
==== Front
Front Mol Neurosci
Front Mol Neurosci
Front. Mol. Neurosci.
Frontiers in Molecular Neuroscience
1662-5099
Frontiers Media S.A.

10.3389/fnmol.2024.1487871
Molecular Neuroscience
Editorial
Editorial: Immune system mechanisms impacting the onset of epilepsy and spontaneous seizures
Espinosa-Garcia Claudia 1 *

Bahramnejad Erfan 2

Li Yi 3 *

1Department of Neurology, Yale University, New Haven, CT, United States
2Department of Pharmacology, University of Arizona, Tucson, AZ, United States
3Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, United States
Edited and reviewed by: Detlev Boison, The State University of New Jersey, United States

*Correspondence: Claudia Espinosa-Garcia claudia.espinosa-garcia@yale.edu
Yi Li lyi@stanford.edu
10 9 2024
2024
17 148787128 8 2024
29 8 2024
Copyright © 2024 Espinosa-Garcia, Bahramnejad and Li.
2024
Espinosa-Garcia, Bahramnejad and Li
https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Editorial on the Research Topic Immune system mechanisms impacting the onset of epilepsy and spontaneous seizuresepilepsy
immune system
epileptogenesis
neuroinflammation
microglia
infiltrating monocytes
complement C3
Brain and Behavior Research Foundation 10.13039/100000874 28380 Stanford Maternal and Child Health Research Institute 10.13039/100015521 American Epilepsy Society 10.13039/100001454 The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Brain & Behavior Research Foundation (NARSAD Young Investigator Grant 28380 to CE-G), Stanford Maternal and Child Health Research Institute (YL), and American Epilepsy Society (Junior Investigator Grant to YL). section-at-acceptanceBrain Disease Mechanisms
==== Body
pmc1 Introduction

Epilepsy, a chronic neurological condition affecting more than 50 million people worldwide (in the U.S. alone almost three million Americans), is characterized by spontaneous recurrent seizures and associated with cognitive decline and behavioral comorbidities (WHO, 2024; CDC, 2024). Despite the major advances made in therapeutics, more than 30% of epilepsy patients suffer from poor control of seizures throughout life (Kalilani et al., 2018). Most of existing drugs are designed to treat the symptoms, but do not prevent epilepsy in people at risk nor modify the disease progression (Galanopoulou et al., 2021; Chen et al., 2018). The development of epilepsy, or epileptogenesis, is a gradual process (Pitkänen et al., 2015); therefore, a better understanding of the underlying pathological processes might lead to identification of more effective targeted therapies or novel avenues to reduce or prevent seizures. Experimental and human evidence builds a solid foundation of a direct link between epileptogenesis and inflammation (Vezzani et al., 2023; Dingledine et al., 2024). This Research Topic provides new insights into the inflammatory and immune mechanisms that might contribute to the onset of epilepsy and spontaneous seizure occurrence.

2 Role of complement C3 in epileptogenesis

The activation of the complement system has been reported to occur in experimental models of status epilepticus (SE) and human temporal lobe epilepsy (TLE). In previous studies complement C3 levels persisted elevated after SE or at the chronic stage of TLE, correlating with seizure severity and cognitive deficits (Aronica et al., 2007; Schartz et al., 2018; Kharatishvili et al., 2014). Here, Schartz et al. demonstrate that C3 knockout mice subjected to pilocarpine-induced SE did not display memory deficits nor astrogliosis, suggesting that C3 ablation prevent cognitive decline during epileptogenesis. These findings nominate complement C3 as a disease-enhancing molecule that might contribute to the development of epilepsy, and hence a novel therapeutic target for epileptogenesis prevention.

3 Neuroinflammation in epileptogenesis

Clinical and experimental lines of evidence support a crucial role for neuroinflammation in the development of epilepsy. For instance, Li et al. reviewed relevant pro-inflammatory mediators and inflammatory pathways that might lead to epileptogenesis, ranging from microglia and astrocytic activation, brain blood barrier dysfunction, and systemic inflammatory events (e.g., monocyte infiltration to the brain). Furthermore, Bröer and Pauletti summarized the beneficial and harmful role of resident microglia and infiltrating monocytes, which upon activation, influence seizure initiation and disease progression. Together this evidence strongly emphasize that inflammatory factors and microglia/infiltrating monocytes could be used as potential biomarkers to identify patients at risk or targets for therapeutic approaches in the treatment of epilepsy.

4 A Src tyrosine kinase inhibitor as a novel avenue for the treatment of epilepsy

Anti-inflammatory drugs targeting neuroinflammation show promising results for disease modification (Vezzani et al., 2024). Recent reports implicate Src tyrosine kinases in epilepsy-related neuroinflammation (Liu et al., 2022; Sharma et al., 2021). In this study, Rao et al. examine the protective effects of inhibiting Src via saracatinib in the rat kainic acid model of SE. Treatment with saracatinib mitigated microgliosis and reactive astrocytes, prevented neurodegeneration, and reduced cortical glial scar. Given its efficacy in targeting epileptogenic processes, saracatinib could be a promising disease-modifying agent to prevent the development and progression of epilepsy.

5 Using bioinformatics to identify new hub genes linked to epilepsy

Neuronal cell death–apoptosis, necroptosis, pyroptosis, ferroptosis, or autophagy–can worsen seizure occurrence and epilepsy progression. Pharmacological inhibition of neuronal cell death has proven to be an effective therapy for SE (Du et al., 2022). Via a differential expression analysis, Wang et al. identified five apoptosis-related genes CD38, FAIM2, IL1B, PAWR, and S100A8 as potential diagnostic biomarkers. Despite small sample size in the data sets, the constructed diagnostic model indicated a remarkable accuracy in patients with TLE compared to controls. Future experimental studies are needed to validate these bioinformatic findings.

6 Early-life environmental insults prime epileptogenesis

Neurofibromatosis type 1 (NF1) patients have an increased risk to develop epilepsy in adulthood (Hébert et al., 2024). Early-life environmental insults, including cerebral ischemia, brain trauma, or infection, share common pathological pathways involving innate immune activation and neuroinflammation (Semple et al., 2020). To address the relevance of early immune activation in epilepsy development, Faidi and Reid used lipopolysaccharide to prime the brain for later spontaneous seizures and cognitive deficits in a mouse model of NF1. Their results showed that early immune activation promotes seizure susceptibility, without effects on learning/memory, suggesting early-life environmental insults are an important risk factor for NF1-associated epilepsy.

7 New onset refractory status epilepticus and febrile infection-related epilepsy syndrome

By consensus, new onset refractory status epilepticus (NORSE) is defined as “a clinical presentation characterized by new onset of refractory SE, in a patient without active epilepsy or other preexisting relevant neurological disorder, and without a clear acute or active structural, toxic or metabolic cause”; in contrast, febrile infection-related epilepsy syndrome (FIRES) is a subcategory of NORSE with a preceding febrile infection (Hirsch et al., 2018). In both conditions, survivors have a poor response to antiepileptic medications leading to a high seizure burden and poor quality of life (Wickstrom et al., 2022). In this review, Champsas et al. analyzed the supporting clinical, preclinical, emerging treatments (e.g., anesthetics, immunological and dietary approaches) and outcome data that highlight the understudied role of immune-mediated inflammatory process in the NORSE/FIRES pathophysiology. Importantly, authors propose future directions for in vivo and in vitro epilepsy research and provide a call-to-action for experts in Neurology, Neuroscience, Immunology, and other Biomedical Sciences to work together for improving patients outcomes.

The molecular and cellular mechanisms underlying epileptogenesis include but are not restricted to neuroinflammation. This Research Topic examined important immune players, risk factors and interventions for neuroinflammation in the context of epilepsy development. With further investigation of inflammatory and immune pathways, the field will get closer to achieving the ultimate goal of finding useful disease-modifying agents for patients with epilepsy.

We are sincerely grateful to all the authors that contributed to this Research Topic.

Author contributions

CE-G: Writing – original draft, Writing – review & editing. EB: Writing – review & editing. YL: Writing – review & editing.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
==== Refs
References

Aronica E. Boer K. van Vliet E. A. Redeker S. Baayen J. C. Spliet W. G. . (2007). Complement activation in experimental and human temporal lobe epilepsy. Neurobiol. Dis. 26 , 497–511. 10.1016/j.nbd.2007.01.015 17412602
CDC (2024). Available at: https://www.cdc.gov/epilepsy/data-research/facts-stats/index.html (accessed August 21, 2024).
Chen Z. Brodie M. J. Liew D. Kwan P. (2018). Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 75 , 279–286. 10.1001/jamaneurol.2017.3949 29279892
Dingledine R. Varvel N. H. Ravizza T. Vezzani A. (2024). Neuroinflammation in Epilepsy: Cellular and Molecular Mechanisms. Oxford: Oxford Medicine Online. 10.1093/med/9780197549469.003.0030
Du K. He M. Zhao D. Wang Y. Ma C. Liang H. . (2022). Mechanism of cell death pathways in status epilepticus and related therapeutic agents. Biomed. Pharmacother. 149 :112875. 10.1016/j.biopha.2022.112875 35367755
Galanopoulou A. S. Löscher W. Lubbers L. O'Brien T. J. Staley K. Vezzani A. . (2021). Antiepileptogenesis and disease modification: progress, challenges, and the path forward-report of the preclinical working group of the 2018 NINDS-sponsored antiepileptogenesis and disease modification workshop. Epilepsia Open 6 , 276–296. 10.1002/epi4.12490 34033232
Hébert J. De Santis R. J. Daniyal L. Mannan S. Ng E. Thain E. . (2024). Epilepsy in neurofibromatosis type 1: prevalence, phenotype, and genotype in adults. Epilepsy Res. 202 :107336. 10.1016/j.eplepsyres.2024.107336 38471245
Hirsch L. J. Gaspard N. van Baalen A. Nabbout R. Demeret S. Loddenkemper T. . (2018). Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions. Epilepsia 59 , 739–744. 10.1111/epi.14016 29399791
Kalilani L. Sun X. Pelgrims B. Noack-Rink M. Villanueva V. (2018). The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia 59 , 2179–2193. 10.1111/epi.14596 30426482
Kharatishvili I. Shan Z. Y. She D. T. Foong S. Kurniawan N. D. Reutens D. C. . (2014). MRI changes and complement activation correlate with epileptogenicity in a mouse model of temporal lobe epilepsy. Brain Struct. Funct. 219 , 683–706. 10.1007/s00429-013-0528-4 23474541
Liu L. Xia L. Li Y. Zhang Y. Wang Q. Ding J. . (2022). Inhibiting SRC activity attenuates kainic-acid induced mouse epilepsy via reducing NR2B phosphorylation and full-length NR2B expression. Epilepsy Res. 185 :106975. 10.1016/j.eplepsyres.2022.106975 35907325
Pitkänen A. Lukasiuk K. Dudek F. E. Staley K. J. (2015). Epileptogenesis. Cold Spring Harb. Perspect. Med. 5 :a022822. 10.1101/cshperspect.a022822 26385090
Schartz N. D. Wyatt-Johnson S. K. Price L. R. Colin S. A. Brewster A. L. (2018). Status epilepticus triggers long-lasting activation of complement C1q-C3 signaling in the hippocampus that correlates with seizure frequency in experimental epilepsy. Neurobiol. Dis. 109 , 163–173. 10.1016/j.nbd.2017.10.012 29074125
Semple B. D. Dill L. K. O'Brien T. J. (2020). Immune challenges and seizures: how do early life insults influence epileptogenesis? Front. Pharmacol. 11 :2. 10.3389/fphar.2020.00002 32116690
Sharma S. Carlson S. Gregory-Flores A. Hinojo-Perez A. Olson A. Thippeswamy T. . (2021). Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy. Neurobiol. Dis. 156 :105410. 10.1016/j.nbd.2021.105410 34087381
Vezzani A. Balosso S. Varvel N. H. Dingledine R. (2024). Anti-Inflammatory Strategies for Disease Modification: Focus on Therapies Close to Clinical Translation. Oxford: Oxford Medicine Online. 10.1093/med/9780197549469.003.0074
Vezzani A. Di Sapia R. Kebede V. Balosso S. Ravizza T. (2023). Neuroimmunology of status epilepticus. Epilepsy Behav. 140 :109095. 10.1016/j.yebeh.2023.109095 36753859
WHO (2024). Available at: https://www.who.int/news-room/fact-sheets/detail/epilepsy (accessed on August 16, 2024).
Wickstrom R. Taraschenko O. Dilena R. Payne E. T. Specchio N. Nabbout R. . (2022). International consensus recommendations for management of new onset refractory status epilepticus (NORSE) incl. febrile infection-related epilepsy syndrome (FIRES): statements and supporting evidence. Epilepsia 63 , 2840–2864. 10.1111/epi.17397 35997591
