Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy


Epilepsy is a chronic neurological disease characterized by an enduring propensity for generation of seizures. The pathogenic processes of seizure generation and recurrence are the subject of intensive preclinical and clinical investigations as their identification would enable development of novel treatments that prevent epileptic seizures and reduce seizure burden. Such treatments are particularly needed for pharmacoresistant epilepsies, which affect ~30% of patients. Neuroinflammation is commonly activated in epileptogenic brain regions in humans and is clearly involved in animal models of epilepsy. An increased understanding of neuroinflammatory mechanisms in epilepsy has identified cellular and molecular targets for new mechanistic therapies or existing anti-inflammatory drugs that could overcome the limitations of current medications, which provide only symptomatic control of seizures. Moreover, inflammatory mediators in the blood and molecular imaging of neuroinflammation could provide diagnostic, prognostic and predictive biomarkers for epilepsy, which will be instrumental for patient stratification in future clinical studies. In this Review, we focus on our understanding of the IL-1 receptor–Toll-like receptor 4 axis, the arachidonic acid–prostaglandin cascade, oxidative stress and transforming growth factor-β signalling associated with blood–brain barrier dysfunction, all of which are pathways that are activated in pharmacoresistant epilepsy in humans and that can be modulated in animal models to produce therapeutic effects on seizures, neuronal cell loss and neurological comorbidities.

Key points

  • Activation of neuroinflammatory pathways in epileptogenic brain areas is common in structural (acquired or genetic) epilepsies.

  • Neuroinflammation is an intrinsic brain response that involves activation of innate immunity mechanisms in glia, neurons and the microvasculature.

  • Inflammatory mediators, such as IL-1β, tumour necrosis factor, high mobility group box 1, transforming growth factor-β and prostaglandins, can alter neuronal, glial and blood–brain barrier functions by activating transcriptional and post-translational mechanisms in brain cells.

  • If not adequately controlled, neuroinflammation contributes to seizures, neuronal cell loss, maladaptive synaptic plasticity and comorbidities.

  • Target-specific anti-inflammatory interventions in animal models of epilepsy have anti-ictogenic, anti-epileptogenic and disease-modifying therapeutic effects.

  • Initial clinical studies have shown that some anti-inflammatory drugs have therapeutic effects on drug-resistant seizures and that neuroinflammatory factors could act as disease biomarkers.

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Fig. 1: Neuroinflammation as a disease modifier in epilepsy.
Fig. 2: Mechanisms of neuroinflammation-driven neuropathology and excitability.


  1. 1.

    Devinsky, O. et al. Epilepsy. Nat. Rev. Dis. Primer 4, 18024 (2018). This paper provides a detailed overview of the epilepsies, focusing on diagnosis, treatments, pathophysiology, animal models and biomarkers.

    Google Scholar 

  2. 2.

    Scheffer, I. E. et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58, 512–521 (2017).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    van Vliet, E. A., Aronica, E., Vezzani, A. & Ravizza, T. Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies. Neuropathol. Appl. Neurobiol. 44, 91–111 (2018). This article provides an extensive review of the inflammatory targets characterized in animal models of epilepsy for drug development.

    PubMed  Google Scholar 

  4. 4.

    Aronica, E. et al. Neuroinflammatory targets and treatments for epilepsy validated in experimental models. Epilepsia 58 (Suppl. 3), 27–38 (2017).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Vezzani, A., Lang, B. & Aronica, E. Immunity and inflammation in epilepsy. Cold Spring Harb. Perspect. Med. 6, a022699 (2015). This paper provides a review of the involvement of innate and adaptive immune mechanisms in the pathogenesis of seizures in autoimmune and common forms of epilepsy.

    PubMed  Google Scholar 

  6. 6.

    Vezzani, A., Maroso, M., Balosso, S., Sanchez, M. A. & Bartfai, T. IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav. Immun. 25, 1281–1289 (2011). This article provides mechanistic insights into the role of innate immune signals in the generation and recurrence of seizures based on animal studies.

    CAS  PubMed  Google Scholar 

  7. 7.

    Xanthos, D. N. & Sandkuhler, J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat. Rev. Neurosci. 15, 43–53 (2014).

    CAS  PubMed  Google Scholar 

  8. 8.

    Vezzani, A. et al. Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. J. Neurosci. 19, 5054–5065 (1999). This article presents seminal evidence of the ictogenic properties of IL-1 in animal models.

    CAS  PubMed  Google Scholar 

  9. 9.

    De Simoni, M. G. et al. Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur. J. Neurosci. 12, 2623–2633 (2000).

    PubMed  Google Scholar 

  10. 10.

    Maroso, M. 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. 16, 413–419 (2010). This article provides the first experimental evidence for the role of HMGB1 and TLR4 in seizure mechanisms.

    CAS  PubMed  Google Scholar 

  11. 11.

    Vezzani, A., French, J., Bartfai, T. & Baram, T. Z. The role of inflammation in epilepsy. Nat. Rev. Neurol. 7, 31–40 (2011).

    CAS  PubMed  Google Scholar 

  12. 12.

    Aronica, E. & Crino, P. B. Inflammation in epilepsy: clinical observations. Epilepsia 52 (Suppl. 3), 26–32 (2011).

    PubMed  Google Scholar 

  13. 13.

    Ramaswamy, V. et al. Inflammasome induction in Rasmussen’s encephalitis: cortical and associated white matter pathogenesis. J. Neuroinflamm. 10, 152 (2013).

    Google Scholar 

  14. 14.

    Luan, G., Gao, Q., Zhai, F., Chen, Y. & Li, T. Upregulation of HMGB1, toll-like receptor and RAGE in human Rasmussen’s encephalitis. Epilepsy Res. 123, 36–49 (2016).

    CAS  PubMed  Google Scholar 

  15. 15.

    Prabowo, A. S. et al. Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation. Brain Pathol. 23, 45–59 (2012).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Pauletti, A. et al. Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain (2019).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Ravizza, T. et al. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol. Dis. 29, 142–160 (2008). This paper presents clinical and experimental evidence for the activation of the IL-1 system in human temporal lobe epilepsy.

    CAS  PubMed  Google Scholar 

  18. 18.

    Vezzani, A. & Friedman, A. Brain inflammation as a biomarker in epilepsy. Biomark. Med. 5, 607–614 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Friedman, A. & Heinemann, U. in Jasper’s Basic Mechanisms of the Epilepsies 4th edn (ed. Noebels, J. L.) (US National Center for Biotechnology Information, 2012). This article provides an overview of the role of BBB dysfunction and its consequences in epilepsy and the mechanisms involved in alterations in BBB permeability and its transport function.

  20. 20.

    Iyer, A. et al. Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias. Epilepsia 51, 1736–1773 (2010).

    Google Scholar 

  21. 21.

    Choi, J. & Koh, S. Role of brain inflammation in epileptogenesis. Yonsei Med. J. 49, 1–18 (2008).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Bauer, J. et al. Innate and adaptive immunity in human epilepsies. Epilepsia 58 (Suppl. 3), 57–68 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Bien, C. G. et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135, 1622–1638 (2012).

    PubMed  Google Scholar 

  24. 24.

    Ravizza, T. et al. The IL-1beta system in epilepsy-associated malformations of cortical development. Neurobiol. Dis. 24, 128–143 (2006). This paper presents the first evidence of activation of the IL-1 system in human drug-refractory epilepsy.

    CAS  PubMed  Google Scholar 

  25. 25.

    Arena, A. et al. Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence. Brain Pathol. 29, 351–365 (2018). This study shows an association between oxidative stress and neuroinflammation in drug-resistant epilepsies.

    PubMed  Google Scholar 

  26. 26.

    Pitkanen, A. et al. Advances in the development of biomarkers for epilepsy. Lancet Neurol. 15, 843–856 (2016). This article provides an overview of non-invasive prognostic, diagnostic and predictive biomarkers of epilepsy.

    CAS  PubMed  Google Scholar 

  27. 27.

    Klein, P. et al. Commonalities in epileptogenic processes from different acute brain insults: do they translate? Epilepsia 59, 37–66 (2018).

    CAS  PubMed  Google Scholar 

  28. 28.

    Ravizza, T. et al. High Mobility Group Box 1 is a novel pathogenic factor and a mechanistic biomarker for epilepsy. Brain. Behav. Immun. 72, 14–21 (2018).

    CAS  PubMed  Google Scholar 

  29. 29.

    Varvel, N. H. et al. Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus. Proc. Natl Acad. Sci. USA 113, E5665–E5674 (2016).

    CAS  PubMed  Google Scholar 

  30. 30.

    O’Neill, L. A. & Bowie, A. G. The family of five: |TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol. 7, 353–364 (2007).

    PubMed  Google Scholar 

  31. 31.

    Vezzani, A. & Viviani, B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology 96, 70–82 (2015). This paper presents a description of the neuromodulatory effects of cytokines and the molecular mechanisms involved in these effects.

    CAS  PubMed  Google Scholar 

  32. 32.

    Hanke, M. L. & Kielian, T. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin. Sci. 121, 367–387 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Xiang, W., Chao, Z.-Y. & Feng, D.-Y. Role of Toll-like receptor/MYD88 signaling in neurodegenerative diseases. Rev. Neurosci. 26, 407–414 (2015).

    CAS  PubMed  Google Scholar 

  34. 34.

    Dinarello, C. A. Introduction to the interleukin-1 family of cytokines and receptors: drivers of innate inflammation and acquired immunity. Immunol. Rev. 281, 5–7 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Tan, C. C. et al. NLRP1 inflammasome is activated in patients with medial temporal lobe epilepsy and contributes to neuronal pyroptosis in amygdala kindling-induced rat model. J. Neuroinflamm. 12, 18 (2015).

    Google Scholar 

  36. 36.

    Henshall, D. C. et al. Alterations in bcl-2 and caspase gene family protein expression in human temporal lobe epilepsy. Neurology 55, 250–257 (2000).

    CAS  PubMed  Google Scholar 

  37. 37.

    Zurolo, E. et al. Activation of TLR, RAGE and HMGB1 signaling in malformations of cortical development. Brain 134, 1015–1032 (2011).

    PubMed  Google Scholar 

  38. 38.

    Pernhorst, K. et al. TLR4, ATF-3 and IL-8 inflammation mediator expression correlates with seizure frequency in human epileptic brain tissue. Seizure 22, 675–678 (2013).

    PubMed  Google Scholar 

  39. 39.

    Zhang, Z. et al. Upregulation of HMGB1-TLR4 inflammatory pathway in focal cortical dysplasia type II. J. Neuroinflamm. 15, 27 (2018).

    Google Scholar 

  40. 40.

    Roseti, C. et al. GABAA currents are decreased by IL-1β in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis. Neurobiol. Dis. 82, 311–320 (2015).

    CAS  PubMed  Google Scholar 

  41. 41.

    Iori, V. et al. Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures. Neurobiol. Dis. 58, 102–114 (2013).

    CAS  PubMed  Google Scholar 

  42. 42.

    Balosso, S., Liu, J., Bianchi, M. E. & Vezzani, A. Disulfide-containing High Mobility Group Box-1 promotes N-methyl-d-aspartate receptor function and excitotoxicity by activating Toll-like receptor 4-dependent signaling in hippocampal neurons. Antioxid. Redox Signal. 21, 1726–1740 (2014).

    CAS  PubMed  Google Scholar 

  43. 43.

    Marchi, N. et al. Antagonism of peripheral inflammation reduces the severity of status epilepticus. Neurobiol. Dis. 33, 171–181 (2009).

    CAS  PubMed  Google Scholar 

  44. 44.

    Vezzani, A. et al. Functional role of inflammatory cytokines and anti-inflammatory molecules in seizures and epileptogenesis. Epilepsia 43 (Suppl. 5), 30–35 (2002).

    CAS  PubMed  Google Scholar 

  45. 45.

    Ravizza, T. et al. Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47, 1160–1168 (2006).

    CAS  PubMed  Google Scholar 

  46. 46.

    Maroso, M. et al. Interleukin-1beta biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics 8, 304–315 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Akin, D. et al. IL-1beta is induced in reactive astrocytes in the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave discharges, and contributes to their occurrence. Neurobiol. Dis. 44, 259–269 (2011).

    CAS  PubMed  Google Scholar 

  48. 48.

    Vezzani, A. et al. Powerful anticonvulsant action of an IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc. Natl Acad. Sci. USA 97, 11534–11539 (2000). This article provides seminal evidence for anti-ictogenic activity of an IL-1Ra in animal models.

    CAS  PubMed  Google Scholar 

  49. 49.

    Kenney-Jung, D. L. et al. Febrile infection-related epilepsy syndrome treated with anakinra. Ann. Neurol. 80, 939–945 (2016). This clinical report is the first on the anti-seizure effect of anakinra in children with unremitting seizures.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Clarkson, B. D. S. et al. Functional deficiency in endogenous interleukin-1 receptor antagonist in patients with febrile infection-related epilepsy syndrome. Ann. Neurol. 85, 526–537 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Dilena, R. et al. Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection–related epilepsy syndrome. Epilepsia Open (2019).

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    DeSena, A. D., Do, T. & Schulert, G. S. Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade. J. Neuroinflamm. 15, 38 (2018).

    Google Scholar 

  53. 53.

    Jyonouchi, H. Intractable epilepsy (IE) and responses to anakinra, a human recombinant IL-1 receptor antagonist (IL-1Ra): case reports. J. Clin. Cell. Immunol. 7, 456–460 (2016).

    Google Scholar 

  54. 54.

    Meng, X. F. et al. Inhibition of the NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-induced status epilepticus. J. Neuroinflamm. 11, 212 (2014).

    Google Scholar 

  55. 55.

    Adinolfi, E. et al. The P2X7 receptor: a main player in inflammation. Biochem. Pharmacol. 151, 234–244 (2018).

    CAS  PubMed  Google Scholar 

  56. 56.

    Jimenez-Pacheco, A. et al. Transient P2X7 receptor antagonism produces lasting reductions in spontaneous seizures and gliosis in experimental temporal lobe epilepsy. J. Neurosci. 36, 5920–5932 (2016). This report presents the anti-ictogenic effects of P2X7 antagonists in a model of chronic epilepsy.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Engel, T. et al. Seizure suppression and neuroprotection by targeting the purinergic P2X7 receptor during status epilepticus in mice. FASEB J. 26, 1616–1628 (2012).

    CAS  PubMed  Google Scholar 

  58. 58.

    Amhaoul, H. et al. P2X7 receptor antagonism reduces the severity of spontaneous seizures in a chronic model of temporal lobe epilepsy. Neuropharmacology 105, 175–185 (2016).

    CAS  PubMed  Google Scholar 

  59. 59.

    Smyth, E. M., Grosser, T., Wang, M., Yu, Y. & FitzGerald, G. A. Prostanoids in health and disease. J. Lipid Res. 50, S423–S428 (2018).

    Google Scholar 

  60. 60.

    Rojas, A. et al. Cyclooxygenase-2 in epilepsy. Epilepsia 55, 17–25 (2014). This article provides an overview of the role of COX2 and prostaglandins in epilepsy.

    CAS  PubMed  Google Scholar 

  61. 61.

    Nomura, D. K. et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 11, 809–813 (2011).

    Google Scholar 

  62. 62.

    Sugaya, Y. et al. Crucial roles of the endocannabinoid 2-arachidonoylglycerol in the suppression of epileptic seizures. Cell Rep. 16, 1405–1415 (2016).

    CAS  PubMed  Google Scholar 

  63. 63.

    Kow, R. L. et al. Modulation of pilocarpine-induced seizures by cannabinoid receptor 1. PLOS ONE 9, e95922 (2014).

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Terrone, G. et al. Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet. Epilepsia 59, 79–91 (2018).

    CAS  PubMed  Google Scholar 

  65. 65.

    Simeone, T. A., Simeone, K. A. & Rho, J. M. Ketone bodies as anti-seizure agents. Neurochem. Res. 42, 2011–2018 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Trinka, E., Brigo, F. & Shorvon, S. Recent advances in status epilepticus. Curr. Opin. Neurol. 29, 189–198 (2016).

    CAS  PubMed  Google Scholar 

  67. 67.

    Holtman, L., van Vliet, E. A., Edelbroek, P. M., Aronica, E. & Gorter, J. A. Cox-2 inhibition can lead to adverse effects in a rat model for temporal lobe epilepsy. Epilepsy Res. 91, 49–56 (2010).

    CAS  PubMed  Google Scholar 

  68. 68.

    Kim, H. J. et al. Involvement of endogenous prostaglandin F2alpha on kainic acid-induced seizure activity through FP receptor: the mechanism of proconvulsant effects of COX-2 inhibitors. Brain Res. 1193, 153–161 (2008).

    CAS  PubMed  Google Scholar 

  69. 69.

    Naffah-Mazzacoratti, M. G., Bellissimo, M. I. & Cavalheiro, E. A. Profile of prostaglandin levels in the rat hippocampus in pilocarpine model of epilepsy. Neurochem. Int. 27, 461–466 (1995).

    CAS  PubMed  Google Scholar 

  70. 70.

    Yoshikawa, K., Kita, Y., Kishimoto, K. & Shimizu, T. Profiling of eicosanoid production in the rat hippocampus during kainic acid-induced seizure: dual phase regulation and differential involvement of COX-1 and COX-2. J. Biol. Chem. 281, 14663–14669 (2006).

    CAS  PubMed  Google Scholar 

  71. 71.

    Jung, K. H. et al. Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neurobiol. Dis. 23, 237–246 (2006).

    CAS  PubMed  Google Scholar 

  72. 72.

    Polascheck, N., Bankstahl, M. & Loscher, W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp. Neurol. 224, 219–233 (2010).

    CAS  PubMed  Google Scholar 

  73. 73.

    Holtman, L. et al. Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy. Epilepsy Res. 84, 56–66 (2009).

    CAS  PubMed  Google Scholar 

  74. 74.

    Ma, L. et al. Aspirin attenuates spontaneous recurrent seizures and inhibits hippocampal neuronal loss, mossy fiber sprouting and aberrant neurogenesis following pilocarpine-induced status epilepticus in rats. Brain Res. 1469, 103–113 (2012).

    CAS  PubMed  Google Scholar 

  75. 75.

    Jiang, J. et al. Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation. Proc. Natl Acad. Sci. USA 110, 3591–3596 (2013).

    CAS  PubMed  Google Scholar 

  76. 76.

    Rojas, A., Ganesh, T., Manji, Z., O’neill, T. & Dingledine, R. Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats. Neuropharmacology 110, 419–430 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Jiang, J. & Dingledine, R. Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection. Trends Pharmacol. Sci. 34, 413–423 (2013).

    CAS  PubMed  Google Scholar 

  78. 78.

    Serhan, C. N., Chiang, N. & Dalli, J. New pro-resolving n-3 mediators bridge resolution of infectious inflammation to tissue regeneration. Mol. Aspects Med. 64, 1–17 (2017).

    PubMed  Google Scholar 

  79. 79.

    Cristante, E. et al. Identification of an essential endogenous regulator of blood-brain barrier integrity, and its pathological and therapeutic implications. Proc. Natl Acad. Sci. USA 110, 832–841 (2013).

    CAS  PubMed  Google Scholar 

  80. 80.

    Musto, A. E., Gjorstrup, P. & Bazan, N. G. The omega-3 fatty acid-derived neuroprotectin D1 limits hippocampal hyperexcitability and seizure susceptibility in kindling epileptogenesis. Epilepsia 52, 1601–1608 (2011).

    CAS  PubMed  Google Scholar 

  81. 81.

    Musto, A. E., Walker, C. P., Petasis, N. A. & Bazan, N. G. Hippocampal neuro-networks and dendritic spine perturbations in epileptogenesis are attenuated by neuroprotectin d1. PLOS ONE 10, e0116543 (2015).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Taha, A. Y., Burnham, W. M. & Auvin, S. Polyunsaturated fatty acids and epilepsy. Epilepsia 51, 1348–1358 (2010).

    CAS  PubMed  Google Scholar 

  83. 83.

    Frigerio, F. et al. n-3 Docosapentaenoic acid-derived protectin D1 promotes resolution of neuroinflammation and arrests epileptogenesis. Brain 141, 3130–3143 (2018).

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Tejada, S. et al. Omega-3 fatty acids in the management of epilepsy. Curr. Top. Med. Chem. 16, 1897–1905 (2016).

    CAS  PubMed  Google Scholar 

  85. 85.

    Li, N., He, J., Schwartz, C. E., Gjorstrup, P. & Bazan, H. E. P. Resolvin E1 improves tear production and decreases inflammation in a dry eye mouse model. J. Ocul. Pharmacol. Ther. 26, 431–439 (2010).

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Gallentine, W. B. et al. Plasma cytokines associated with febrile status epilepticus in children: a potential biomarker for acute hippocampal injury. Epilepsia 58, 1102–1111 (2017). This paper presents a description of potential inflammatory biomarkers of epileptogenesis in children with febrile status epilepticus.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Lugrin, J., Rosenblatt-Velin, N., Parapanov, R. & Liaudet, L. The role of oxidative stress during inflammatory processes. Biol. Chem. 395, 203–230 (2014). This article provides a description of the cellular and molecular mechanisms that link neuroinflammation to oxidative stress.

    CAS  PubMed  Google Scholar 

  88. 88.

    Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

    CAS  PubMed  Google Scholar 

  89. 89.

    Kovac, S., Domijan, A.-M., Walker, M. C. & Abramov, A. Y. Seizure activity results in calcium- and mitochondria-independent ROS production via NADPH and xanthine oxidase activation. Cell Death Dis. 5, e1442 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Pearson, J. N. et al. Reactive oxygen species mediate cognitive deficits in experimental temporal lobe epilepsy. Neurobiol. Dis. 82, 289–297 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Pearson-Smith, J. N., Liang, L.-P., Rowley, S. D., Day, B. J. & Patel, M. Oxidative stress contributes to status epilepticus associated mortality. Neurochem. Res. 42, 2024–2032 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Williams, S., Hamil, N., Abramov, A. Y., Walker, M. C. & Kovac, S. Status epilepticus results in persistent overproduction of reactive oxygen species, inhibition of which is neuroprotective. Neuroscience 303, 160–165 (2015).

    CAS  PubMed  Google Scholar 

  93. 93.

    Kim, J. H. et al. Post-treatment of an NADPH oxidase inhibitor prevents seizure-induced neuronal death. Brain Res. 1499, 163–172 (2013).

    CAS  PubMed  Google Scholar 

  94. 94.

    Terrone, G., Frigerio, F., Balosso, S., Ravizza, T. & Vezzani, A. Inflammation and reactive oxygen species in status epilepticus: biomarkers and implications for therapy. Epilepsy Behav. (2019).

  95. 95.

    Shekh-Ahmad, T. et al. KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain 141, 1390–1403 (2018). This study identifies a novel target for anti-epileptogenesis based on activation of antioxidant mechanisms.

    PubMed  Google Scholar 

  96. 96.

    Puttachary, S. et al. 1400 W, a highly selective inducible nitric oxide synthase inhibitor is a potential disease modifier in the rat kainate model of temporal lobe epilepsy. Neurobiol. Dis. 93, 184–200 (2016).

    CAS  PubMed  Google Scholar 

  97. 97.

    Mazzuferi, M. et al. Nrf2 defense pathway: Experimental evidence for its protective role in epilepsy. Ann. Neurol. 74, 560–568 (2013).

    CAS  PubMed  Google Scholar 

  98. 98.

    Ben-Menachem, E., Kyllerman, M. & Marklund, S. Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies. Epilepsy Res. 40, 33–39 (2000).

    CAS  PubMed  Google Scholar 

  99. 99.

    Hurd, R. W., Wilder, B. J., Helveston, W. R. & Uthman, B. M. Treatment of four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type with N-acetylcysteine. Neurology 47, 1264–1268 (1996).

    CAS  PubMed  Google Scholar 

  100. 100.

    Abbott, J. N. Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol. Neurobiol. 20, 131–147 (2000).

    CAS  PubMed  Google Scholar 

  101. 101.

    Rüber, T. et al. Evidence for peri-ictal blood-brain barrier dysfunction in patients with epilepsy. Brain 141, 2952–2965 (2018).

    PubMed  Google Scholar 

  102. 102.

    Frigerio, F. et al. Long-lasting pro-ictogenic effects induced in vivo by rat brain exposure to serum albumin in the absence of concomitant pathology. Epilepsia 53, 1887–1897 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Weissberg, I. et al. Albumin induces excitatory synaptogenesis through astrocytic TGF-beta/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol. Dis. 78, 115–125 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Kim, S. Y. et al. TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults. Sci. Rep. 7, 7711 (2017).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Bar-Klein, G. et al. Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis. Brain 140, 1692–1705 (2017).

    PubMed  Google Scholar 

  106. 106.

    Bar-Klein, G. et al. Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann. Neurol. 75, 864–875 (2014). This study identifies a novel target for anti-epileptogenesis based on BBB dysfunction.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Okuneva, O. et al. Brain inflammation is accompanied by peripheral inflammation in Cstb-/- mice, a model for progressive myoclonus epilepsy. J. Neuroinflamm. 13, 298 (2016).

    Google Scholar 

  108. 108.

    Lehtinen, M. K. et al. Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1. J. Neurosci. 29, 5910–5915 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Kovács, Z., Dobolyi, A., Juhász, G. & Kékesi, K. A. Lipopolysaccharide induced increase in seizure activity in two animal models of absence epilepsy WAG/Rij and GAERS rats and Long Evans rats. Brain Res. Bull. 104, 7–18 (2014).

    PubMed  Google Scholar 

  110. 110.

    Russo, E. et al. Early molecular and behavioral response to lipopolysaccharide in the WAG/Rij rat model of absence epilepsy and depressive-like behavior, involves interplay between AMPK, AKT/mTOR pathways and neuroinflammatory cytokine release. Brain Behav. Immun. 42, 157–168 (2014).

    CAS  PubMed  Google Scholar 

  111. 111.

    French, J. A. et al. Clinical studies and anti-inflammatory mechanisms of treatments. Epilepsia 58 (Suppl. 3), 69–82 (2017). This article provides a description of the design of clinical trials of anti-inflammatory drugs in epilepsy and a discussion of the issues faced in clinical trials in this new domain.

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Sochocka, M., Diniz, B. S. & Leszek, J. Inflammatory response in the CNS: friend or foe? Mol. Neurobiol. 54, 8071–8089 (2017).

    CAS  PubMed  Google Scholar 

  113. 113.

    Rogawski, M. A. & Loscher, W. The neurobiology of antiepileptic drugs. Nat. Rev. Neurosci. 5, 553–564 (2004).

    CAS  PubMed  Google Scholar 

  114. 114.

    Bialer, M. et al. Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI). Epilepsy Res. 103, 2–30 (2013).

    PubMed  Google Scholar 

  115. 115.

    Kwon, Y. S. et al. Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain. J. Neuroinflamm. 10, 30 (2013).

    CAS  Google Scholar 

  116. 116.

    Iori, V. et al. Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol. Dis. 99, 12–23 (2017).

    CAS  PubMed  Google Scholar 

  117. 117.

    Noé, F. M. et al. Pharmacological blockade of IL-1β/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. Neurobiol. Dis. 59, 183–193 (2013).

    PubMed  Google Scholar 

  118. 118.

    Xu, Z.-H. et al. Interleukin-1 receptor is a target for adjunctive control of diazepam-refractory status epilepticus in mice. Neuroscience 328, 22–29 (2016).

    CAS  PubMed  Google Scholar 

  119. 119.

    Vezzani, A. et al. ICE/caspase 1 inhibitors and IL-1beta receptor antagonists as potential therapeutics in epilepsy. Curr. Opin. Investig. Drugs. 11, 43–50 (2010).

    CAS  PubMed  Google Scholar 

  120. 120.

    Dinarello, C. A., Simon, A. & van der Meer, J. W. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug Discov. 11, 633–652 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Pollard, J. R. et al. The TARC/sICAM5 Ratio in patient plasma is a candidate biomarker for drug resistant epilepsy. Front. Neurol. 3, 181 (2013).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Walker, L. et al. High mobility group Box 1 in the inflammatory pathogenesis of epilepsy: profiling circulating levels after experimental and clinical seizures. Lancet 383, S105 (2014).

    Google Scholar 

  123. 123.

    Wang, K.-Y., Yu, G.-F., Zhang, Z.-Y., Huang, Q. & Dong, X.-Q. Plasma high-mobility group Box 1 levels and prediction of outcome in patients with traumatic brain injury. Clin. Chim. Acta 413, 1737–1741 (2012).

    CAS  PubMed  Google Scholar 

  124. 124.

    Diamond, M. L. et al. IL-1beta associations with posttraumatic epilepsy development: a genetics and biomarker cohort study. Epilepsia 55, 1109–1119 (2014). This article provides a report on CSF and blood levels of IL-1β in patients with neurotrauma as a prognostic marker of post-traumatic epilepsy.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Bartfai, T. et al. Interleukin-1 system in CNS stress: seizures, fever, and neurotrauma. Ann. NY Acad. Sci. 1113, 173–177 (2007).

    CAS  PubMed  Google Scholar 

  126. 126.

    Darrel, V. et al. Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT Study. Ann. Neurol. 75, 178–185 (2014).

    Google Scholar 

  127. 127.

    Dubé, C., Vezzani, A., Behrens, M., Bartfai, T. & Baram, T. Z. Interleukin-1beta contributes to the generation of experimental febrile seizures. Ann. Neurol. 57, 152–155 (2005). This paper presents a demonstration of the causal link between IL-1 system activation and the threshold for febrile seizures in animal models.

    PubMed  PubMed Central  Google Scholar 

  128. 128.

    Heida, J. G. & Pittman, Q. J. Causal links between brain cytokines and experimental febrile convulsions in the rat. Epilepsia 46, 1906–1913 (2005).

    CAS  PubMed  Google Scholar 

  129. 129.

    Hirvonen, J. et al. Increased in vivo expression of an inflammatory marker in temporal lobe epilepsy. J. Nucl. Med. 53, 234–240 (2012).

    CAS  PubMed  Google Scholar 

  130. 130.

    Gershen, L. D. et al. Neuroinflammation in temporal lobe epilepsy measured using positron emission tomographic imaging of translocator protein. JAMA Neurol. 72, 882–888 (2015). This article presents a study in which molecular imaging of neuroinflammation was used in patients with temporal lobe epilepsy to detect the seizure focus.

    PubMed  PubMed Central  Google Scholar 

  131. 131.

    Butler, T. et al. Transient and chronic seizure-induced inflammation in human focal epilepsy. Epilepsia 57, e191–e194 (2016). This study shows the persistence of neuroinflammation in the interictal phase of human epilepsy.

    PubMed  PubMed Central  Google Scholar 

  132. 132.

    Butler, T. et al. Imaging inflammation in a patient with epilepsy due to focal cortical dysplasia. J. Neuroimaging 23, 129–131 (2013).

    PubMed  Google Scholar 

  133. 133.

    Bertoglio, D. et al. Non-invasive PET imaging of brain inflammation at disease onset predicts spontaneous recurrent seizures and reflects comorbidities. Brain. Behav. Immun. 61, 69–79 (2017).

    PubMed  Google Scholar 

  134. 134.

    Nguyen, D.-L. et al. Longitudinal positron emission tomography imaging of glial cell activation in a mouse model of mesial temporal lobe epilepsy: Toward identification of optimal treatment windows. Epilepsia 59, 1234–1244 (2018).

    CAS  PubMed  Google Scholar 

  135. 135.

    Owen, D. R. J. et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J. Nucl. Med. 52, 24–32 (2011).

    CAS  PubMed  Google Scholar 

  136. 136.

    Pascente, R. et al. Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy. Neurobiol. Dis. 93, 146–155 (2016). This study demonstrates molecular neuroimaging of astrocytes to predict epilepsy onset in animal models.

    CAS  PubMed  Google Scholar 

  137. 137.

    Koepp, M. J. et al. Neuroinflammation imaging markers for epileptogenesis. Epilepsia 58 (Suppl. 3), 11–19 (2017).

    PubMed  Google Scholar 

  138. 138.

    Brooks, W. M. et al. Metabolic and cognitive response to human traumatic brain injury: a quantitative proton magnetic resonance study. J. Neurotrauma 17, 629–640 (2000).

    CAS  PubMed  Google Scholar 

  139. 139.

    Garnett, M. R. et al. Early proton magnetic resonance spectroscopy in normal-appearing brain correlates with outcome in patients following traumatic brain injury. Brain 123, 2046–2054 (2000).

    PubMed  Google Scholar 

  140. 140.

    Ashwal, S. et al. Proton spectroscopy detected myoinositol in children with traumatic brain injury. Pediatr. Res. 56, 630–638 (2004).

    CAS  PubMed  Google Scholar 

  141. 141.

    Kumlien, E. et al. Positron emission tomography with [11C]deuterium-deprenyl in temporal lobe epilepsy. Epilepsia 36, 712–721 (1995).

    CAS  PubMed  Google Scholar 

  142. 142.

    Buck, A. et al. Monoamine oxidase B signle-photon emission tomography with 123Ro 43-0463: imaging in volunteers and patients with temporal lobe epilepsy. Eur. J. Nucl. Med. 25, 464–470 (1998).

    CAS  PubMed  Google Scholar 

  143. 143.

    Fabene, P. F. et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat. Med. 14, 1377–1383 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Duffy, B. A. et al. Imaging seizure-induced inflammation using an antibody targeted iron oxide contrast agent. Neuroimage 60, 1149–1155 (2012).

    CAS  PubMed  Google Scholar 

  145. 145.

    Patel, N., Duffy, B. A., Badar, A., Lythgoe, M. F. & Arstad, E. Bimodal imaging of inflammation with SPECT/CT and MRI using iodine-125 labeled VCAM-1 targeting microparticle conjugates. Bioconjug. Chem. 26, 1542–1549 (2015).

    CAS  PubMed  Google Scholar 

  146. 146.

    Galic, M. A., Riazi, K. & Pittman, Q. J. Cytokines and brain excitability. Front. Neuroendocrinol. 33, 116–125 (2012).

    CAS  PubMed  Google Scholar 

  147. 147.

    Vezzani, A. et al. Infections, inflammation and epilepsy. Acta Neuropathol. 131, 211–234 (2016).

    CAS  PubMed  Google Scholar 

  148. 148.

    Yuen, A. W. C., Keezer, M. R. & Sander, J. W. Epilepsy is a neurological and a systemic disorder. Epilepsy Behav. 78, 57–61 (2018).

    PubMed  Google Scholar 

  149. 149.

    Mazarati, A. M., Lewis, M. L. & Pittman, Q. J. Neurobehavioral comorbidities of epilepsy: role of inflammation. Epilepsia 58 (Suppl. 3), 48–56 (2017). This article provides a review of the evidence for involvement of neuroinflammation in neurological comorbidities in epilepsy.

    PubMed  Google Scholar 

  150. 150.

    Kanner, A. M., Mazarati, A. & Koepp, M. Biomarkers of epileptogenesis: psychiatric comorbidities (?). Neurotherapeutics 11, 358–372 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Ravizza, T. et al. WONOEP appraisal: Biomarkers of epilepsy-associated comorbidities. Epilepsia 58, 331–342 (2017).

    PubMed  Google Scholar 

  152. 152.

    Aronica, E. et al. Complement activation in experimental and human temporal lobe epilepsy. Neurobiol. Dis. 26, 497–511 (2007).

    CAS  PubMed  Google Scholar 

  153. 153.

    Sun, F.-J. et al. Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex. J. Neuroinflamm. 13, 85 (2016).

    Google Scholar 

  154. 154.

    Fuso, A. et al. Promoter-specific hypomethylation correlates with IL-1β overexpression in tuberous sclerosis complex (TSC). J. Mol. Neurosci. 59, 464–470 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    van Vliet, E. A. et al. COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats. Neuropharmacology 58, 404–412 (2010).

    PubMed  Google Scholar 

  156. 156.

    van Vliet, E. A., Aronica, E. & Gorter, J. A. Role of blood-brain barrier in temporal lobe epilepsy and pharmacoresistance. Neuroscience 277, 455–473 (2014).

    PubMed  Google Scholar 

  157. 157.

    Eid, T., Lee, T.-S. W., Patrylo, P. & Zaveri, H. P. Astrocytes and glutamine synthetase in epileptogenesis. J. Neurosci. Res. (2018).

  158. 158.

    Boison, D. & Steinhäuser, C. Epilepsy and astrocyte energy metabolism. Glia 66, 1235–1243 (2018).

    PubMed  Google Scholar 

  159. 159.

    Hubbard, J. A., Szu, J. I. & Binder, D. K. The role of aquaporin-4 in synaptic plasticity, memory and disease. Brain Res. Bull. 136, 118–129 (2018).

    CAS  PubMed  Google Scholar 

  160. 160.

    van Stuijvenberg, M., Derksen-Lubsen, G., Steyerberg, E. W., Habbema, J. D. & Moll, H. A. Randomized, controlled trial of ibuprofen syrup administered during febrile illnesses to prevent febrile seizure recurrences. Pediatrics 102, E51 (1998).

    PubMed  Google Scholar 

  161. 161.

    Lance, E. I., Sreenivasan, A. K., Zabel, T. A., Kossoff, E. H. & Comi, A. M. Aspirin use in Sturge-Weber syndrome: side effects and clinical outcomes. J. Child Neurol. 28, 213–218 (2013).

    PubMed  Google Scholar 

  162. 162.

    Bay, M. J., Kossoff, E. H., Lehmann, C. U., Zabel, T. A. & Comi, A. M. Survey of aspirin use in Sturge-Weber syndrome. J. Child Neurol. 26, 692–702 (2011).

    PubMed  Google Scholar 

  163. 163.

    Godfred, R. M. et al. Does aspirin use make it harder to collect seizures during elective video-EEG telemetry? Epilepsy Behav. 27, 115–117 (2013).

    PubMed  Google Scholar 

  164. 164.

    Lagarde, S. et al. Anti-tumor necrosis factor alpha therapy (adalimumab) in Rasmussen’s encephalitis. An open pilot study. Epilepsia 57, 956–966 (2016).

    CAS  PubMed  Google Scholar 

  165. 165.

    Jun, J.-S., Lee, S.-T., Kim, R., Chu, K. & Lee, S. K. Tocilizumab treatment for new onset refractory status epilepticus. Ann. Neurol. 84, 940–945 (2018).

    CAS  PubMed  Google Scholar 

  166. 166.

    Nowak, M. et al. Minocycline as potent anticonvulsivant in a patient with astrocytoma and drug resistant epilepsy. Seizure 21, 227–228 (2012).

    CAS  PubMed  Google Scholar 

  167. 167.

    Bittner, S. et al. Rasmussen encephalitis treated with natalizumab. Neurology 81, 395–397 (2013).

    PubMed  Google Scholar 

  168. 168.

    Sotgiu, S., Murrighile, M. R. & Constantin, G. Treatment of refractory epilepsy with natalizumab in a patient with multiple sclerosis. Case report. BMC Neurol. 10, 84 (2010).

    PubMed  PubMed Central  Google Scholar 

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The authors gratefully acknowledge their sources of support: the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n°602102 (EPITARGET), the Associazione Italiana Contro l’Epilessia (AICE-FIRE) and Citizen United for Research in Epilepsy (CURE).

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A.V. wrote the article. T.R. and S.B. reviewed and collected the recent literature related to animal studies and helped to prepare the updated reference list and the figures.

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Correspondence to Annamaria Vezzani.

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A cytosolic, multiprotein, intracellular complex that assembles upon detection of pathogen-associated molecular patterns and damage-associated molecular patterns, resulting in activation of caspase 1, a protease that is responsible for the maturation and release of IL-1β and IL-18.

Ketogenic diet

A dietary treatment with a high fat content, moderate protein content and low carbohydrate content, mimicking the biochemical changes of starvation. This diet and its variants represent alternative treatments for patients with pharmacoresistant seizures.

Unverricht–Lundborg disease

An autosomal recessive neurodegenerative disease, also called progressive myoclonic epilepsy type 1, caused by mutation of the gene that encodes cystatin B (CSTB) on chromosome 21q22.3. Typical clinical features are myoclonic and tonic–clonic seizures and ataxia.

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Vezzani, A., Balosso, S. & Ravizza, T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol 15, 459–472 (2019).

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