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Biomolecules
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Exploring the Pathophysiology of Epilepsy: Metabolic Mechanisms and Therapeutic Potential
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Exploring the Pathophysiology of Epilepsy: Metabolic Mechanisms and Therapeutic Potential

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

Deadline for manuscript submissions: 31 August 2026 | Viewed by 3412

Special Issue Editors

Prof. Dr. Halina Baran

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Guest Editor
1. Karl Landsteiner Research Institute for Neurochemistry, Neuropharmacology, Neurorehabilitation and Pain Therapy, 3362 Mauer-Amstetten, Austria
2. Neurophysiology Unit, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
3. Institute of Biochemical Pharmacology, University of Vienna, Borschkegasse 8, 1090 Vienna, Austria
Interests: tryptophan metabolism; epilepsy; neurodegenerative diseases; Alzheimer’s disease
Prof. Dr. Christoph Baumgartner

E-Mail Website
Guest Editor
1. Department of Neurology, Clinic Hietzing, Wolkersbergenstrasse 1, 1090 Vienna, Austria
2. Karl Landsteiner Institute for Clinical Epilepsy Research and Cognitive Neurology, Wolkersbergenstrasse 1, 1090 Vienna, Austria
3. Medical Faculty, Sigmund Freud University, Freudplatz 3, 1020 Vienna, Austria
Interests: epilepsy; Alzheimer’s disease; Parkinson; stroke

Special Issue Information

Dear Colleagues,

Epilepsy is a complex neurological disorder characterized by recurrent, unprovoked seizures resulting from abnormal, synchronous neuronal activity in the brain. It is often accompanied by cognitive, psychological, and social comorbidities that significantly impair quality of life. This Special Issue aims to compile high-quality original research, reviews, and short communications, with a focus on the molecular mechanisms and signaling pathways of metabolic regulation in epilepsy, as well as the application of metabolism in epilepsy pathology, detection methods, and innovative therapies. By focusing on cutting-edge discoveries and insights, this Special Issue seeks to bridge basic science with practical applications, offering valuable perspectives for researchers and clinicians dedicated to improving the health outcomes of epilepsy patients.

Topics for this Special Issue include, but are not limited to, the following:

  • Behavioral, biochemical, and pharmacological studies in the kainic acid animal model for human temporal lobe epilepsy;
  • Enzymology, neurodegeneration, and neuroprotection;
  • Neuromodulators, neurotransmitters, and amino acids;
  • Kynurenine metabolism in the central and peripheral nervous systems of humans and animals.

Prof. Dr. Halina Baran
Prof. Dr. Christoph Baumgartner
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • epilepsy
  • metabolic regulation
  • signaling pathways
  • kynurenic acid
  • seizure detection
  • antiseizure drugs
  • innovative therapies

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Published Papers (4 papers)

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Research

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29 pages, 3748 KB  
Article
Continuous Pyruvate Supplementation Enhances Neuroprotective Resilience Against Kainate-Induced Status Epilepticus Through Metabolic Preconditioning
by Yong Jae Cho, Soo Jin Lee, Yuna Kim, Yeeun Kim, Seog-Young Kim, Kyunggon Kim, Dong-Cheol Woo, Hyun Ju Yoo and Joo-Yong Lee
Biomolecules 2026, 16(6), 805; https://doi.org/10.3390/biom16060805 - 29 May 2026
Viewed by 319
Abstract
Refractory status epilepticus refers to persistent and recurrent seizures unresponsive to medication, often leading to neuronal injury and neurobehavioral deficits. Studies have demonstrated that intraperitoneal bolus administration of pyruvate attenuates neuronal damage in rodent models of chemically induced status epilepticus (SE), while the [...] Read more.
Refractory status epilepticus refers to persistent and recurrent seizures unresponsive to medication, often leading to neuronal injury and neurobehavioral deficits. Studies have demonstrated that intraperitoneal bolus administration of pyruvate attenuates neuronal damage in rodent models of chemically induced status epilepticus (SE), while the precise neuroprotective mechanism remains to be further explored. This study investigated the neuroprotective effects of long-term supplementation with exogenous pyruvate against SE. When male C57BL/6 mice received 3% sodium pyruvate (SP) in the drinking water ad libitum for 20 weeks, they exhibited elevated levels of essential neurochemicals and energy metabolites in the brain compared to the control mice that received the equimolar saline solution. Following the intraperitoneal administration of kainate (KA) to induce severe SE, the SP-fed mice showed enhanced resistance to seizure activity, reduced neuronal injury, and improved neurobehavioral performance compared to the saline-fed mice. Regarding the molecular mechanisms underlying their neuroprotective properties, the levels of pyruvate metabolism-mediating proteins, neuronal and synaptic proteins, and neuroprotective proteins remained upregulated in the brains of the SP-fed mice following KA-induced SE. Conversely, the levels of pro-apoptotic and oxidative stress markers were suppressed. Collectively, this study indicates that long-term pyruvate supplementation may sustainably augment neurochemical and energy metabolism in the normal brain, thereby eliciting intrinsic neuroprotective properties. These effects contribute to preventing or ameliorating seizure activity, neuronal damage, and neurobehavioral deficits in mice following KA-induced SE, suggesting its prophylactic or therapeutic potential against epileptic seizures and SE through metabolic preconditioning. Full article
(This article belongs to the Special Issue Exploring the Pathophysiology of Epilepsy: Metabolic Mechanisms and Therapeutic Potential)
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15 pages, 724 KB  
Article
Inverse Correlation Between Nesfatin-1 and Ghrelin O-Acyltransferase (GOAT) in Adolescents with Epilepsy: A Cross-Sectional Study
by Anna Sojka, Ozgun Yetkin, Yasmin Bartosik, Barbara Steinborn, Barbara Dorocka-Bobkowska and Marcin Zarowski
Biomolecules 2026, 16(5), 658; https://doi.org/10.3390/biom16050658 - 28 Apr 2026
Viewed by 449
Abstract
Nesfatin-1 and ghrelin O-acyltransferase (GOAT) have established roles in metabolic regulation and neuronal excitability, yet their relationship in epilepsy remains conflicted. This cross-sectional study compared 22 adolescent epilepsy patients (13.1 ± 2.0 years; 11 women/11 men) with 20 age-matched healthy controls (HCs) (12.3 [...] Read more.
Nesfatin-1 and ghrelin O-acyltransferase (GOAT) have established roles in metabolic regulation and neuronal excitability, yet their relationship in epilepsy remains conflicted. This cross-sectional study compared 22 adolescent epilepsy patients (13.1 ± 2.0 years; 11 women/11 men) with 20 age-matched healthy controls (HCs) (12.3 ± 2.2 years; 8 women/12 men). Serum and salivary nesfatin-1 and GOAT levels were measured by enzyme-linked immunosorbent assay; Spearman’s rank correlation assessed inter-neuropeptide relationships. Serum nesfatin-1 was markedly elevated in patients with epilepsy compared to HCs (44.04 (interquartile range 38.19–76.72) vs. 8.65 (interquartile range 7.82–9.01) ng/mL, p < 0.001; ~5-fold). Serum GOAT was similarly elevated (4.90 (interquartile range 4.17–6.66) vs. 1.41 (interquartile range 1.21–1.79) ng/mL, p < 0.001; 3.5-fold). A significant inverse correlation between serum nesfatin-1 and GOAT levels was identified in patients with epilepsy (rho = −0.68, 95% CI [−0.86, −0.36], p < 0.001) but not in HCs (p = 0.53) and remained independent of age, sex, body mass index and epilepsy type. This inverse correlation was significant in women (rho = −0.68, p = 0.021) with a similar trend in men (rho = −0.53, p = 0.096). Salivary nesfatin-1 mirrored serum patterns (2.3-fold increase; p < 0.001), while salivary GOAT showed a 9-fold reduction (p < 0.001). This study provides the first evidence of an inverse nesfatin-1/GOAT correlation in adolescent epilepsy, suggesting disease-specific neuroendocrine dysregulation. These exploratory findings support the potential of these neuropeptides as candidate biomarkers warranting further validation and offer new insights into the metabolic-excitability axis in epilepsy. Full article
(This article belongs to the Special Issue Exploring the Pathophysiology of Epilepsy: Metabolic Mechanisms and Therapeutic Potential)
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37 pages, 4285 KB  
Article
Calretinin and Parvalbumin Trapping of TDP43 and XRCC1 Instructs Neocortical Interneuron Death in Neonatal Hypoxic-Ischemic Encephalopathy
by Lee J. Martin, Rebecca N. Ichord, Caitlin E. O’Brien, Sophie Yohannan, Danay Fernandez, Annalise Garrido, Naya Amauri, Dongseok Park, Jordan Benderoth and Jennifer K. Lee
Biomolecules 2026, 16(5), 621; https://doi.org/10.3390/biom16050621 - 22 Apr 2026
Viewed by 803
Abstract
We examined neocortical pathology and interneuron degeneration in neonatal hypoxia-ischemic encephalopathy (HIE). Piglets in two age groups (2–3 or 7–10 days old, n = 4–12/group) underwent global cerebral hypoxia–ischemia (HI) or sham treatment. Piglets (2–3 days old) had epidural electrodes for continuous electroencephalography [...] Read more.
We examined neocortical pathology and interneuron degeneration in neonatal hypoxia-ischemic encephalopathy (HIE). Piglets in two age groups (2–3 or 7–10 days old, n = 4–12/group) underwent global cerebral hypoxia–ischemia (HI) or sham treatment. Piglets (2–3 days old) had epidural electrodes for continuous electroencephalography (cEEG) and were treated with hypothermia (HT) or remained at normothermia (NT). Older piglets, all NT, had scalp EEG. Piglets at both ages had seizures and survived for 1–7 days. Cortical damage was assessed by hematoxylin & eosin staining and immunohistochemistry; calretinin (CR), parvalbumin (PV), and vasoactive intestinal peptide (VIP) interneurons (INs) were counted. Cell injury was assessed by DNA fragmentation and protein nitration. TAR DNA binding protein-43 (TDP43) and the DNA repair scaffold protein X-ray repair cross complementing-1 (XRCC1) were examined for degeneration mechanisms. Cortical layers 3 and 4 showed high vulnerability; damage emerged as isolated cells, focal and laminar, and distributed as panlaminar throughout different cortical regions that correlated with seizure burden. HT protected strongly against cortical damage. CR- and PV-INs were severely depleted in HI-NT piglets compared to sham. VIP INs appeared invulnerable. HT partially rescued the loss of INs. CR and PV formed nuclear and cytoplasmic inclusions that colocalized with TDP43 and XRCC1; co-immunoprecipitation identified interactions among these proteins, and tyrosine nitration of CR. CR and PV INs accumulated DNA single- and double-strand breaks and appeared as attritional apoptosis variants with proteinopathy. This cell death is identified as aggreosis. IN loss correlated with seizure presence. Postmortem human neonatal HIE cases had a similar loss of CR and PV INs and nuclear depletion of TDP43 in the neocortex. Thus, neonatal HIE causes the loss of neocortical inhibitory IN subtypes with vulnerabilities instructed by their intrinsic calcium-binding protein signature and by mechanisms consistent with toxic sequestration and the nuclear depletion of XRCC1 and TDP43 underlying DNA damage accumulation. Early inhibitory IN deletion could drive seizure evolution in HIE; TDP43 and XRCC1 could be therapeutic targets for neonatal HIE. Full article
(This article belongs to the Special Issue Exploring the Pathophysiology of Epilepsy: Metabolic Mechanisms and Therapeutic Potential)
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Review

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30 pages, 3258 KB  
Review
The Role of GABA and Its Receptors in Temporal Lobe Epilepsy
by Günther Sperk and Susanne Pirker
Biomolecules 2026, 16(3), 422; https://doi.org/10.3390/biom16030422 - 12 Mar 2026
Viewed by 1159
Abstract
Mesial temporal lobe epilepsy (TLE) is the most common and severe form of focal epilepsy. This review examines the diverse mechanisms by which the GABAergic system contributes both to seizure generation and to protective processes that limit epileptogenesis and seizure progression in TLE. [...] Read more.
Mesial temporal lobe epilepsy (TLE) is the most common and severe form of focal epilepsy. This review examines the diverse mechanisms by which the GABAergic system contributes both to seizure generation and to protective processes that limit epileptogenesis and seizure progression in TLE. We focus on findings from established animal models of TLE as well as studies of surgically resected tissue from patients who had undergone therapeutic intervention. Experimental models include sustained electrical stimulation of the perforant path, as well as the kainic acid (KA) and Li-pilocarpine models. Although these paradigms induce status epilepticus (SE) through distinct mechanisms, they ultimately converge on prolonged excitation of hippocampal CA3 pyramidal neurons and interconnected regions of the hippocampus and broader limbic network. In response to epileptic seizures, GABA synthesis is enhanced, as evidenced by the marked upregulation of the GABA-synthesizing enzymes GAD65 and GAD67, along with their ectopic expression in glutamatergic mossy fibers of the hippocampus. Shortly after acute seizures, a transient expression of the embryonic GAD67 splice variant, GAD25, is observed, although its functional significance remains unclear. At the receptor level, animal models of TLE show upregulation of GABAA receptor subunits α2, α4, β3, and γ2, accompanied by downregulation of α5 and δ subunits, suggesting reduced tonic inhibition. In contrast, hippocampal tissue from patients with TLE exhibits pronounced upregulation of α5 and δ subunits, indicative of enhanced extrasynaptic tonic inhibition. Similarly, whereas GABAA receptor subunits are mildly downregulated in animal models, they are consistently upregulated across hippocampal subfields in human TLE, pointing toward strengthened GABAergic inhibition. Conversely, genetic variants of GABAA receptor subunits and autoantibodies targeting these receptors can contribute to the etiology of epilepsy, often with onset in childhood. Moreover, degeneration or functional silencing of specific GABAergic interneuron populations—such as parvalbumin-positive neurons in the subiculum—can induce epilepsy in rodent models and is likewise associated with TLE in humans. Full article
(This article belongs to the Special Issue Exploring the Pathophysiology of Epilepsy: Metabolic Mechanisms and Therapeutic Potential)
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