Electrophysiological and histological investigation of the effect of interleukin-1 receptor antagonist on acute and PTZ kindling model of experimental epilepsy

Year 2026, Volume: 43 Issue: 1 , 8 - 16 , 01.04.2026

Hayriye Soytürk , Ümit Kılıç , Ayşegül Yıldız , Ömür Gülsüm Deniz , Eylem Suveren , Mehtap Ayvacı , Şerif Demir

https://izlik.org/JA52UC75HD

Abstract

This study aimed to electrophysiologically and histopathologically evaluate the effects of the interleukin-1 receptor antagonist (IL-1Ra) on epileptogenesis in acute and chronic pentylenetetrazole (PTZ)-induced seizure models. A total of 42 male rats were divided into seven groups, including acute PTZ and PTZ kindling models. The effects of IL-1Ra (50 mg/kg, intraperitoneal) on seizure activity were assessed using electrocorticographic recordings, analyzing total seizure number, spike-wave number, and spike-wave duration. Histopathological examinations were performed to evaluate neuronal integrity. In the acute PTZ model, IL-1Ra administration resulted in a significant increase in the total number of seizures compared with the PTZ group (p < 0.05), while spike-wave duration was reduced. In contrast, in the PTZ kindling model, IL-1Ra decreased seizure frequency and total spike-wave duration (p < 0.05). Histopathological analysis revealed improved neuronal morphology in both the PTZ+Diazepam and PTZ+IL-1Ra groups compared with the acute PTZ group. These findings indicate that IL-1Ra exerts phase-dependent effects in experimental epilepsy. While early IL-1 receptor blockade may aggravate seizure frequency in the acute phase, it appears to attenuate epileptiform activity and provide partial neuroprotection in the chronic stage of epileptogenesis. The results underscore the importance of timing and inflammatory context in cytokine-targeted therapeutic strategies.

Keywords

Neuroinflammation , Epilepsy , IL-1Ra , Electrophysiology , Histopathology

Ethical Statement

"All experimental animals have been treated based on the guiding principles approved by the animal ethical committee of Bolu Abant Izzet Baysal University"(2023/18)

References

• Karabulut S, Bayramov R, Korkmaz Bayramov K, Filiz AK, TAS, OE. Effect of the allopregnanolone and allotetrahydrodeoxycorticosteron on spike-wave discharges in the EEG of absence epilepsy rat models. Gen Physiol Biophys. 2018;37(2):205-211. doi:10.4149/gpb_2017041
• Laxer KD, Trinka E, Hirsch LJ, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59-70. doi:10.1016/j.yebeh.2014.05.031
• Josephson CB, Jetté N. Psychiatric comorbidities in epilepsy. Int Rev Psychiatry. 2017;29(5):409-424. doi:10.1080/09540261.2017.1302412
• Alyu F, Dikmen M. Inflammatory aspects of epileptogenesis: Contribution of molecular inflammatory mechanisms. Acta Neuropsychiatr. 2017;29(1):1-16. doi:10.1017/neu.2016.47
• Dey A, Kang X, Qiu J, Du Y, et al. Anti-inflammatory small molecules to treat seizures and epilepsy: From bench to bedside. Trends Pharmacol Sci. 2017;37(6):463-484. doi:10.1016/j.tips.2016.03.001
• Vezzani A, Aronica E, Mazarati A, Pittman QJ. Epilepsy and brain inflammation. Exp Neurol. 2013;244:11-21. doi:10.1016/j.expneurol.2011.09.033
• Hopkins SJ, Rothwell NJ. Cytokines and the nervous system I: Expression and recognition. Trends Neurosci. 1995;18(2):83-88. doi:10.1016/0166-2236(95)80029-2
• Lehtimäki KA, Keränen T, Palmio J, et al. Increased plasma levels of cytokines after seizures in localization-related epilepsy. Acta Neurol Scand. 2007;116(4):226-230. doi:10.1111/j.1600-0404.2007.00882.x
• Kobylarek D, Iwanowski P, Lewandowska Z, et al. Advances in the potential biomarkers of epilepsy. Front Neurol. 2019;10:685. doi:10.3389/fneur.2019.00685
• Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol. 2019;15(8):459-472. doi:10.1038/s41582-019-0217-x
• de Vries EE, van den Munckhof B, Braun KPJ, van Royen-Kerkhof A, de Jager W, Jansen FE. Inflammatory mediators in human epilepsy: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2016;63:177-190. doi:10.1016/j.neubiorev.2016.02.007
• De Simoni MG, Perego C, Ravizza T, et al. Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur J Neurosci. 2000;12(7):2623-2633. doi:10.1046/j.1460- 9568.2000.00140.x
• Shen Y, Peng W, Chen Q, et al. Anti-inflammatory treatment with a soluble epoxide hydrolase inhibitor attenuates seizures and epilepsy-associated depression in the LiCl-pilocarpine post-status epilepticus rat model. Brain Behav Immun. 2019;81:535-544. doi:10.1016/j.bbi.2019.07.014
• Rijkers K, Majoie HJ, Hoogland G, Kenis G, De Baets M, Vles JS. The role of interleukin-1 in seizures and epilepsy: A critical review. Exp Neurol. 2009;216(2):258-271. doi:10.1016/j.expneurol.2008.12.014
• Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol. 2005;5(8):629-640. doi:10.1038/nri1664
• Minami M, Kuraishi Y, Yamaguchi T, Nakai S, Hirai Y, et al. Convulsants induce interleukin-1 beta messenger RNA in rat brain. Biochem Biophys Res Commun. 1990;171(2):832-837
• Nishiyori A, Minami M, Takami S, Satoh M. Type 2 interleukin-1 receptor mRNA is induced by kainic acid in the rat brain. Mol Brain Res. 1997;50(1-2):237-245. doi:10.1016/S0169-328X(97)00195-2
• Eriksson C, Winblad B, Schultzberg M. Kainic acid-induced expression of interleukin-1 receptor antagonist mRNA in the rat brain. Mol Brain Res. 1998;58(1-2):195-208. doi:10.1016/S0169-328X(98)00125-9
• Vezzani A, Conti M, De Luigi A, et al. Interleukin-1β immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: Functional evidence for enhancement of electrographic seizures. J Neurosci. 1999;19(12):5054-5065. doi:10.1523/jneurosci.19-12-05054.1999
• Vezzani A, Moneta D, Conti M, et al. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci U S A. 2000;97(21):11534-11539. doi:10.1073/pnas.190206797
• 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. doi:10.1016/j.nbd.2016.12.007
• 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(2):129-133. doi:10.1016/S0920-1211(98)00024-2
• 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(3):205-211. doi:10.1016/S0920-1211(00)00140-6
• Dinarello CA, Simon A, van der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633-652. doi:10.1038/nrd3800
• Vezzani A, Balosso S, Ravizza T. The role of cytokines in the pathophysiology of epilepsy. Brain Behav Immun. 2008;22(6):797-803. doi:10.1016/j.bbi.2008.03.009
• Löscher W, Klitgaard H, Twyman RE, Schmidt D. New avenues for anti-epileptic drug discovery and development. Nat Rev Drug Discov. 2013;12(10):757-776. doi:10.1038/nrd4126
• Wang X, Liu Y, Li M, et al. Neuroinflammation catching nanobubbles for microglia-neuron unit modulation against epilepsy. Biomaterials. 2023;302:122302. doi:10.1016/j.biomaterials.2023.122302
• Dyomina AV, Zubareva OE, Smolensky IV, et al. Anakinra reduces epileptogenesis, provides neuroprotection, and attenuates behavioral impairments in rats in the lithium-pilocarpine model of epilepsy. Pharmaceuticals (Basel). 2020;13(11):340. doi:10.3390/ph13110340
• Yıldız A, Soytürk H, Him A. Exploring the role of TRP channels and neurotrophic factors in epileptogenesis: Insights from diverse seizure models. Neurochem J. 2024;18:459-468. doi:10.1134/S1819712424700065
• Davoudi M, Shojaei A, Palizvan MR, Javan M, Mirnajafi-Zadeh J. Epilepsy Res. 2013;106:54-63. doi:10.1016/j.eplepsyres.2013.03.016
• Chen Y, He X, Sun Q, Fang Z, Zhou L. Brain Behav. 2017;7:e00727. doi:10.1002/brb3.727
• Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117(14):3720- 3732. doi:10.1182/blood-2010-07-273417
• Weber A, Wasiliew P, Kracht M. Interleukin-1 pathway. Sci Signal. 2010;3(105):cm1. doi:10.1126/scisignal.3105cm1
• Girard S, Kadhim H, Larouche A, Roy M, Gobeil F, Sébire G. Pro-inflammatory disequilibrium of the IL-1β/IL-1ra ratio in an experimental model of perinatal brain damages induced by lipopolysaccharide and hypoxia-ischemia. Cytokine. 2008;43(1):54-62. doi:10.1016/j.cyto.2008.04.007
• 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. Mol Brain Res. 2003;110(2):253-260. doi:10.1016/S0169- 328X(02)00654-X
• Młodzikowska-Albrecht J, Steinborn B, Zarowski M. Cytokines, epilepsy, and antiepileptic drugs: Is there a mutual influence? Pharmacol Rep. 2007;59(2):129-138
• Sheng JG, Boop FA, Mrak RE, Griffin WST. Increased neuronal β-amyloid precursor protein expression in human temporal lobe epilepsy: Association with interleukin-1α immunoreactivity. J Neurochem. 1994;63(5):1872-1879. doi:10.1046/j.1471-4159.1994.63051872.x
• Uludag IF, Bilgin S, Zorlu Y, Tuna G, Kirkali G. Interleukin-6, interleukin-1 beta and interleukin-1 receptor antagonist levels in epileptic seizures. Seizure. 2013;22(6):457-461. doi:10.1016/j.seizure.2013.03.004
• 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. doi:10.1016/j.jneuroim.2004.01.024
• Klein P, Dingledine R, Aronica E, et al. Commonalities in epileptogenic processes from different acute brain insults: Does it translate? Epilepsia. 2018;59(1):37-66. doi:10.1111/epi.13965
• Łukawski K, Czuczwar SJ. Oxidative stress and neurodegeneration in animal models of seizures and epilepsy. Antioxidants. 2023;12(5):1-29. doi:10.3390/antiox12051049.