Neuroinflammatory Nexus of Pediatric Epilepsy

Abstract

A rapidly growing body of evidence supports the premise that neuroinflammation plays an important role in initiating and sustaining seizures in a range of pediatric epilepsies. Clinical and experimental evidence indicates that neuroinflammation is both an outcome and a contributor to seizures. In this manner, seizures that arise from an initial insult (e.g., infection, trauma, and genetic mutation) contribute to an inflammatory response that subsequently promotes recurrent seizures. This cyclic relationship between seizures and neuroinflammation has been described as a “vicious cycle.” Studies of human tissue resected for surgical treatment of refractory epilepsy have reported activated inflammatory and immune signaling pathways, while animal models have been used to demonstrate that key inflammatory mediators lead to increased seizure susceptibility. Further characterization of the molecular mechanisms involved in this cycle may ultimately enable the development of new therapeutic approaches for the treatment of epilepsy. In this brief review, we focus on key inflammatory mediators that have become prominent in recent literature of epilepsy, including newly characterized microRNAs and their potential role in neuroinflammatory signaling.

Keywords

epilepsy - neuroinflammation - cytokine - microRNA

• References

• 1 Boer K, Jansen F, Nellist M. , et al. Inflammatory processes in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex. Epilepsy Res 2008; 78 (01) 7-21
• 2 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 (04) 704-719
• 3 Zhang B, Zou J, Rensing NR, Yang M, Wong M. Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex. Neurobiol Dis 2015; 80: 70-79
• 4 Mühlebner A, van Scheppingen J, Hulshof HM. , et al. Novel histopathological patterns in cortical tubers of epilepsy surgery patients with tuberous sclerosis complex. PLoS One 2016; 11 (06) e0157396
• 5 Boer K, Spliet WG, van Rijen PC, Redeker S, Troost D, Aronica E. Evidence of activated microglia in focal cortical dysplasia. J Neuroimmunol 2006; 173 (1–2): 188-195
• 6 Aronica E, Crino PB. Inflammation in epilepsy: clinical observations. Epilepsia 2011; 52 (Suppl. 03) 26-32
• 7 Iffland II PH, Crino PB. Focal cortical dysplasia: gene mutations, cell signaling, and therapeutic implications. Annu Rev Pathol 2017; 12: 547-571
• 8 Choi J, Koh S. Role of brain inflammation in epileptogenesis. Yonsei Med J 2008; 49 (01) 1-18
• 9 Korff CM, Dale RC. the immune system in pediatric seizures and epilepsies. Pediatrics 2017; 140 (03) e20163534
• 10 Martin KR, Zhou W, Bowman MJ. , et al. The genomic landscape of tuberous sclerosis complex. Nat Commun 2017; 8: 15816
• 11 Rodgers KM, Hutchinson MR, Northcutt A, Maier SF, Watkins LR, Barth DS. The cortical innate immune response increases local neuronal excitability leading to seizures. Brain 2009; 132 (Pt 9): 2478-2486
• 12 Gross A, Benninger F, Madar R. , et al. Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice. Epilepsia 2017; 58 (04) 586-596
• 13 Dupuis N, Mazarati A, Desnous B. , et al. Pro-epileptogenic effects of viral-like inflammation in both mature and immature brains. J Neuroinflammation 2016; 13 (01) 307
• 14 Vezzani A, Balosso S, Ravizza T. Inflammation and epilepsy. Handb Clin Neurol 2012; 107: 163-175
• 15 Marchi N, Lerner-Natoli M. Cerebrovascular remodeling and epilepsy. Neuroscientist 2013; 19 (03) 304-312
• 16 Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T. IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav Immun 2011; 25 (07) 1281-1289
• 17 Vezzani A, Aronica E, Mazarati A, Pittman QJ. Epilepsy and brain inflammation. Exp Neurol 2013; 244: 11-21
• 18 Vitaliti G, Pavone P, Mahmood F, Nunnari G, Falsaperla R. Targeting inflammation as a therapeutic strategy for drug-resistant epilepsies: an update of new immune-modulating approaches. Hum Vaccin Immunother 2014; 10 (04) 868-875
• 19 van Vliet EA, Aronica E, Vezzani A, Ravizza T. Review: Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies. Neuropathol Appl Neurobiol 2018; 44 (01) 91-111
• 20 DiSabato DJ, Quan N, Godbout JP. Neuroinflammation: the devil is in the details. J Neurochem 2016; 139 (Suppl. 02) 136-153
• 21 Graeber MB, Li W, Rodriguez ML. Role of microglia in CNS inflammation. FEBS Lett 2011; 585 (23) 3798-3805
• 22 Streit WJ, Mrak RE, Griffin WS. Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 2004; 1 (01) 14
• 23 Koh S. Role of Neuroinflammation in Evolution of Childhood Epilepsy. J Child Neurol 2018; 33 (01) 64-72
• 24 Xu D, Miller SD, Koh S. Immune mechanisms in epileptogenesis. Front Cell Neurosci 2013; 7: 195
• 25 Zattoni M, Mura ML, Deprez F. , et al. Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. J Neurosci 2011; 31 (11) 4037-4050
• 26 Cusick MF, Libbey JE, Patel DC, Doty DJ, Fujinami RS. Infiltrating macrophages are key to the development of seizures following virus infection. J Virol 2013; 87 (03) 1849-1860
• 27 Iyer A, Zurolo E, Spliet WG. , et al. Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias. Epilepsia 2010; 51 (09) 1763-1773
• 28 Gupta R, Appleton R. Corticosteroids in the management of the paediatric epilepsies. Arch Dis Child 2005; 90 (04) 379-384
• 29 Rosati A, Ilvento L, Lucenteforte E. , et al. Comparative efficacy of antiepileptic drugs in children and adolescents: anetwork meta-analysis. Epilepsia 2018; 59 (02) 297-314
• 30 Pellock JM, Hrachovy R, Shinnar S. , et al. Infantile spasms: a U.S. consensus report. Epilepsia 2010; 51 (10) 2175-2189
• 31 Özkara Ç, Vigevano F. Immuno- and antiinflammatory therapies in epileptic disorders. Epilepsia 2011; 52 (Suppl. 03) 45-51
• 32 Chen J, Cai F, Jiang L, Hu Y, Feng C. A prospective study of dexamethasone therapy in refractory epileptic encephalopathy with continuous spike-and-wave during sleep. Epilepsy Behav 2016; 55: 1-5
• 33 van den Munckhof B, van Dee V, Sagi L. , et al. Treatment of electrical status epilepticus in sleep: apooled analysis of 575 cases. Epilepsia 2015; 56 (11) 1738-1746
• 34 Marchi N, Granata T, Freri E. , et al. Efficacy of anti-inflammatory therapy in a model of acute seizures and in a population of pediatric drug resistant epileptics. PLoS One 2011; 6 (03) e18200
• 35 Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001; 291 (5503): 484-486
• 36 Duse M, Tiberti S, Plebani A. , et al. IgG2 deficiency and intractable epilepsy of childhood. Monogr Allergy 1986; 20: 128-134
• 37 Dalakas MC. Role of IVIg in autoimmune, neuroinflammatory and neurodegenerative disorders of the central nervous system: present and future prospects. J Neurol 2006; 253 (Suppl. 05) V25-V32
• 38 Andersson UG, Björk L, Skansén-Saphir U, Andersson JP. Down-regulation of cytokine production and interleukin-2 receptor expression by pooled human IgG. Immunology 1993; 79 (02) 211-216
• 39 Chen M, Arumugam TV, Leanage G. , et al. Disease-modifying effect of intravenous immunoglobulin in an experimental model of epilepsy. Sci Rep 2017; 7: 40528
• 40 Al Amrani F, Dudley R, Bello-Espinosa LE, Rosenblatt B, Srour M, Sébire G. intravenous immunoglobulin as a treatment for intractable epilepsy secondary to focal cortical dysplasia: a meta-analysis. Pediatr Neurol 2017; 76: 79-81
• 41 Gogou M, Papadopoulou-Alataki E, Spilioti M, Alataki S, Evangeliou A. Clinical applications of intravenous immunoglobulins in child neurology. Curr Pharm Biotechnol 2017; 18 (08) 628-637
• 42 Tang-Wai R, Mailo J, Rosenblatt B. Breaking the cycle: acomparison between intravenous immunoglobulins and high dosage prednisone in the treatment of medically intractable epilepsy in children. Seizure 2017; 47: 34-41
• 43 Matsuura R, Hamano S, Hirata Y, Oba A, Suzuki K, Kikuchi K. Intravenous immunoglobulin therapy is rarely effective as the initial treatment in West syndrome: a retrospective study of 70 patients. J Neurol Sci 2016; 368: 140-144
• 44 Geng J, Dong J, Li Y. , et al. Intravenous immunoglobulins for epilepsy. Cochrane Database Syst Rev 2017; 7: CD008557
• 45 Andersson JP, Andersson UG. Human intravenous immunoglobulin modulates monokine production in vitro. Immunology 1990; 71 (03) 372-376
• 46 Ling ZD, Yeoh E, Webb BT, Farrell K, Doucette J, Matheson DS. Intravenous immunoglobulin induces interferon-gamma and interleukin-6 in vivo. J Clin Immunol 1993; 13 (05) 302-309
• 47 Aukrust P, Müller F, Svenson M, Nordøy I, Bendtzen K, Frøland SS. Administration of intravenous immunoglobulin (IVIG) in vivo--down-regulatory effects on the IL-1 system. Clin Exp Immunol 1999; 115 (01) 136-143
• 48 Inci A, Sahintürk Ünal D, Osman Özeş N, Erin N, Akçakuş M, Oygür N. The efficacy of intravenous immunoglobulin on lipopolysaccharide-induced fetal brain inflammation in preterm rats. Am J Obstet Gynecol 2013; 209 (04) 347.e1-347.e8
• 49 Barratt-Due A, Sokolov A, Gustavsen A. , et al. Polyvalent immunoglobulin significantly attenuated the formation of IL-1β in Escherichia coli-induced sepsis in pigs. Immunobiology 2013; 218 (05) 683-689
• 50 Cameron MJ KD. Cytokines, Chemokines and Their Receptors. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000. –2013. Available at: https://www.ncbi.nlm.nih.gov/books/NBK6294/
• 51 Dinarello CA. Historical insights into cytokines. Eur J Immunol 2007; 37 (Suppl. 01) S34-S45
• 52 de Vries EE, van den Munckhof B, Braun KP, van Royen-Kerkhof A, de Jager W, Jansen FE. Inflammatory mediators in human epilepsy: asystematic review and meta-analysis. Neurosci Biobehav Rev 2016; 63: 177-190
• 53 Basu A, Krady JK, Levison SW. Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res 2004; 78 (02) 151-156
• 54 Rothwell NJ, Luheshi GN. Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci 2000; 23 (12) 618-625
• 55 Stoll G, Jander S, Schroeter M. Detrimental and beneficial effects of injury-induced inflammation and cytokine expression in the nervous system. Adv Exp Med Biol 2002; 513: 87-113
• 56 Vezzani A, Ravizza T, Balosso S, Aronica E. Glia as a source of cytokines: implications for neuronal excitability and survival. Epilepsia 2008; 49 (Suppl. 02) 24-32
• 57 Cogswell JP, Godlevski MM, Wisely GB. , et al. NF-kappa B regulates IL-1 beta transcription through a consensus NF-kappa B binding site and a nonconsensus CRE-like site. J Immunol 1994; 153 (02) 712-723
• 58 Dombkowski AA, Batista CE, Cukovic D. , et al. Cortical tubers: windows into dysregulation of epilepsy risk and synaptic signaling genes by microRNAs. Cereb Cortex 2016; 26 (03) 1059-1071
• 59 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 (02) 279-290
• 60 Shi Y, Zhang L, Teng J, Miao W. HMGB1 mediates microglia activation via the TLR4/NF-κB pathway in coriaria lactone induced epilepsy. Mol Med Rep 2018; 17 (04) 5125-5131
• 61 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 (02) E21
• 62 Hiscott J, Marois J, Garoufalis J. , et al. Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop. Mol Cell Biol 1993; 13 (10) 6231-6240
• 63 Streicher KL, Willmarth NE, Garcia J, Boerner JL, Dewey TG, Ethier SP. Activation of a nuclear factor kappaB/interleukin-1 positive feedback loop by amphiregulin in human breast cancer cells. Mol Cancer Res 2007; 5 (08) 847-861
• 64 Fuso A, Iyer AM, van Scheppingen J. , et al. Promoter-specific hypomethylation correlates with IL-1βoverexpression in tuberous sclerosis complex (TSC). J Mol Neurosci 2016; 59 (04) 464-470
• 65 Vezzani A, Baram TZ. New roles for interleukin-1 Beta in the mechanisms of epilepsy. Epilepsy Curr 2007; 7 (02) 45-50
• 66 Choi J, Nordli Jr DR, Alden TD. , et al. Cellular injury and neuroinflammation in children with chronic intractable epilepsy. J Neuroinflammation 2009; 6: 38
• 67 Varella PP, Santiago JF, Carrete Jr H. , et al. Relationship between fluid-attenuated inversion-recovery (FLAIR) signal intensity and inflammatory mediator's levels in the hippocampus of patients with temporal lobe epilepsy and mesial temporal sclerosis. Arq Neuropsiquiatr 2011; 69 (01) 91-99
• 68 Lachos J, Zattoni M, Wieser HG. , et al. Characterization of the gene expression profile of human hippocampus in mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsy Res Treat 2011; 2011: 758407
• 69 Choi J, Min HJ, Shin JS. Increased levels of HMGB1 and pro-inflammatory cytokines in children with febrile seizures. J Neuroinflammation 2011; 8: 135
• 70 Ravizza T, Vezzani A. Status epilepticus induces time-dependent neuronal and astrocytic expression of interleukin-1 receptor type I in the rat limbic system. Neuroscience 2006; 137 (01) 301-308
• 71 Ravizza T, Boer K, Redeker S. , et al. The IL-1beta system in epilepsy-associated malformations of cortical development. Neurobiol Dis 2006; 24 (01) 128-143
• 72 Basu A, Krady JK, Enterline JR, Levison SW. Transforming growth factor beta1 prevents IL-1beta-induced microglial activation, whereas TNFalpha- and IL-6-stimulated activation are not antagonized. Glia 2002; 40 (01) 109-120
• 73 Ching S, He L, Lai W, Quan N. IL-1 type I receptor plays a key role in mediating the recruitment of leukocytes into the central nervous system. Brain Behav Immun 2005; 19 (02) 127-137
• 74 Shaftel SS, Carlson TJ, Olschowka JA, Kyrkanides S, Matousek SB, O'Banion MK. Chronic interleukin-1beta expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration. J Neurosci 2007; 27 (35) 9301-9309
• 75 Liu X, Yamashita T, Chen Q. , et al. Interleukin 1 type 1 receptor restore: a genetic mouse model for studying interleukin 1 receptor-mediated effects in specific cell types. J Neurosci 2015; 35 (07) 2860-2870
• 76 Xiao Z, Peng J, Wu L, Arafat A, Yin F. The effect of IL-1β on synaptophysin expression and electrophysiology of hippocampal neurons through the PI3K/Akt/mTOR signaling pathway in a rat model of mesial temporal lobe epilepsy. Neurol Res 2017; 39 (07) 640-648
• 77 Chiavegato A, Zurolo E, Losi G, Aronica E, Carmignoto G. The inflammatory molecules IL-1β and HMGB1 can rapidly enhance focal seizure generation in a brain slice model of temporal lobe epilepsy. Front Cell Neurosci 2014; 8: 155
• 78 Somera-Molina KC, Nair S, Van Eldik LJ, Watterson DM, Wainwright MS. Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a ‘two-hit’ seizure model. Brain Res 2009; 1282: 162-172
• 79 Feng B, Tang Y, Chen B. , et al. Transient increase of interleukin-1β after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling. Sci Rep 2016; 6: 21931
• 80 Erta M, Quintana A, Hidalgo J. Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 2012; 8 (09) 1254-1266
• 81 Ringheim GE, Burgher KL, Heroux JA. Interleukin-6 mRNA expression by cortical neurons in culture: evidence for neuronal sources of interleukin-6 production in the brain. J Neuroimmunol 1995; 63 (02) 113-123
• 82 Schöbitz B, Voorhuis DA, De Kloet ER. Localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain. Neurosci Lett 1992; 136 (02) 189-192
• 83 Hirano T, Yasukawa K, Harada H. , et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 1986; 324 (6092): 73-76
• 84 Hirano T, Taga T, Nakano N. , et al. Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). Proc Natl Acad Sci U S A 1985; 82 (16) 5490-5494
• 85 Kishimoto T. The biology of interleukin-6. Blood 1989; 74 (01) 1-10
• 86 Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol 1993; 54: 1-78
• 87 Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of cytokines and gp130. Blood 1995; 86 (04) 1243-1254
• 88 Jones SA. Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol 2005; 175 (06) 3463-3468
• 89 Peltola J, Hurme M, Miettinen A, Keränen T. Elevated levels of interleukin-6 may occur in cerebrospinal fluid from patients with recent epileptic seizures. Epilepsy Res 1998; 31 (02) 129-133
• 90 Peltola J, Palmio J, Korhonen L. , et al. Interleukin-6 and interleukin-1 receptor antagonist in cerebrospinal fluid from patients with recent tonic-clonic seizures. Epilepsy Res 2000; 41 (03) 205-211
• 91 Nowak M, Bauer S, Haag A. , et al. Interictal alterations of cytokines and leukocytes in patients with active epilepsy. Brain Behav Immun 2011; 25 (03) 423-428
• 92 Hulkkonen J, Koskikallio E, Rainesalo S, Keränen T, Hurme M, Peltola J. The balance of inhibitory and excitatory cytokines is differently regulated in vivo and in vitro among therapy resistant epilepsy patients. Epilepsy Res 2004; 59 (2–3): 199-205
• 93 Bauer S, Cepok S, Todorova-Rudolph A. , et al. Etiology and site of temporal lobe epilepsy influence postictal cytokine release. Epilepsy Res 2009; 86 (01) 82-88
• 94 Liimatainen S, Fallah M, Kharazmi E, Peltola M, Peltola J. Interleukin-6 levels are increased in temporal lobe epilepsy but not in extra-temporal lobe epilepsy. J Neurol 2009; 256 (05) 796-802
• 95 Lehtimäki KA, Liimatainen S, Peltola J, Arvio M. The serum level of interleukin-6 in patients with intellectual disability and refractory epilepsy. Epilepsy Res 2011; 95 (1–2): 184-187
• 96 Ishikawa N, Kobayashi Y, Fujii Y, Kobayashi M. Increased interleukin-6 and high-sensitivity C-reactive protein levels in pediatric epilepsy patients with frequent, refractory generalized motor seizures. Seizure 2015; 25: 136-140
• 97 Lehtimäki KA, Keränen T, Palmio J. , et al. Increased plasma levels of cytokines after seizures in localization-related epilepsy. Acta Neurol Scand 2007; 116 (04) 226-230
• 98 Lehtimäki KA, Keränen T, Huhtala H. , et al. Regulation of IL-6 system in cerebrospinal fluid and serum compartments by seizures: the effect of seizure type and duration. J Neuroimmunol 2004; 152 (1–2): 121-125
• 99 Shu HF, Zhang CQ, Yin Q, An N, Liu SY, Yang H. Expression of the interleukin 6 system in cortical lesions from patients with tuberous sclerosis complex and focal cortical dysplasia type IIb. J Neuropathol Exp Neurol 2010; 69 (08) 838-849
• 100 Alapirtti T, Lehtimäki K, Nieminen R. , et al. The production of IL-6 in acute epileptic seizure: avideo-EEG study. J Neuroimmunol 2018; 316: 50-55
• 101 Lehtimäki KA, Peltola J, Koskikallio E, Keränen T, Honkaniemi J. Expression of cytokines and cytokine receptors in the rat brain after kainic acid-induced seizures. Brain Res Mol Brain Res 2003; 110 (02) 253-260
• 102 Vezzani A, Moneta D, Richichi C. , et al. Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis. Epilepsia 2002; 43 (Suppl. 05) 30-35
• 103 Levy N, Milikovsky DZ, Baranauskas G. , et al. Differential TGF-βsignaling in glial subsets underlies IL-6-mediated epileptogenesis in mice. J Immunol 2015; 195 (04) 1713-1722
• 104 Kalueff AV, Lehtimaki KA, Ylinen A, Honkaniemi J, Peltola J. Intranasal administration of human IL-6 increases the severity of chemically induced seizures in rats. Neurosci Lett 2004; 365 (02) 106-110
• 105 Iyer A, Zurolo E, Prabowo A. , et al. MicroRNA-146a: a key regulator of astrocyte-mediated inflammatory response. PLoS One 2012; 7 (09) e44789
• 106 van Scheppingen J, Iyer AM, Prabowo AS. , et al. Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA-derived cell cultures. Glia 2016; 64 (06) 1066-1082
• 107 Prabowo AS, van Scheppingen J, Iyer AM. , et al. Differential expression and clinical significance of three inflammation-related microRNAs in gangliogliomas. J Neuroinflammation 2015; 12: 97
• 108 Aronica E, Fluiter K, Iyer A. , et al. Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. Eur J Neurosci 2010; 31 (06) 1100-1107
• 109 Roncon P, Soukupovà M, Binaschi A. , et al. MicroRNA profiles in hippocampal granule cells and plasma of rats with pilocarpine-induced epilepsy--comparison with human epileptic samples. Sci Rep 2015; 5: 14143
• 110 Gorter JA, Iyer A, White I. , et al. Hippocampal subregion-specific microRNA expression during epileptogenesis in experimental temporal lobe epilepsy. Neurobiol Dis 2014; 62: 508-520
• 111 Kan AA, van Erp S, Derijck AA. , et al. Genome-wide microRNA profiling of human temporal lobe epilepsy identifies modulators of the immune response. Cell Mol Life Sci 2012; 69 (18) 3127-3145
• 112 Iori V, Iyer AM, Ravizza T. , et al. Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol Dis 2017; 99: 12-23
• 113 Sheedy FJ, O'Neill LA. Adding fuel to fire: microRNAs as a new class of mediators of inflammation. Ann Rheum Dis 2008; 67 (Suppl. 03) iii50-iii55
• 114 Quinn SR, O'Neill LA. A trio of microRNAs that control Toll-like receptor signalling. Int Immunol 2011; 23 (07) 421-425
• 115 O'Neill LA, Sheedy FJ, McCoy CE. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol 2011; 11 (03) 163-175
• 116 He X, Jing Z, Cheng G. MicroRNAs: new regulators of Toll-like receptor signalling pathways. BioMed Res Int 2014; 2014: 945169
• 117 Tili E, Michaille JJ, Cimino A. , et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 2007; 179 (08) 5082-5089
• 118 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 (03) 950-958
• 119 Ponomarev ED, Veremeyko T, Barteneva N, Krichevsky AM, Weiner HL. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU.1 pathway. Nat Med 2011; 17 (01) 64-70
• 120 Brennan GP, Dey D, Chen Y. , et al. Dual and opposing roles of microRNA-124 in epilepsy are mediated through inflammatory and NRSF-dependent gene networks. Cell Reports 2016; 14 (10) 2402-2412
• 121 Haenisch S, von Rüden EL, Wahmkow H. , et al. miRNA-187-3p-mediated regulation of the KCNK10/TREK-2 potassium channel in a rat epilepsy model. ACS Chem Neurosci 2016; 7 (11) 1585-1594
• 122 Bot AM, Dębski KJ, Lukasiuk K. Alterations in miRNA levels in the dentate gyrus in epileptic rats. PLoS One 2013; 8 (10) e76051
• 123 Zhang S, Kou Y, Hu C, Han Y. MicroRNA profiling in the dentate gyrus in epileptic rats: the role of miR-187-3p. Medicine (Baltimore) 2017; 96 (22) e6744
• 124 Alsharafi WA, Xiao B, Abuhamed MM, Bi FF, Luo ZH. Correlation between IL-10 and microRNA-187 expression in epileptic rat hippocampus and patients with temporal lobe epilepsy. Front Cell Neurosci 2015; 9: 466
• 125 Bagla S, Cukovic D, Asano E. , et al. A distinct microRNA expression profile is associated with α[¹¹C]-methyl-L-tryptophan (AMT) PET uptake in epileptogenic cortical tubers resected from patients with tuberous sclerosis complex. Neurobiol Dis 2018; 109 (Pt A): 76-87
• 126 Chugani DC. α-methyl-L-tryptophan: mechanisms for tracer localization of epileptogenic brain regions. Biomarkers Med 2011; 5 (05) 567-575
• 127 Juhász C, Buth A, Chugani DC. , et al. Successful surgical treatment of an inflammatory lesion associated with new-onset refractory status epilepticus. Neurosurg Focus 2013; 34 (06) E5
• 128 Talebi F, Ghorbani S, Chan WF. , et al. MicroRNA-142 regulates inflammation and T cell differentiation in an animal model of multiple sclerosis. J Neuroinflammation 2017; 14 (01) 55
• 129 Mandolesi G, De Vito F, Musella A. , et al. miR-142-3p is a key regulator of IL-1β-dependent synaptopathy in neuroinflammation. J Neurosci 2017; 37 (03) 546-561