from the intestine to the brain. What has been called the inflammatory response is the way of communication between organs, with repair as the object of communication.

Characteristic of the inflammatory response is the cascade of cytokines, divided into pro-inflammatory ones, which produce greater necrosis, and anti-inflammatory ones which reconstruct the tissues, even more damaged by the former. Therefore, cytokines play an important role in defining the seizure threshold.

Already in 1995, altered cytokine production was evident in epileptic patients, which we now know depends on the biodiversity of the microbiota. While we are always capable of producing the first cytokines, the second ones are produced capable or unable to reconstruct tissues depending on the biodiversity of the microbiota. Furthermore, we know that cytokines are the operational arm of the microbiota with which it controls all the functions of the human body, even the functioning of organs, including the brain and immune system. It is not healthy to entrust the control of the human body to incapable cytokines, in fact this type of inflammatory response, called low-grade chronic, has been defined as the mother of pathologies.

All this leads us to consider the intestine and the microbiota as organs responsible for epileptic seizures, as was already known from Hippocrates, 400 BC, to 1930, when 50% of the treatment on epilepsy was on the ketogenic diet. We have known for some time that ketones are not responsible for its effectiveness in controlling seizures, but rather its anti-inflammatory action, modifying microbiota. Similarly, an intestinal anti-inflammatory action of antiepileptic drugs can contribute to the control of seizures. Thus, an intestinal anti-inflammatory action is reported for levetiracetam, a drug whose effectiveness was discovered causally, having not given answers to the usual tests, for Cannabidiol, and for Topiramate.

To find new therapeutic strategies, we will have to adapt ancient knowledge with current evidence, and understand what the optimal diet is to allow the microbiota to take care of us.

This Special Issue will be supervised by Dr. Paolo Mainardi, with assistance from Dr. Gianmichele Villano (University of Genova).

Dr. Paolo Mainardi
Guest Editor

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Keywords

  • epilepsy
  • molecular pathology
  • disease
  • therapeutic strategies
  • celluar advance

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Published Papers (3 papers)

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Research

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23 pages, 2532 KB  
Article
Audiogenic Kindling Stimulation Fails to Induce Cerebral Overexpression of P-Glycoprotein and Limbic Crises in the GASH/Sal Model of Epilepsy
by Laura Zeballos, Jerónimo Auzmendi, Alberto Lazarowski and Dolores E. López
Int. J. Mol. Sci. 2026, 27(8), 3377; https://doi.org/10.3390/ijms27083377 - 9 Apr 2026
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Abstract
Experimental evidence indicates that a high seizure burden can induce cerebral overexpression of P-glycoprotein (P-gp) at the blood–brain barrier, a phenomenon associated with drug-resistant epilepsy under the “transporter hypothesis”, but also at the neuronal level, linked to a reduced seizure threshold, increased seizure [...] Read more.
Experimental evidence indicates that a high seizure burden can induce cerebral overexpression of P-glycoprotein (P-gp) at the blood–brain barrier, a phenomenon associated with drug-resistant epilepsy under the “transporter hypothesis”, but also at the neuronal level, linked to a reduced seizure threshold, increased seizure severity (SS), status epilepticus (SE), and a high spontaneous death (SD) rate. In contrast, we recently described a progressive reduction in SS and the absence of SE and SD in GASH/Sal hamsters subjected to 45 audiogenic seizures. Here, we examined SS, SE, and the SD, and the expression of P-gp, erythropoietin receptor (EPO-R), hypoxia-inducible factor 1 alpha subunit (HIF-1α) and cyclooxygenase 2 (COX-2), in the brains of GASH/Sal hamsters following 20 audiogenic kindling stimulations (AUK-20). SS was evaluated using the midbrain and limbic severity scales; gene expression was assessed by RT-qPCR and P-gp protein levels were measured by immunohistochemistry and Western blot (IHC/WB) analysis. A modest decrease in midbrain SS was observed, without an increase in the already low limbic SS scores, and no SE or SD events occurred. P-gp levels remained low in both IHC and WB analyses. At the mRNA level, we detected increased EPO-R expression, decreased HIF-1α, and increased COX-2 without an accompanying increased in Abcb1b. Unlike findings from other experimental epilepsy models, AUK-20 in GASH/Sal hamsters does not enhance limbic SS, trigger SE or SD, or induce P-gp overexpression in the brain. Independently of the implications for drug resistance, the lack of cerebral P-gp overexpression without increased SS in the AUK-20-GASH/Sal model supports a potential role of P-gp in modulating seizure severity and epilepsy-associated mortality risk. Full article
(This article belongs to the Special Issue New Insights into Epilepsy: From Molecular Physiology to Pathology)
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18 pages, 2036 KB  
Article
An Evaluation of Cation–Chloride Cotransporters NKCC1 and KCC2 in Carbamazepine-Resistant Rats
by Cecilia Zavala-Tecuapetla, Sandra Orozco-Suárez, Angélica Vega-García and Joaquín Manjarrez-Marmolejo
Int. J. Mol. Sci. 2025, 26(10), 4764; https://doi.org/10.3390/ijms26104764 - 16 May 2025
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Abstract
Approximately one-third of epileptic patients do not respond adequately to drug therapy, leading to the development of drug-resistant epilepsy. Given the established role of dysregulated expression of two cation–chloride cotransporter proteins, NKCC1 and KCC2, in susceptibility to convulsion generation and epilepsy development, the [...] Read more.
Approximately one-third of epileptic patients do not respond adequately to drug therapy, leading to the development of drug-resistant epilepsy. Given the established role of dysregulated expression of two cation–chloride cotransporter proteins, NKCC1 and KCC2, in susceptibility to convulsion generation and epilepsy development, the present study evaluates the anticonvulsant potential of bumetanide (BUM, 10 mg/kg, i.p.) and probenecid (PROB, 50 mg/kg, i.p.), the potential of adenosine receptor activation (NECA, 1 mg/kg, i.p.) to modify the anticonvulsant efficacy of BUM, and the changes in NKCC1 and KCC2 protein expression levels in carbamazepine (CBZ)-resistant animals. In the window–pentylenetetrazole (PTZ) kindling model, male Wistar rats that undergo full kindling develop CBZ-resistance. The combination of BUM + PROB appears to have an anticonvulsant effect on CBZ-resistant convulsions, while alterations in the protein levels of the NKCC1 and KCC2 cotransporters are observed in CBZ-resistant animals. Despite the absence of therapeutic efficacy in managing convulsions through adenosine receptor activation (BUM + NECA), the activation of adenosine receptors exhibits the capacity to modulate the levels of the NKCC1 protein in the hippocampus of CBZ-resistant animals. This effect provides the initial evidence for a new therapeutic role of adenosine receptors in regulating the pathological levels of NKCC1 in drug-resistant epilepsy. Full article
(This article belongs to the Special Issue New Insights into Epilepsy: From Molecular Physiology to Pathology)
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Review

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31 pages, 990 KB  
Review
Neurobehavioral Signatures of Epileptogenesis: Molecular Programs, Trait-like Phenotypes, and Translational Biomarkers Beyond Seizures
by Ekaterina Andreevna Narodova
Int. J. Mol. Sci. 2026, 27(5), 2511; https://doi.org/10.3390/ijms27052511 - 9 Mar 2026
Viewed by 484
Abstract
Epileptogenesis is commonly defined by the emergence of spontaneous seizures after an initial insult; however, convergent experimental and clinical evidence indicates that the underlying disease process begins well before seizures become clinically detectable. During this pre-seizure phase, persistent molecular cascades remodel synaptic plasticity, [...] Read more.
Epileptogenesis is commonly defined by the emergence of spontaneous seizures after an initial insult; however, convergent experimental and clinical evidence indicates that the underlying disease process begins well before seizures become clinically detectable. During this pre-seizure phase, persistent molecular cascades remodel synaptic plasticity, circuit architecture, and glial–immune signaling. These processes are associated with trait-like alterations in cognition, affect, and behavior. Despite their clinical relevance, these neurobehavioral signatures remain poorly integrated into molecular models of epileptogenesis and are rarely considered as translational biomarkers of disease progression. This review synthesizes evidence linking core epileptogenic molecular cascades—maladaptive synaptic plasticity, glial–immune signaling, oxidative–metabolic stress, and activity-dependent gene regulation—to reproducible alterations in executive control, cognitive flexibility, emotional regulation, and motivational–social behavior. We outline an integrative framework in which these phenotypes are conceptualized as system-level readouts of progressive network reconfiguration rather than nonspecific “comorbidities” or mere consequences of recurrent seizures. Within this perspective, neurobehavioral markers can complement electrophysiological and molecular measures by capturing disease-relevant changes during windows when anti-epileptogenic interventions would be most effective. To increase mechanistic specificity, we provide representative pathway and gene-level anchors across epileptogenesis stages, a structured molecular-to-neurobehavioral mapping, and an operational biomarker panel specifying confounders and minimal controls. These anchors are included to ground the framework in experimentally documented molecular nodes with stage-dependent relevance; examples are representative rather than exhaustive, and evidence strength is indicated as preclinical mechanistic versus associative human observations. Finally, we discuss methodological requirements for biomarker validity (specificity, temporal anchoring, and cross-model consistency) and outline how integrating molecular and neurobehavioral trajectories may refine target discovery and improve the translation of anti-epileptogenic strategies. Conceptualizing epileptogenesis as a progressive disease process with measurable pre-seizure neurobehavioral signatures may broaden biomarker strategies beyond seizure occurrence and support the development of disease-modifying interventions. Full article
(This article belongs to the Special Issue New Insights into Epilepsy: From Molecular Physiology to Pathology)
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