Research progress on the role of inflammatory mediators in the pathogenesis of epilepsy

Abstract

Epilepsy is an abnormal neurologic disorder distinguished by the recurrent manifestation of seizures, and the precise underlying mechanisms for its development and progression remain uncertain. In recent years, the hypothesis that inflammatory mediators and corresponding pathways contribute to seizures has been supported by experimental results. The potential involvement of neuroinflammation in the development of epilepsy has garnered growing interest. This review centers attention on the involvement of inflammatory mediators in the emergence and progression of epilepsy within recent years, focusing on both clinical research and animal models, to enhance comprehension of the intricate interplay between brain inflammation and epileptogenesis.

Keywords

epilepsy / immune reaction / inflammatory mediators / inflammatory signal pathway / seizure

References

[1] Laxer KD, Trinka E, Hirsch LJ, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 2014; 37: 59-70.

[2] Klement W, Garbelli R, Zub E, et al. Seizure progression and inflammatory mediators promote pericytosis and pericyte-microglia clustering at the cerebrovasculature. Neurobiol Dis. 2018; 113: 70-81.

[3] Geis C, Planagumà J, Carreño M, Graus F, Dalmau J. Autoimmune seizures and epilepsy. J Clin Invest. 2019; 129(3): 926-940.

[4] Alyu F, Dikmen M. Inflammatory aspects of epileptogenesis: contribution of molecular inflammatory mechanisms. Acta Neuropsychiatrica. 2017; 29(1): 1-16.

[5] Butler T, Li Y, Tsui W, et al. Transient and chronic seizure-induced inflammation in human focal epilepsy. Epilepsia. 2016; 57(9): e191-e194.

[6] Sokolova TV, Zabrodskaya YM, Litovchenko AV, et al. Relationship between neuroglial apoptosis and neuroinflammation in the epileptic focus of the brain and in the blood of patients with drug-resistant epilepsy. Int J Mol Sci. 2022; 23(20):12561.

[7] Strauss KI, Elisevich KV. Brain region and epilepsy-associated differences in inflammatory mediator levels in medically refractory mesial temporal lobe epilepsy. J Neuroinflammation. 2016; 13(1): 270.

[8] Chen Y, Chen X, Liang Y. Meta-analysis of HMGB1 levels in the cerebrospinal fluid and serum of patients with epilepsy. Neurol Sci. 2023; 44(7): 2329-2337.

[9] Kamaşak T, Dilber B, Yaman SÖ, et al. HMGB-1, TLR4, IL-1R1, TNF-α, and IL-1β: novel epilepsy markers? Epileptic Disord. 2020; 22(2): 183-193.

[10] Li S, Zhao Q, Sun J, et al. Association between high-mobility group box 1 levels and febrile seizures in children: a systematic review and meta-analysis. Sci Rep. 2023; 13(1): 3619.

[11] Wang N, Liu H, Ma B, et al. CSF high-mobility group box 1 is associated with drug-resistance and symptomatic etiology in adult patients with epilepsy. Epilepsy Res. 2021; 177:106767.

[12] Zhu M, Chen J, Guo H, Ding L, Zhang Y, Xu Y. High mobility group protein B1 (HMGB1) and interleukin-1β as prognostic biomarkers of epilepsy in children. J Child Neurol. 2018; 33(14): 909-917.

[13] Xu J, Firouz SM, Farrokhian M, et al. Potential anti-inflammatory effect of anti-HMGB1 in animal models of ICH by downregulating the TLR4 signaling pathway and regulating the inflammatory cytokines along with increasing HO1 and NRF2. Eur J Pharmacol. 2022; 915:174694.

[14] Rosciszewski G, Cadena V, Auzmendi J, et al. Detrimental effects of HMGB-1 require microglial-astroglial interaction: implications for the status epilepticus -induced neuroinflammation. Front Cell Neurosci. 2019; 13:380.

[15] Butler T, Ichise M, Teich AF, et al. Imaging inflammation in a patient with epilepsy due to focal cortical dysplasia. J Neuroimaging. 2013; 23(1): 129-131.

[16] Li D, Zhang X, Liu R, et al. Kainic acid induced hyperexcitability in thalamic reticular nucleus that initiates an inflammatory response through the HMGB1/TLR4 pathway. Neurotoxicology. 2023; 95: 94-106.

[17] Zhao J, Zheng Y, Liu K, et al. HMGB1 is a therapeutic target and biomarker in diazepam-refractory status epilepticus with wide time window. Neurotherapeutics. 2020; 17(2): 710-721.

[18] Scorza CA, Marques MJG, Gomes da Silva S, Naffah-Mazzacoratti MG, Scorza FA, Cavalheiro EA. Status epilepticus does not induce acute brain inflammatory response in the Amazon rodent proechimys, an animal model resistant to epileptogenesis. Neurosci Lett. 2018; 668: 169-173.

[19] Wei J, Liu H, Liu Z, Jiang X, Wang W. The temporal and spatial changes of Th17, tregs, and related cytokines in epilepsy lesions. Appl Bionics Biomech. 2022; 2022: 1-10.

[20] Aulická S, Česká K, Šána J, et al. Cytokine-chemokine profiles in the hippocampus of patients with mesial temporal lobe epilepsy and hippocampal sclerosis. Epilepsy Res. 2022; 180:106858.

[21] Choudhary A, Varshney R, Kumar A, Kaushik K. A prospective study of novel therapeutic targets interleukin 6, tumor necrosis factor α, and interferon γ as predictive biomarkers for the development of posttraumatic epilepsy. World Neurosurgery: X. 2021; 12:100107.

[22] Mochol M, Taubøll E, Aukrust P, Ueland T, Andreassen OA, Svalheim S. Interleukin 18 (IL-18) and its binding protein (IL-18BP) are increased in patients with epilepsy suggesting low-grade systemic inflammation. Seizure. 2020; 80: 221-225.

[23] Ethemoglu O, Calık M, Koyuncu I, et al. Interleukin-33 and oxidative stress in epilepsy patients. Epilepsy Res. 2021; 176:106738.

[24] Talebian A, Hassani F, Nikoueinejad H, Akbari H. Investigating the relationship between serum levels of Interleukin-22 and Interleukin-1 beta with febrile seizure. Iran J Allergy Asthma Immunol. 2020; 19(4): 409-415.

[25] Wu C, Zhang G, Chen L, et al. The role of NLRP3 and IL-1β in refractory epilepsy brain injury. Front Neurol. 2020; 10:1418.

[26] Choi J, Choi SA, Kim SY, et al. Association analysis of interleukin-1β, interleukin-6, and HMGB1 variants with postictal serum cytokine levels in children with febrile seizure and generalized epilepsy with febrile seizure plus. J Clin Neurol. 2019; 15(4): 555-563.

[27] Zaben M, Haan N, Sharouf F, Ahmed A, Sundstrom LE, Gray WP. IL-1β and HMGB1 are anti-neurogenic to endogenous neural stem cells in the sclerotic epileptic human hippocampus. J Neuroinflammation. 2021; 18(1): 218.

[28] Choi J, Kim SY, Kim H, et al. Serum α-synuclein and IL-1β are increased and correlated with measures of disease severity in children with epilepsy: potential prognostic biomarkers? BMC Neurol. 2020; 20(1): 85.

[29] Zhang Q, Li G, Zhao D, Yang P, Shabier T, Tuerxun T. Association between IL-1β and recurrence after the first epileptic seizure in ischemic stroke patients. Sci Rep. 2020; 10(1):13505.

[30] Yamanaka G, Takamatsu T, Morichi S, et al. Interleukin-1β in peripheral monocytes is associated with seizure frequency in pediatric drug-resistant epilepsy. J Neuroimmunol. 2021; 352:577475.

[31] Basnyat P, Peltola M, Raitanen J, et al. Elevated IL-6 plasma levels are associated with GAD antibodies-associated autoimmune epilepsy. Front Cell Neurosci. 2023; 17:1129907.

[32] Chen J, Jin M, Tang L, Liu Y, Ni H. Acute phase serum leptin, adiponectin, interleukin-6, and visfatin are altered in Chinese children with febrile seizures: a cross-sectional study. Front Endocrinol. 2020; 11:531.

[33] Han Y, Yang L, Liu X, Feng Y, Pang Z, Lin Y. HMGB1/CXCL12-mediated immunity and Th17 cells might underlie highly suspected autoimmune epilepsy in elderly individuals. Neuropsychiatr Dis Treat. 2020; 16: 1285-1293.

[34] Bäckström F, Ahl M, Wickham J, Ekdahl CT. Reduced epilepsy development in synapsin 2 knockout mice with autistic behavior following early systemic treatment with interleukin-6 receptor antibody. Epilepsy Res. 2023; 191:107114.

[35] Radpour M, Khoshkroodian B, Asgari T, Pourbadie HG, Sayyah M. 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: 1810-1831.

[36] Ahras-Sifi N, Laraba-Djebari F. Immunomodulatory and protective effects of interleukin-4 on the neuropathological alterations induced by a potassium channel blocker. J Neuroimmunol. 2021; 355:577549.

[37] Kocatürk M, Kirmit A. Evaluation of IL-10, IFN-γ, and thiol-disulfide homeostasis in patients with drug-resistant epilepsy. Neurol Sci. 2022; 43(1): 485-492.

[38] Basnyat P, Pesu M, Söderqvist M, et al. Chronically reduced IL-10 plasma levels are associated with hippocampal sclerosis in temporal lobe epilepsy patients. BMC Neurol. 2020; 20(1): 241.

[39] Choi IY, Cho ML, Cho KO. Interleukin-17A mediates hippocampal damage and aberrant neurogenesis contributing to epilepsy-associated anxiety. Front Mol Neurosci. 2022; 15:917598.

[40] Liang R, Zheng L, Ji T, et al. Elevated serum free IL-18 in neuropsychiatric systemic lupus erythematosus patients with seizure disorders. Lupus. 2022; 31(2): 187-193.

[41] Nazarinia D, Karimpour S, Hashemi P, Dolatshahi M. Neuroprotective effects of royal jelly (RJ) against pentylenetetrazole (PTZ)-induced seizures in rats by targeting inflammation and oxidative stress. J Chem Neuroanat. 2023; 129:102255.

[42] Gillinder L, McCombe P, Powell T, et al. Cytokines as a marker of central nervous system autoantibody associated epilepsy. Epilepsy Res. 2021; 176:106708.

[43] Saengow VE, Chiangjong W, Khongkhatithum C, et al. Proteomic analysis reveals plasma haptoglobin, interferon-γ, and interleukin-1β as potential biomarkers of pediatric refractory epilepsy. Brain Dev. 2021; 43(3): 431-439.

[44] Tang X, Chen X, Li X, Cheng H, Gan J, Liu Z. The TLR4 mediated inflammatory signal pathway might be involved in drug resistance in drug-resistant epileptic rats. J Neuroimmunol. 2022; 365:577802.

[45] Liang W, Wang J, Sui J, et al. Inflammation as a target for the treatment of fever-associated epilepsy in zebrafish larvae. Int Immunopharmacol. 2023; 116:109802.

[46] Cumbres-Vargas IM, Zamudio SR, Pichardo-Macías LA, Ramírez-San Juan E. Thalidomide attenuates epileptogenesis and seizures by decreasing brain inflammation in lithium pilocarpine rat model. Int J Mol Sci. 2023; 24(7):6488.

[47] Qi R, Wang M, Zhong Q, et al. Chronic vagus nerve stimulation (VNS) altered IL-6, IL-1β, CXCL-1 and IL-13 levels in the hippocampus of rats with LiCl-pilocarpine-induced epilepsy. Brain Res. 2022; 1780:147800.

[48] Qin Z, Song J, Lin A, et al. GPR120 modulates epileptic seizure and neuroinflammation mediated by NLRP3 inflammasome. J Neuroinflammation. 2022; 19(1): 121.

[49] Lu Y, Wang W, Ma Y, et al. miR-10a induces inflammatory responses in epileptic hippocampal neurons of rats via PI3K/Akt/mTOR signaling pathway. Neuroreport. 2023; 34(10): 526-534.

[50] Cui H, Zhang W. The neuroprotective effect of miR-136 on Pilocarpine-Induced temporal lobe epilepsy rats by inhibiting Wnt/β-Catenin signaling pathway. Comput Math Methods Med. 2022; 2022: 1-7.

[51] Cerri C, Caleo M, Bozzi Y. Chemokines as new inflammatory players in the pathogenesis of epilepsy. Epilepsy Res. 2017; 136: 77-83.

[52] Bozzi Y, Caleo M. Epilepsy, seizures, and inflammation: role of the C-C motif ligand 2 chemokine. DNA Cell Biol. 2016; 35(6): 257-260.

[53] Labh R, Gupta R, Narang M, Halder S, Kar R. Effect of valproate and add-on levetiracetam on inflammatory biomarkers in children with epilepsy. Epilepsy Behav. 2021; 125:108358.

[54] Altinoz E, Erdemli M, Gul M, et al. Neuroprotection against CCl(4) induced brain damage with crocin in Wistar rats. Biotech Histochem. 2018; 93(8): 623-631.

[55] Lin J, Xu Y, Guo P, et al. CCL5/CCR5-mediated peripheral inflammation exacerbates blood‒brain barrier disruption after intracerebral hemorrhage in mice. J Transl Med. 2023; 21(1): 196.

[56] Du Y, Xiao X, You HZ, et al. Association of high plasma levels of serpin E1, IGFBP2, and CCL5 with refractory epilepsy in children by cytokine profiling. Clin Pediatr. 2023: 63(7): 953-962.

[57] Zhang Z, Li Y, Jiang S, Shi FD, Shi K, Jin WN. Targeting CCL5 signaling attenuates neuroinflammation after seizure. CNS Neurosci Ther. 2023; 29(1): 317-330.

[58] Parajuli B, Horiuchi H, Mizuno T, Takeuchi H, Suzumura A. CCL11 enhances excitotoxic neuronal death by producing reactive oxygen species in microglia. GLIA. 2015; 63(12): 2274-2284.

[59] Gakharia T, Bakhtadze S, Lim M, Khachapuridze N, Kapanadze N. Alterations of plasma pro-inflammatory cytokine levels in children with refractory epilepsies. Children. 2022; 9(10):1506.

[60] Bartolini L, Moran MP, Norato G, et al. Differential activation of neuroinflammatory pathways in children with seizures: a cross-sectional study. Seizure. 2021; 91: 150-158.

[61] Yue J, Wei YJ, Yang XL, Liu SY, Yang H, Zhang CQ. NLRP3 inflammasome and endoplasmic reticulum stress in the epileptogenic zone in temporal lobe epilepsy: molecular insights into their interdependence. Neuropathol Appl Neurobiol. 2020; 46(7): 770-785.

[62] Cristina de Brito Toscano E, Leandro Marciano Vieira É, Boni Rocha Dias B, et al. NLRP3 and NLRP1 inflammasomes are up-regulated in patients with mesial temporal lobe epilepsy and may contribute to overexpression of caspase-1 and IL-β in sclerotic hippocampi. Brain Res. 2021; 1752:147230.

[63] Xiang T, Luo X, Ye L, Huang H, Wu Y. Klotho alleviates NLRP3 inflammasome-mediated neuroinflammation in a temporal lobe epilepsy rat model by activating the Nrf2 signaling pathway. Epilepsy Behav. 2022; 128:108509.

[64] Jiang Q, Tang G, Zhong XM, Ding DR, Wang H, Li JN. Role of Stat3 in NLRP3/caspase-1-mediated hippocampal neuronal pyroptosis in epileptic mice. Synapse. 2021; 75(12):e22221.

[65] Song L, Zhang H, Qu XP, et al. Increased expression of Rho-associated protein kinase 2 confers astroglial Stat3 pathway activation during epileptogenesis. Neurosci Res. 2022; 177: 25-37.

[66] Han CL, Ge M, Liu YP, et al. LncRNA H19 contributes to hippocampal glial cell activation via JAK/STAT signaling in a rat model of temporal lobe epilepsy. J Neuroinflammation. 2018; 15(1): 103.

[67] Han CL, Liu YP, Guo CJ, et al. The lncRNA H19 binding to let-7b promotes hippocampal glial cell activation and epileptic seizures by targeting Stat3 in a rat model of temporal lobe epilepsy. Cell Proliferation. 2020; 53(8):e12856.

[68] Zhang X, Li X, Li B, Sun C, Zhang P. miR-21-5p protects hippocampal neurons of epileptic rats via inhibiting STAT3 expression. Adv Clin Exp Med. 2020; 29(7): 793-801.

[69] Martín-Suárez S, Cortes JM, Bonifazi P. Blockage of STAT3 during epileptogenesis prevents GABAergic loss and imprinting of the epileptic state. Brain. 2023; 146(8): 3416-3430.

[70] Tipton AE, Cruz Del Angel Y, Hixson K, et al. Selective neuronal knockout of STAT3 function inhibits epilepsy progression, improves cognition, and restores dysregulated gene networks in a temporal lobe epilepsy model. Ann Neurol. 2023; 94(1): 106-122.

[71] Swissa E, Serlin Y, Vazana U, Prager O, Friedman A. Blood-brain barrier dysfunction in status epileptics: mechanisms and role in epileptogenesis. Epilepsy Behav. 2019; 101(Pt B):106285.

[72] Yu W, Du Y, Zou Y, Wang X, Stephani U, Lü Y. Smad anchor for receptor activation contributes to seizures in temporal lobe epilepsy. Synapse. 2017; 71(3).

[73] Liu B, Wang Y, He D, et al. LTBP1 gene expression in the cerebral cortex and its neuroprotective mechanism in mice with postischemic stroke epilepsy. Curr Pharm Biotechnol. 2023; 24(2): 317-329.

[74] Zhu X, Yao Y, Yang J, et al. COX-2-PGE(2) signaling pathway contributes to hippocampal neuronal injury and cognitive impairment in PTZ-kindled epilepsy mice. Int Immunopharmacol. 2020; 87:106801.

[75] Rawat C, Kukal S, Dahiya UR, Kukreti R. Cyclooxygenase-2 (COX-2) inhibitors: future therapeutic strategies for epilepsy management. J Neuroinflammation. 2019; 16(1): 197.

[76] Wu Q, Wang H, Liu X, Zhao Y, Zhang J. The role of the negative regulation of microglia-mediated neuroinflammation in improving emotional behavior after epileptic seizures. Front Neurol. 2022; 13:823908.

[77] Yu L, Yang J, Yu W, Cao J, Li X. Rhein attenuates PTZ‑induced epilepsy and exerts neuroprotective activity via inhibition of the TLR4-NFκB signaling pathway. Neurosci Lett. 2021; 758:136002.

[78] Liang XS, Qian TL, Xiong YF, et al. IRAK-M ablation promotes status epilepticus-induced neuroinflammation via activating M1 microglia and impairing excitatory synaptic function. Mol Neurobiol. 2023; 60: 5199-5213.

[79] Hu A, Yuan H, Qin Y, et al. Lipopolysaccharide (LPS) increases susceptibility to epilepsy via interleukin-1 type 1 receptor signaling. Brain Res. 2022; 1793:148052.

[80] 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(4): 586-596.

[81] Dombkowski AA, Cukovic D, Bagla S, et al. TLR7 activation in epilepsy of tuberous sclerosis complex. Inflamm Res. 2019; 68(12): 993-998.

[82] Liu J, Ke P, Guo H, et al. Activation of TLR7-mediated autophagy increases epileptic susceptibility via reduced KIF5A-dependent GABA(A) receptor transport in a murine model. Exp Mol Med. 2023; 55(6): 1159-1173.

[83] Xie Y, Wang M, Shao Y, Chen Y. LncRNA H19 regulates p-glycoprotein expression through the NF-κB signaling pathway in the model of status epilepticus. Neurochem Res. 2023; 48(3): 929-941.

[84] Liu C, Zhao XM, Wang Q, et al. Astrocyte-derived SerpinA3N promotes neuroinflammation and epileptic seizures by activating the NF-κB signaling pathway in mice with temporal lobe epilepsy. J Neuroinflammation. 2023; 20(1): 161.

[85] Do HTT, Bui BP, Sim S, Jung JK, Lee H, Cho J. Anti-Inflammatory and anti-migratory activities of isoquinoline-1-carboxamide derivatives in LPS-treated BV2 microglial cells via inhibition of MAPKs/NF-κB pathway. Int J Mol Sci. 2020; 21(7):2319.

[86] Jia Y, Tang L, Yao Y, et al. Low-intensity exercise combined with sodium valproate attenuates kainic acid-induced seizures and associated co-morbidities by inhibiting NF-κB signaling in mice. Front Neurol. 2022; 13:993405.

[87] Khodaverdian S, Dashtban-Moghadam E, Dabirmanesh B, et al. CD38 and MGluR1 as possible signaling molecules involved in epileptogenesis: a potential role for NAD(+) homeostasis. Brain Res. 2021; 1765:147509.

[88] Li X, Zhou R, Peng H, Peng J, Li Q, Mei M. Microglia PKM2 mediates neuroinflammation and neuron loss in mice epilepsy through the astrocyte C3-neuron C3R signaling pathway. Brain Sci. 2023; 13(2):262.

[89] Wei Y, Chen T, Bosco DB, et al. The complement C3-C3aR pathway mediates microglia-astrocyte interaction following status epilepticus. GLIA. 2021; 69(5): 1155-1169.

[90] Kumari K, Sharma MC, Kakkar A, et al. mTOR pathway activation in focal cortical dysplasia. Ann Diagn Pathol. 2020; 46:151523.

[91] Park S, Zhu J, Jeong KH, Kim WJ. Adjudin prevents neuronal damage and neuroinflammation via inhibiting mTOR activation against pilocarpine-induced status epilepticus. Brain Res Bull. 2022; 182: 80-89.

[92] Zhao Y, Zhao W, Han Y. Inhibition of mTORC2 improves brain injury in epileptic rats by promoting chaperone-mediated autophagy. Epilepsy Res. 2023; 193:107161.

[93] Liu AH, Chu M, Wang YP. Up-regulation of Trem2 inhibits hippocampal neuronal apoptosis and alleviates oxidative stress in epilepsy via the PI3K/Akt pathway in mice. Neurosci Bull. 2019; 35(3): 471-485.

[94] Wang R, An X, Zhao S. Effect of miR-124 on PI3K/Akt signal pathway in refractory epilepsy rats. Cell Mol Biol. 2020; 66(2): 146-152.

[95] Yang J, Feng G, Chen M, et al. Glucosamine promotes seizure activity via activation of the PI3K/Akt pathway in epileptic rats. Epilepsy Res. 2021; 175:106679.

[96] Zhang H, Tao J, Zhang S, Lv X. LncRNA MEG3 reduces hippocampal neuron apoptosis via the PI3K/AKT/mTOR pathway in a rat model of temporal lobe epilepsy. Neuropsychiatr Dis Treat. 2020; 16: 2519-2528.

[97] Feng H, Gui Q, Wu G, et al. Long noncoding RNA Nespas inhibits apoptosis of epileptiform hippocampal neurons by inhibiting the PI3K/Akt/mTOR pathway. Exp Cell Res. 2021; 398(1):112384.

[98] Huang X, Hu Q, Shi H, Zheng Y, Hu R, Guo Q. Everolimus inhibits PI3K/Akt/mTOR and NF-kB/IL-6 signaling and protects seizure-induced brain injury in rats. J Chem Neuroanat. 2021; 114:101960.

[99] Qin H, Buckley JA, Li X, et al. Inhibition of the JAK/STAT pathway protects against α-synuclein-induced neuroinflammation and dopaminergic neurodegeneration. J Neurosci. 2016; 36(18): 5144-5159.

[100] Hu Q, Yan H, Peng F, et al. Genistein protects epilepsy-induced brain injury through regulating the JAK2/STAT3 and Keap1/Nrf2 signaling pathways in the developing rats. Eur J Pharmacol. 2021; 912:174620.

[101] Sandouka S, Saadi A, Singh PK, Olowe R, Shekh-Ahmad T. Nrf2 is predominantly expressed in hippocampal neurons in a rat model of temporal lobe epilepsy. Cell Biosci. 2023; 13(1): 3.

[102] Sandouka S, Saadi A, Olowe R, Singh PK, Shekh-Ahmad T. Nrf2 is expressed more extensively in neurons than in astrocytes following an acute epileptic seizure in rats. J Neurochem. 2023; 165(4): 550-562.

[103] Alvi AM, Al Kury LT, Alattar A, et al. Carveol attenuates seizure severity and neuroinflammation in Pentylenetetrazole-Kindled epileptic rats by regulating the Nrf2 signaling pathway. Oxid Med Cell Longevity. 2021; 2021: 1-19.

[104] Sandouka S, Shekh-Ahmad T. Induction of the Nrf2 pathway by sulforaphane is neuroprotective in a rat temporal lobe epilepsy model. Antioxidants. 2021; 10(11):1702.

[105] Chen X, Bao G, Liu F. Inhibition of USP15 prevent glutamate-induced oxidative damage by activating Nrf2/HO-1 signaling pathway in HT22 cells. Cell Mol Neurobiol. 2020; 40(6): 999-1010.

[106] Hu Y, Wang P, Han K. Hydrogen attenuated inflammation response and oxidative in hypoxic ischemic encephalopathy via Nrf2 mediated the inhibition of NLRP3 and NF-κB. Neuroscience. 2022; 485: 23-36.

[107] Wu Y, Wang Y, Wu Y, Li T, Wang W. Salidroside shows anticonvulsant and neuroprotective effects by activating the Nrf2-ARE pathway in a pentylenetetrazol-kindling epileptic model. Brain Res Bull. 2020; 164: 14-20.

[108] Shi Y, Miao W, Teng J, Zhang L. Ginsenoside Rb1 protects the brain from damage induced by epileptic seizure via Nrf2/ARE signaling. Cell Physiol Biochem. 2018; 45(1): 212-225.

[109] Liu K, Cai GL, Zhuang Z, et al. Interleukin-1β-treated mesenchymal stem cells inhibit inflammation in hippocampal astrocytes through exosome-activated Nrf-2 signaling. Int J Nanomed. 2021; 16: 1423-1434.

[110] Zhang YN, Dong HT, Yang FB, et al. Nrf2-ARE signaling pathway regulates the expressions of A1R and ENT1 in the brain of epileptic rats. Eur Rev Med Pharmacol Sci. 2018; 22(20): 6896-6904.

[111] Qu Z, Su F, Qi X, et al. Wnt/β-catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid-induced epilepsy. Cell Biochem Funct. 2017; 35(7): 472-476.

[112] Rawat K, Gautam V, Sandhu A, Bhatia A, Saha L. Differential regulation of Wnt/β-catenin signaling in acute and chronic epilepsy in repeated low dose lithium-pilocarpine rat model of status epilepticus. Neuroscience. 2023; 535: 36-49.

[113] Sun C, Fu J, Qu Z, et al. Chronic intermittent hypobaric hypoxia restores hippocampus function and rescues cognitive impairments in chronic epileptic rats via Wnt/β-catenin signaling. Front Mol Neurosci. 2021; 13:617143.

[114] Diao L, Yu H, Li H, et al. LncRNA UCA1 alleviates aberrant hippocampal neurogenesis through regulating miR-375/SFRP1-mediated WNT/β-catenin pathway in kainic acid-induced epilepsy. Acta Biochim Pol. 2021; 68(2): 159-167.

[115] Tang H, Wang X. PD-1 is an Immune-inflammatory potential biomarker in cerebrospinal fluid and serum of intractable epilepsy. BioMed Res Int. 2021; 2021: 1-10.

[116] Yang Y, Chen Z, Zhou J, et al. Anti-PD-1 treatment protects against seizure by suppressing sodium channel function. CNS Neurosci Ther. 2023; 30(4):e14504.

[117] Dyńka D, Kowalcze K, Paziewska A. The role of ketogenic diet in the treatment of neurological diseases. Nutrients. 2022; 14(23):5003.

[118] El-Shafie AM, Bahbah WA, Abd El Naby SA, et al. Impact of two ketogenic diet types in refractory childhood epilepsy. Pediatr Res. 2023; 94: 1978-1989.

[119] Shen J, Jiang T, Gao F, Jiang K. Efficacy, retention rate, and influencing factors of ketogenic diet therapy in children with refractory epilepsy: a retrospective study. Neuropediatrics. 2023; 54(1): 37-43.

[120] Gogou M, Pujar S, Nemani T, et al. Antiseizure medication reduction and withdrawal in children with drug-resistant epilepsy after starting the ketogenic diet. Dev Med Child Neurol. 2023; 65(3): 424-430.

[121] Shaaban S, Al-Beltagi M, El Rashidy O, Nassar M, El Gendy Y. Ketogenic diet in childhood epilepsy: clinical algorithm in a tertiary care center. Front Pediatr. 2023; 11:1221781.

[122] He F, Qiu J, Li H, et al. Efficacy of the ketogenic diet in Chinese adults versus children with drug-resistant epilepsy: a pilot study. Epilepsy Behav. 2022; 134:108820.

[123] Alanis Guevara MI, García de Alba García JE, López Alanis AL, González Ojeda A, Fuentes Orozco C. Prospective study of the modified Atkins diet in adult drug-resistant epilepsy: effectiveness, tolerability, and adherence. Neurología (English Edition). 2023.

[124] Devi N, Madaan P, Kandoth N, Bansal D, Sahu JK. Efficacy and safety of dietary therapies for childhood drug-resistant epilepsy: a systematic review and network meta-analysis. JAMA Pediatr. 2023; 177(3): 258-266.

[125] Manral M, Dwivedi R, Gulati S, et al. Safety, efficacy, and tolerability of modified atkins diet in persons with drug-resistant epilepsy: a randomized controlled trial. Neurology. 2023; 100(13): e1376-e1385.

[126] Lanzone J, Boscarino M, Tufo T, et al. Vagal nerve stimulation cycles alter EEG connectivity in drug-resistant epileptic patients: a study with graph theory metrics. Clin Neurophysiol. 2022; 142: 59-67.

[127] Shan M, Mao H, Xie H, et al. Vagus nerve stimulation for drug resistant epilepsy: clinical outcome, adverse events, and potential prognostic factors in a single center experience. J Clin Med. 2022; 11(24):7536.

[128] Li Y, Zhu H, Chen Q, et al. Immediate effects of vagal nerve stimulation in drug-resistant epilepsy revealed by magnetoencephalographic recordings. Brain Connect. 2023; 13(1): 51-59.

[129] Feygina AA, Koshelyaevskaya YN, Dibué M, et al. Efficacy and safety following two or more years of vagus nerve stimulation (VNS Therapy) in pediatric patients with drug-resistant epilepsy enrolled in a Russian VNS registry. Brain Behav. 2023; 13(7):e3076.

[130] Singh C, Rao K, Yadav N, et al. Current cannabidiol safety: a review. Curr Drug Saf. 2023; 18(4): 465-473.

[131] Navarro CE. Cannabis-based magistral formulation is highly effective as an adjuvant treatment in drug-resistant focal epilepsy in adult patients: an open-label prospective cohort study. Neurol Sci. 2023; 44(1): 297-304.

[132] Kochen S, Villanueva M, Bayarres L, Daza-Restrepo A, Gonzalez Martinez S, Oddo S. Cannabidiol as an adjuvant treatment in adults with drug-resistant focal epilepsy. Epilepsy Behav. 2023; 144:109210.

[133] Reddy DS. Therapeutic and clinical foundations of cannabidiol therapy for difficult-to-treat seizures in children and adults with refractory epilepsies. Exp Neurol. 2023; 359:114237.

[134] Wang RF, Xue GF, Hölscher C, et al. Post-treatment with the GLP-1 analogue liraglutide alleviate chronic inflammation and mitochondrial stress induced by status epilepticus. Epilepsy Res. 2018; 142: 45-52.

[135] Erdogan MA, Erdogan A, Erbas O. The anti-seizure effect of liraglutide on Ptz-induced convulsions through its anti-oxidant and anti-inflammatory properties. Neurochem Res. 2023; 48(1): 188-195.

RIGHTS & PERMISSIONS

2024 The Author(s). Ibrain published by Affiliated Hospital of Zunyi Medical University (AHZMU) and Wiley-VCH GmbH.