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Biomolecules
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Molecular Biomarkers of Epileptogenesis
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Molecular Biomarkers of Epileptogenesis

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biomarkers".

Deadline for manuscript submissions: 20 June 2026 | Viewed by 17384

Special Issue Editor

Dr. Pedro J. Serrano-Castro

E-Mail Website
Guest Editor
Department of Medicine, University of Málaga, 29071 Málaga, Spain
Interests: epilepsy; neuroinflammation

Special Issue Information

Dear Colleagues,

Epileptogenesis is the process by which a normal neural network becomes hyperexcitable and capable of causing seizures of epilepsy on its own.

Numerous research studies have examined the potential involvement of neuroinflammation in epileptogenesis in recent years. In this condition, the blood–brain barrier's permeability may be compromised, and aberrant angiogenesis may result from inflammatory mediators. Thus, it is closely linked to epileptogenesis, even though the molecular mechanisms underlying these pathophysiological processes are not fully understood.

On the other hand, unregulated focal or systemic inflammatory processes cause the creation of abnormal neuronal connections and hyperexcitable neural networks, as well as an altered response to neurotransmitters, all of which contribute to epileptogenesis.

For both reasons, over the recent two decades, there has been a growing number of both clinical and basic studies providing strong support for the notion that neuroinflammation is involved in epileptogenesis.

Lastly, understanding the process of epileptogenesis may also be aided by the role of cytokines as putative pro-inflammatory mediators in the neuropathology of epilepsy. Therefore, the activation of multiple pro- and anti-epileptogenic immune pathways is indicated by the upregulation of several of these inflammatory mediators in the neocortex and hippocampal regions of epileptic patients.

Given the boiling state of research into all these neuroinflammatory mechanisms of epileptogenesis, we believe that it may be a good time to launch a Special Issue of Biomolecules aimed at encouraging groups related to these lines of research to disseminate their findings. Therefore, this is the aim of this Special Issue.

Dr. Pedro J. Serrano-Castro
Guest Editor

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Keywords

  • epileptogenesis
  • neuroinflammation
  • biomarkers
  • drug-resistant epilepsy
  • personalized neurology

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Published Papers (6 papers)

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Research

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15 pages, 3442 KB  
Article
Transcriptomic Profiles from Stereo-EEGs May Reflect the Local Brain Cell Microenvironment in Human Epilepsy
by Julian Larkin, Anuj Kumar Dwivedi, Arun Mahesh, Albert Sanfeliu, Kieron J. Sweeney, Donncha F. O’Brien, Vijay K. Tiwari, Peter Widdess-Walsh and David C. Henshall
Biomolecules 2025, 15(12), 1684; https://doi.org/10.3390/biom15121684 - 2 Dec 2025
Viewed by 938
Abstract
Background: Our understanding of the pathomechanisms of epilepsy has improved through techniques that access the living human brain. We recently reported that explanted stereo-electroencephalography (SEEG) electrodes from patients with epilepsy carry residual biomolecules and cells, which may be utilised for transcriptome and DNA [...] Read more.
Background: Our understanding of the pathomechanisms of epilepsy has improved through techniques that access the living human brain. We recently reported that explanted stereo-electroencephalography (SEEG) electrodes from patients with epilepsy carry residual biomolecules and cells, which may be utilised for transcriptome and DNA methylation profiling. Methods: Here, we applied bioinformatic and other analyses to explore the transcriptomes (RNA sequencing-based) of those SEEG cases to better understand the types of recovered transcripts in terms of representation of genes expressed by different cell types, brain structures, and the extent to which the signal may reflect local epileptiform activity. Results: Electrodes from all clinical cases retained protein-coding transcripts which reflected the local molecular microenvironment as well as epileptiform activity. Expression of genes involved in housekeeping functions, as well as markers of neuronal activity, was consistent between patients and between the electrode locations within the brain. We detected transcripts representing various cell types and subtypes, including excitatory and inhibitory neurons, all major classes of glia, and endothelial cells, as well as transcripts enriched in specific brain regions. Several genes showed a gradient of expression depending on the electrode position within the brain. We found examples of gene expression that correlated with epileptiform activity as recorded by SEEG. Conclusions: These findings extend the evidence that SEEG electrodes reflect the molecular microenvironments of brain activity in patients with epilepsy, both at sites of seizure onset and within the wider seizure network. The approach has potential applications in intraoperative surgical decision-making, as well as to identify molecular biomarkers or therapeutic targets for the drug-resistant epilepsies. Full article
(This article belongs to the Special Issue Molecular Biomarkers of Epileptogenesis)
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15 pages, 524 KB  
Article
Inflammatory Drug-Resistant Epilepsy Index (IDREI) as a Molecular Compound Biomarker in Focal Epilepsies
by Maria José Aguilar-Castillo, Guillermo Estivill-Torrús, Guillermina García-Martín, Pablo Cabezudo-García, Yolanda López-Moreno, Jesús Ortega-Pinazo, Teresa Ramírez-García, Nicolas Lundahl Ciano-Petersen and Pedro Jesus Serrano-Castro
Biomolecules 2025, 15(7), 914; https://doi.org/10.3390/biom15070914 - 22 Jun 2025
Cited by 1 | Viewed by 3217
Abstract
Background: There is growing evidence that neuroinflammation is involved in epileptogenesis. Identifying its biomarkers can be important for distinguishing epilepsy patients from healthy individuals and differentiating well-controlled epilepsy from drug-resistant epilepsy (DRE). Methods: An observational case-control study at Malaga’s Regional University Hospital involved [...] Read more.
Background: There is growing evidence that neuroinflammation is involved in epileptogenesis. Identifying its biomarkers can be important for distinguishing epilepsy patients from healthy individuals and differentiating well-controlled epilepsy from drug-resistant epilepsy (DRE). Methods: An observational case-control study at Malaga’s Regional University Hospital involved epilepsy patients divided into three groups: healthy controls (HC), seizure-free epilepsy (SFE), and DRE. Demographic and clinical data and plasmatic and/or CSF levels of 24 different inflammation-related molecules were collected for each patient and were analyzed through univariate and multivariate analysis. Results: The study included 68 patients: 38 in the DRE group, 14 in the SFE group, and 16 in the HC group. A new Inflammatory Drug-Resistant Epilepsy Index (IDREI) was created using key variables with significant or trending significance. This index combined pro-inflammatory mediators (ICAM-1 and NfL) and anti-inflammatory factors (IL-10 and IL-4), showing statistical significance (p = 0.002). ROC curve analysis for the IDREI gave an AUC of 0.731 (95% CI: 0.608–0.854). A multivariate logistic regression model’s ROC analysis resulted in a higher AUC of 0.891 (95% CI: 0.791–0.991). Conclusions: The IDREI molecular index shows promise in predicting epilepsy and drug-resistant epilepsy (DRE). Additional prospective studies are required to assess its clinical utility. Full article
(This article belongs to the Special Issue Molecular Biomarkers of Epileptogenesis)
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Review

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15 pages, 302 KB  
Review
Classical and Emerging Biomarkers in Pyridoxine-Dependent Epilepsy (PDE-ALDH7A1): Implications for Early Diagnosis and Therapeutic Development
by Muna Abedrabbo, Safiya Al Yazeedi, Blair R. Leavitt and Hilal Al-Shekaili
Biomolecules 2026, 16(4), 486; https://doi.org/10.3390/biom16040486 - 24 Mar 2026
Viewed by 370
Abstract
Pyridoxine-dependent epilepsy due to ALDH7A1 deficiency (PDE-ALDH7A1) is a rare but treatable epileptic encephalopathy caused by disruption of lysine catabolism and secondary depletion of pyridoxal-5′-phosphate (PLP). Although seizures are often controlled with pyridoxine supplementation, many patients continue to experience neurodevelopmental impairment, underscoring the [...] Read more.
Pyridoxine-dependent epilepsy due to ALDH7A1 deficiency (PDE-ALDH7A1) is a rare but treatable epileptic encephalopathy caused by disruption of lysine catabolism and secondary depletion of pyridoxal-5′-phosphate (PLP). Although seizures are often controlled with pyridoxine supplementation, many patients continue to experience neurodevelopmental impairment, underscoring the importance of early diagnosis and improved therapeutic strategies. Central to both diagnosis and pathophysiology is the accumulation of lysine-derived metabolites, most notably α-aminoadipate semialdehyde (α-AASA), its cyclic Schiff base Δ1-piperideine-6-carboxylate (P6C), and pipecolic acid. These metabolites have become the biochemical hallmarks of PDE-ALDH7A1, linking ALDH7A1 pathogenic variants to PLP inactivation and neuronal dysfunction. However, their chemical instability and analytical requirements pose challenges for universal diagnostics and newborn screening. This review summarizes current understanding of lysine catabolism in health and disease, critically evaluates the diagnostic utility and limitations of classical biomarkers, and discusses emerging insights into their pathophysiological roles. We further highlight recent discoveries of novel, chemically stable biomarkers, including 6-oxopiperidine-2-carboxylic acid (6-oxo-PIP), 2-oxopropylpiperidine-2-carboxylic acid (2-OPP), and 6-hydroxy-2-aminocaproic acid (HACA), identified through advanced metabolomics approaches. These metabolites show promise for newborn screening and provide new mechanistic links between metabolic stress, seizure susceptibility, and ongoing neurological morbidity despite pyridoxine treatment. Collectively, advances in biomarker discovery are reshaping diagnostic strategies for PDE-ALDH7A1 and offering new perspectives on disease mechanisms, paving the way for earlier detection and the development of more effective, mechanism-based therapies. Full article
(This article belongs to the Special Issue Molecular Biomarkers of Epileptogenesis)
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16 pages, 885 KB  
Review
Therapeutic Potential Target of Adenosine for Epilepsy: Focusing on Its Interaction with the Molecular Epileptogenic Network
by Xiaoning Zhao, Jiahui Deng, Zhonghua Xiong and Tianfu Li
Biomolecules 2026, 16(3), 453; https://doi.org/10.3390/biom16030453 - 17 Mar 2026
Viewed by 366
Abstract
Epilepsy is a neurological disorder characterized by a long-lasting predisposition to recurrently generate unprovoked seizures. Epilepsy affects over 70 million people worldwide, with approximately one-third suffering from pharmacoresistant seizures. Currently, the clinical antiseizure drugs lack efficacy in preventing epileptogenesis. Adenosine, as an endogenous [...] Read more.
Epilepsy is a neurological disorder characterized by a long-lasting predisposition to recurrently generate unprovoked seizures. Epilepsy affects over 70 million people worldwide, with approximately one-third suffering from pharmacoresistant seizures. Currently, the clinical antiseizure drugs lack efficacy in preventing epileptogenesis. Adenosine, as an endogenous anticonvulsant, inhibits the development of epilepsy via interaction with the molecular epileptogenic network on several levels: (i) Activation of A1 receptor inhibits glutamate release via presynaptic inhibition, and hyperpolarizes the synaptic potentials in postsynaptic neurons. (ii) The A2A receptor on astrocytes interacts with astroglial glutamate transporter GLT-1, controlling glial glutamate homeostasis. (iii) Activation of the A3 receptor inhibits GABA transporter type 1-mediated GABA uptake. (iv) Adenosine kinase (ADK) is highlighted as a pathological hallmark of epilepsy, with its distinct isoforms driving different mechanisms. The cytoplasmic short isoform (ADK-S) in astrocytes controls extracellular adenosine and receptor-mediated pathways, whereas the nuclear long isoform (ADK-L) in astrocytes and specific neurons regulates epigenetic mechanisms without relying on adenosine receptors. Collectively, this review clarifies the adenosine system’s critical regulatory role in the epileptogenic network, highlights adenosine receptors and ADK isoforms as promising therapeutic targets for epilepsy, and provides a theoretical basis for developing novel disease-modifying therapies for pharmacoresistant epilepsy while laying a foundation for subsequent preclinical and clinical translation. Full article
(This article belongs to the Special Issue Molecular Biomarkers of Epileptogenesis)
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27 pages, 393 KB  
Review
Psychosis of Epilepsy: An Update on Clinical Classification and Mechanism
by Zhiruo Qiu, Jiahui Guo, Bofei Chen and Jiajia Fang
Biomolecules 2025, 15(1), 56; https://doi.org/10.3390/biom15010056 - 3 Jan 2025
Cited by 8 | Viewed by 9222
Abstract
Epilepsy is a prevalent chronic neurological disorder that can significantly impact patients’ lives. The incidence and risk of psychosis in individuals with epilepsy are notably higher than in the general population, adversely affecting both the management and rehabilitation of epilepsy and further diminishing [...] Read more.
Epilepsy is a prevalent chronic neurological disorder that can significantly impact patients’ lives. The incidence and risk of psychosis in individuals with epilepsy are notably higher than in the general population, adversely affecting both the management and rehabilitation of epilepsy and further diminishing patients’ quality of life. This review provides an overview of the classification and clinical features of psychosis of epilepsy, with the aim of offering insights and references for the clinical diagnosis and treatment of various types of psychosis of epilepsy. Additionally, we examine the potential pathophysiological mechanisms underlying the psychosis of epilepsy from three perspectives: neuroimaging, neurobiology, and genetics. The alterations in brain structure and function, neurotransmitters, neuroinflammatory mediators, and genetic factors discussed in this review may offer insights into the onset and progression of psychotic symptoms in epilepsy patients and are anticipated to inform the identification of novel therapeutic targets in the future. Full article
(This article belongs to the Special Issue Molecular Biomarkers of Epileptogenesis)
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Other

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15 pages, 1050 KB  
Systematic Review
Etiologies of Multidrug-Resistant Epilepsy in Latin America: A Comprehensive Review of Structural, Genetic, Metabolic, Inflammatory, and Infectious Origins: A Systematic Review
by Mario S. Hinojosa-Figueroa, Mishell Cruz-Caraguay, Alejandro Torres Pasquel, Vanesa Puga Rosero, Camila Belen Eguiguren Chavez, Jose A. Rodas and Jose E. Leon-Rojas
Biomolecules 2025, 15(4), 576; https://doi.org/10.3390/biom15040576 - 12 Apr 2025
Cited by 6 | Viewed by 2059
Abstract
Epilepsy is a prevalent neurological disorder that affects millions worldwide, with a significant portion of individuals experiencing drug-resistant forms of the condition. In Latin America, the challenge of identifying the underlying causes of multidrug-resistant epilepsy (MDRE) is particularly pressing. (1) Background: This systematic [...] Read more.
Epilepsy is a prevalent neurological disorder that affects millions worldwide, with a significant portion of individuals experiencing drug-resistant forms of the condition. In Latin America, the challenge of identifying the underlying causes of multidrug-resistant epilepsy (MDRE) is particularly pressing. (1) Background: This systematic review aims to highlight the critical importance of understanding the etiology of MDRE in Latin America. (2) Methods: A systematic review of Medline (PubMed), Scopus, and Web of Science was conducted following the PRISMA methodology; articles were selected if they included information on the etiology of MDRE in Latin-American participants, and the NHLBI tool was used to assess bias. (3) Results: A total of 37 published articles were finally included in the review. The most frequently documented cause of drug-resistant epilepsy was structural, affecting 725 patients, with hippocampal atrophy and sclerosis predominantly involving both the right and left lobes. The second most common cause was genetic, identified in 362 individuals who exhibited polymorphisms in genes such as ABCB1, CYP2C9, SCN1A, SLC6A4, and MDR-1, among others. The third most frequent cause was metabolic, and the fourth was inflammatory, affecting 258 individuals, which was associated with various inflammatory markers, including IL-1β, IL-6, CD8+, CD-25, and HLA-DR. Finally, infectious causes were also reported. (4) Conclusions: Structural causes are the leading etiology of MDRE in Latin America, followed by genetic, metabolic, inflammatory, and infectious origins. The regional pattern contrasts with findings from Europe and Asia, highlighting the influence of socioeconomic, environmental, and population-specific genetic factors. Our findings underscore the urgent need for regionally tailored research and interventions, particularly in understudied areas such as infectious causes and neuroinflammation. Full article
(This article belongs to the Special Issue Molecular Biomarkers of Epileptogenesis)
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