Role of neuroinflammation factors as potential biomarkers of epilepsy: a narrative review
Abstract
Epilepsy is a common neurological condition with a significant socioeconomic impact. Approximately one in three patients is resistant to the available therapies, and the mechanisms of this resistance are often unclear. Neuroinflammation, recognised as a potential cause of drug-resistant epilepsy, plays a key role in modulating synaptic transmission and hyperexcitability.
In this narrative review, we explore the molecular basis of neuroinflammation in epilepsy and its potential as a source of biomarkers for diagnosis and treatment. Evidence from human and animal studies indicates a strong association between neuroinflammation and epilepsy, with significant involvement of pro-inflammatory molecules and blood-brain barrier dysfunction. We highlight the roles of microglia, astrocytes and inflammatory molecules in epilepsy, suggesting that targeted anti-inflammatory therapies could be promising for treatment. Further research is needed to fully understand the role of neuroinflammation in epilepsy and to develop new therapeutic approaches.
Keywords: neuroinflammationblood-brain barriercytokineepilepsyseizure
References
- Perucca E, Perucca P, White HS, et al. Drug resistance in epilepsy. Lancet Neurol. 2023; 22(8): 723–734.
- Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010; 51(6): 1069–1077.
- Löscher W, Potschka H, Sisodiya SM, et al. Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options. Pharmacol Rev. 2020; 72(3): 606–638.
- Alvim MKM, Morita-Sherman ME, Yasuda CL, et al. Inflammatory and neurotrophic factor plasma levels are related to epilepsy independently of etiology. Epilepsia. 2021; 62(10): 2385–2394.
- Campos-Bedolla P, Feria-Romero I, Orozco-Suárez S. Factors not considered in the study of drug-resistant epilepsy: Drug-resistant epilepsy: Assessment of neuroinflammation. Epilepsia Open. 2022; 7 Suppl 1(Suppl 1): S68–S80.
- Chen Yu, Nagib MM, Yasmen N, et al. Neuroinflammatory mediators in acquired epilepsy: an update. Inflamm Res. 2023; 72(4): 683–701.
- Iyer A, Zurolo E, Spliet WGM, et al. Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias. Epilepsia. 2010; 51(9): 1763–1773.
- Crespel A, Coubes P, Rousset MC, et al. Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res. 2002; 952(2): 159–169.
- Boer K, Crino PB, Gorter JA, et al. Gene expression analysis of tuberous sclerosis complex cortical tubers reveals increased expression of adhesion and inflammatory factors. Brain Pathol. 2010; 20(4): 704–719.
- Maldonado M, Baybis M, Newman D, et al. Expression of ICAM-1, TNF-alpha, NF kappa B, and MAP kinase in tubers of the tuberous sclerosis complex. Neurobiol Dis. 2003; 14(2): 279–290.
- Lorigados Pedre L, Morales Chacón LM, Pavón Fuentes N, et al. Follow-Up of Peripheral IL-1β and IL-6 and Relation with Apoptotic Death in Drug-Resistant Temporal Lobe Epilepsy Patients Submitted to Surgery. Behav Sci (Basel). 2018; 8(2).
- Li W, Wu J, Zeng Y, et al. Neuroinflammation in epileptogenesis: from pathophysiology to therapeutic strategies. Front Immunol. 2023; 14: 1269241.
- Mukhtar I. Inflammatory and immune mechanisms underlying epileptogenesis and epilepsy: From pathogenesis to treatment target. Seizure. 2020; 82: 65–79.
- Ma H, Lin H. Advances regarding Neuroinflammation Biomarkers with Noninvasive Techniques in Epilepsy. Behav Neurol. 2021; 2021: 7946252.
- Du Y, Li R, Fu D, et al. Multi-omics technologies and molecular biomarkers in brain tumor-related epilepsy. CNS Neurosci Ther. 2024; 30(4): e14717.
- Srivastava A, Dixit AB, Banerjee J, et al. Role of inflammation and its miRNA based regulation in epilepsy: Implications for therapy. Clin Chim Acta. 2016; 452: 1–9.
- Löscher W, Friedman A. Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both? Int J Mol Sci. 2020; 21(2).
- Lischper M, Beuck S, Thanabalasundaram G, et al. Metalloproteinase mediated occludin cleavage in the cerebral microcapillary endothelium under pathological conditions. Brain Res. 2010; 1326: 114–127.
- Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med. 2013; 19(12): 1584–1596.
- Varvel NH, Neher JJ, Bosch A, et al. Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus. Proc Natl Acad Sci U S A. 2016; 113(38): E5665–E5674.
- Fabene PF, Navarro Mora G, Martinello M, et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med. 2008; 14(12): 1377–1383.
- Reiter JT, Schulte F, Bauer T, et al. Evidence for interictal blood-brain barrier dysfunction in people with epilepsy. Epilepsia. 2024; 65(5): 1462–1474.
- Rüber T, David B, Lüchters G, et al. Evidence for peri-ictal blood-brain barrier dysfunction in patients with epilepsy. Brain. 2018; 141(10): 2952–2965.
- Hanael E, Veksler R, Friedman A, et al. Blood-brain barrier dysfunction in canine epileptic seizures detected by dynamic contrast-enhanced magnetic resonance imaging. Epilepsia. 2019; 60(5): 1005–1016.
- Mendes NF, Pansani AP, Carmanhães ER, et al. The Blood-Brain Barrier Breakdown During Acute Phase of the Pilocarpine Model of Epilepsy Is Dynamic and Time-Dependent. Front Neurol. 2019; 10: 382.
- Dannhauser D, Rossi D, De Gregorio V, et al. Single cell classification of macrophage subtypes by label-free cell signatures and machine learning. R Soc Open Sci. 2022; 9(9): 220270.
- Devinsky O, Vezzani A, Najjar S, et al. Glia and epilepsy: excitability and inflammation. Trends Neurosci. 2013; 36(3): 174–184.
- Yu C, Deng XJ, Xu Da. Microglia in epilepsy. Neurobiol Dis. 2023; 185: 106249.
- Sun H, Ma Di, Cheng Yu, et al. The JAK-STAT Signaling Pathway in Epilepsy. Curr Neuropharmacol. 2023; 21(10): 2049–2069.
- Maroso M, Balosso S, Ravizza T, et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med. 2010; 16(4): 413–419.
- Jangde N, Ray R, Rai V. RAGE and its ligands: from pathogenesis to therapeutics. Crit Rev Biochem Mol Biol. 2020; 55(6): 555–575.
- Walker LE, Sills GJ, Jorgensen A, et al. High-mobility group box 1 as a predictive biomarker for drug-resistant epilepsy: A proof-of-concept study. Epilepsia. 2022; 63(1): e1–e6.
- Fu Li, Liu K, Wake H, et al. Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice. Sci Rep. 2017; 7(1): 1179.
- Paudel YN, Angelopoulou E, Akyuz E, et al. Role of Innate Immune Receptor TLR4 and its endogenous ligands in epileptogenesis. Pharmacol Res. 2020; 160: 105172.
- Zhu X, Liu J, Chen Ou, et al. Neuroprotective and anti-inflammatory effects of isoliquiritigenin in kainic acid-induced epileptic rats via the TLR4/MYD88 signaling pathway. Inflammopharmacology. 2019; 27(6): 1143–1153.
- Hu QP, Mao DA. Histone deacetylase inhibitor SAHA attenuates post-seizure hippocampal microglia TLR4/MYD88 signaling and inhibits TLR4 gene expression via histone acetylation. BMC Neurosci. 2016; 17(1): 22.
- Pernhorst K, Herms S, Hoffmann P, et al. TLR4, ATF-3 and IL8 inflammation mediator expression correlates with seizure frequency in human epileptic brain tissue. Seizure. 2013; 22(8): 675–678.
- Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. 2018; 281(1): 8–27.
- Dong Y, Zhang X, Wang Y. Interleukins in Epilepsy: Friend or Foe. Neurosci Bull. 2024; 40(5): 635–657.
- Shi LM, Chen RJ, Zhang H, et al. Cerebrospinal fluid neuron specific enolase, interleukin-1β and erythropoietin concentrations in children after seizures. Childs Nerv Syst. 2017; 33(5): 805–811.
- Soltani Khaboushan A, Yazdanpanah N, Rezaei N. Neuroinflammation and Proinflammatory Cytokines in Epileptogenesis. Mol Neurobiol. 2022; 59(3): 1724–1743.
- Rana A, Musto AE. The role of inflammation in the development of epilepsy. J Neuroinflammation. 2018; 15(1): 144.
- Santos RO, Secolin R, Barbalho PG, et al. Multidimensional Approach Assessing the Role of Interleukin 1 Beta in Mesial Temporal Lobe Epilepsy. Front Neurol. 2021; 12: 690847.
- Aledo-Serrano A, Hariramani R, Gonzalez-Martinez A, et al. Anakinra and tocilizumab in the chronic phase of febrile infection-related epilepsy syndrome (FIRES): Effectiveness and safety from a case-series. Seizure. 2022; 100: 51–55.
- Girardin ML, Flamand T, Roignot O, et al. Treatment of new onset refractory status epilepticus/febrile infection-related epilepsy syndrome with tocilizumab in a child and a young adult. Epilepsia. 2023; 64(6): e87–e92.
- Ethemoglu O, Calık M, Koyuncu I, et al. Interleukin-33 and oxidative stress in epilepsy patients. Epilepsy Res. 2021; 176: 106738.
- Grebenciucova E, VanHaerents S. Interleukin 6: at the interface of human health and disease. Front Immunol. 2023; 14: 1255533.
- Fang W, Chen S, Xia X, et al. Interictal interleukin-6 and tumor necrosis factor α levels are associated with seizure recurrence in adults with epilepsy. Epilepsy Behav. 2024; 155: 109786.
- Alyu F, Dikmen M. Inflammatory aspects of epileptogenesis: contribution of molecular inflammatory mechanisms. Acta Neuropsychiatr. 2017; 29(1): 1–16.
- Steinborn B, Zarowski M, Winczewska-Wiktor A, et al. Concentration of Il-1β, Il-2, Il-6, TNFα in the blood serum in children with generalized epilepsy treated by valproate. Pharmacol Rep. 2014; 66(6): 972–975.
- Česká K, Papež J, Ošlejšková H, et al. CCL2/MCP-1, interleukin-8, and fractalkine/CXC3CL1: Potential biomarkers of epileptogenesis and pharmacoresistance in childhood epilepsy. Eur J Paediatr Neurol. 2023; 46: 48–54.
- Asano T, Ichiki K, Koizumi S, et al. IL-8 in cerebrospinal fluid from children with acute encephalopathy is higher than in that from children with febrile seizure. Scand J Immunol. 2010; 71(6): 447–451.
- Lim JA, Lee ST, Moon J, et al. New feasible treatment for refractory autoimmune encephalitis: Low-dose interleukin-2. J Neuroimmunol. 2016; 299: 107–111.
- Mazumder AG, Patial V, Singh D. Mycophenolate mofetil contributes to downregulation of the hippocampal interleukin type 2 and 1β mediated PI3K/AKT/mTOR pathway hyperactivation and attenuates neurobehavioral comorbidities in a rat model of temporal lobe epilepsy. Brain Behav Immun. 2019; 75: 84–93.
- Guo W, Zheng DH, Sun FJ, et al. Expression and cellular distribution of the interleukin 2 signaling system in cortical lesions from patients with focal cortical dysplasia. J Neuropathol Exp Neurol. 2014; 73(3): 206–222.
- Gadani SP, Cronk JC, Norris GT, et al. IL-4 in the brain: a cytokine to remember. J Immunol. 2012; 189(9): 4213–4219.
- Radpour M, Khoshkroodian B, Asgari T, et al. Interleukin 4 Reduces Brain Hyperexcitability after Traumatic Injury by Downregulating TNF-α, Upregulating IL-10/TGF-β, and Potential Directing Macrophage/Microglia to the M2 Anti-inflammatory Phenotype. Inflammation. 2023; 46(5): 1810–1831.
- Sun FJ, Zhang CQ, Chen X, et al. Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex. J Neuroinflammation. 2016; 13(1): 85.
- Ouyang W, O'Garra A. IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation. Immunity. 2019; 50(4): 871–891.
- Ruffolo G, Alfano V, Romagnolo A, et al. GABA receptor function is enhanced by Interleukin-10 in human epileptogenic gangliogliomas and its effect is counteracted by Interleukin-1β. Sci Rep. 2022; 12(1): 17956.
- Cerri C, Caleo M, Bozzi Y. Chemokines as new inflammatory players in the pathogenesis of epilepsy. Epilepsy Res. 2017; 136: 77–83.
- Kothur K, Bandodkar S, Wienholt L, et al. Etiology is the key determinant of neuroinflammation in epilepsy: Elevation of cerebrospinal fluid cytokines and chemokines in febrile infection-related epilepsy syndrome and febrile status epilepticus. Epilepsia. 2019; 60(8): 1678–1688.
- Meng F, Yao L. The role of inflammation in epileptogenesis. Acta Epileptologica. 2020; 2(1).
- Sinha S, Patil SA, Jayalekshmy V, et al. Do cytokines have any role in epilepsy? Epilepsy Res. 2008; 82(2-3): 171–176.
- Lagarde S, Villeneuve N, Trébuchon A, et al. Anti-tumor necrosis factor alpha therapy (adalimumab) in Rasmussen's encephalitis: An open pilot study. Epilepsia. 2016; 57(6): 956–966.
- Luo X, Li D, Cen D, et al. Effect of intravenous immunoglobulin treatment on brain interferon-gamma and interleukin-6 levels in a rat kindling model. Epilepsy Res. 2010; 88(2-3): 162–167.
- Gao F, Gao Y, Zhang SJ, et al. Alteration of plasma cytokines in patients with active epilepsy. Acta Neurol Scand. 2017; 135(6): 663–669.
- Luo J. TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications. Biomedicines. 2022; 10(5).
- Yu W, Zou Y, Du Y, et al. Altered cerebrospinal fluid concentrations of TGFβ1 in patients with drug-resistant epilepsy. Neurochem Res. 2014; 39(11): 2211–2217.
- Zheng Z, Yan Y, Guo Qi, et al. Genetic Interaction of and Polymorphisms with Risk of Epilepsy in a Chinese Population. Pharmgenomics Pers Med. 2021; 14: 77–86.
- Ivens S, Kaufer D, Flores LP, et al. TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain. 2007; 130(Pt 2): 535–547.
- Cacheaux LP, Ivens S, David Y, et al. Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. J Neurosci. 2009; 29(28): 8927–8935.
- Bar-Klein G, Cacheaux LP, Kamintsky L, et al. Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann Neurol. 2014; 75(6): 864–875.
- Weissberg I, Wood L, Kamintsky L, et al. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol Dis. 2015; 78: 115–125.
- Shimada T, Takemiya T, Sugiura H, et al. Role of inflammatory mediators in the pathogenesis of epilepsy. Mediators Inflamm. 2014; 2014: 901902.
- Warwick CA, Keyes AL, Woodruff TM, et al. The complement cascade in the regulation of neuroinflammation, nociceptive sensitization, and pain. J Biol Chem. 2021; 297(3): 101085.
- Kobylarek D, Iwanowski P, Lewandowska Z, et al. Advances in the Potential Biomarkers of Epilepsy. Front Neurol. 2019; 10: 685.
- Başaran N, Hincal F, Kansu E, et al. Humoral and cellular immune parameters in untreated and phenytoin-or carbamazepine-treated epileptic patients. Int J Immunopharmacol. 1994; 16(12): 1071–1077.
- Liguori C, Romigi A, Izzi F, et al. Complement system dysregulation in patients affected by Idiopathic Generalized Epilepsy and the effect of antiepileptic treatment. Epilepsy Res. 2017; 137: 107–111.
- Wyatt SK, Witt T, Barbaro NM, et al. Enhanced classical complement pathway activation and altered phagocytosis signaling molecules in human epilepsy. Exp Neurol. 2017; 295: 184–193.
- Jamali S, Salzmann A, Perroud N, et al. Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures. PLoS One. 2010; 5(9).
- Aronica E, Boer K, van Vliet EA, et al. Complement activation in experimental and human temporal lobe epilepsy. Neurobiol Dis. 2007; 26(3): 497–511.
- Kopczynska M, Zelek WM, Vespa S, et al. Complement system biomarkers in epilepsy. Seizure. 2018; 60: 1–7.
- Fu M, Tao J, Wang D, et al. Downregulation of MicroRNA-34c-5p facilitated neuroinflammation in drug-resistant epilepsy. Brain Res. 2020; 1749: 147130.
- Lu J, Zhou N, Yang P, et al. MicroRNA-27a-3p Downregulation Inhibits Inflammatory Response and Hippocampal Neuronal Cell Apoptosis by Upregulating Mitogen-Activated Protein Kinase 4 (MAP2K4) Expression in Epilepsy: In Vivo and In Vitro Studies. Med Sci Monit. 2019; 25: 8499–8508.
- Ashhab MU, Omran A, Kong H, et al. Expressions of tumor necrosis factor alpha and microRNA-155 in immature rat model of status epilepticus and children with mesial temporal lobe epilepsy. J Mol Neurosci. 2013; 51(3): 950–958.
- Zhang H, Qu Y, Wang A. Antagonist targeting microRNA 146a protects against lithium-pilocarpine-induced status epilepticus in rats by nuclear factor-B pathway. Mol. Med. Rep. 2018; 17(4): 5356–5361.
- Tao H, Zhao J, Liu T, et al. Intranasal Delivery of miR-146a Mimics Delayed Seizure Onset in the Lithium-Pilocarpine Mouse Model. Mediators Inflamm. 2017; 2017: 6512620.
- Fu M, Tao J, Wang D, et al. Downregulation of MicroRNA-34c-5p facilitated neuroinflammation in drug-resistant epilepsy. Brain Res. 2020; 1749: 147130.
- Costagliola G, Depietri G, Michev A, et al. Targeting Inflammatory Mediators in Epilepsy: A Systematic Review of Its Molecular Basis and Clinical Applications. Front Neurol. 2022; 13: 741244.
- Zhao L, Murray S, Mariani LH, et al. Incorporating longitudinal biomarkers for dynamic risk prediction in the era of big data: A pseudo-observation approach. Stat Med. 2020; 39(26): 3685–3699.
- Ma H, Lin H. Advances regarding Neuroinflammation Biomarkers with Noninvasive Techniques in Epilepsy. Behav Neurol. 2021; 2021: 7946252.
- Ng S, Masarone S, Watson D, et al. The benefits and pitfalls of machine learning for biomarker discovery. Cell Tissue Res. 2023; 394(1): 17–31.
