We investigated the role of two cytokines, IL-1β and TNF-α, in the development of absence seizures using a genetic model of absence epilepsy in WAG/Rij rats. We administered these cytokines to animals systemically and measured the number of spike-wave discharges (SWDs) in the EEG. We also coadministered IL-1β with the GABA reuptake inhibitor tiagabine and measured the levels of IL-1β and TNF-α in the brain and blood plasma of 2-, 4-, and 6-month-old WAG/Rij rats and animals that served as a non-epileptic control (ACI). We found that IL-1β induced a significant increase in SWDs 2-5 h after administration, while TNF-α enhanced SWDs much later. Both cytokines enhanced passive behavior; body temperature was elevated only after TNF-α. The action of tiagabine was potentiated by earlier IL-1β injection, even when IL-1β was no longer active. Young WAG/Rij rats showed higher levels of TNF-α in blood serum than young ACI rats; the effects in the brain tended to be opposite. The marked differences in timing of the increase in SWDs suggest different time scales for the action of both cytokines tested. It is proposed that the results found after TNF-α are due to the de novo synthesis of IL-1β. TNF-α may possess neuroprotective effects. IL-1β might increase GABA-ergic neurotransmission. The changes in the efficacy of antiepileptic drugs related to changes in the cytokine systems may have some clinical relevance.
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References
K. Schotanus, G. M. Holtkamp, R. H. Meloen, et al., “Domains of rat Il-1ß involved in type I receptor binding,” Endocrinology, 136, 332-339 (1995).
N. C. Danbolt, “Glutamate uptake,” Prog. Neurobiol., 65, 1-105 (2001).
N. J. Rothwell and S. J. Hopkins, “Cytokines and the nervous system II, Actions and mechanisms of action,” Trends Neurosci., 18, 130-136 (1995).
A. Vezzani and T. Granata, “Brain inflammation in epilepsy, experimental and clinical evidence,” Epilepsia, 46, 1724-1743 (2005).
M. Hauf, R. Wiest, A. Nirkko, et al., “Dissociation of epileptic and inflammatory activity in Rasmussen Encephalitis,” Epilepsy Res., 83, 265-268 (2009).
Z. Kovács, K. A. Kékesi, N. Szilágyi, et al., “Facilitation of spike-wave discharge activity by lipopolysaccharides in Wistar Albino Glaxo/Rijswijk rats,” Neuroscience, 140, 731-742 (2006).
B. G. van Engelen, C. M. Weemaes, W. O. Renier, et al., ”A dysbalanced immune system in cryptogenic Lennox-Gastaut syndrome,” Scand. J. Immunol., 41, 209-213 (1995).
M. Sayyah, S. Beheshti, M. A. Shokrgozar, et al., “Antiepileptogenic and anticonvulsant activity of interleukin-1 beta in amygdala-kindled rats,” Exp. Neurol., 191, 145-153 (2005).
A. Vezzani, D. Moneta, C. Richichi, et al., “Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis,” Epilepsia, 43, S 5, 30-35 (2002).
A. Vezzani, S. Balosso, and T. Ravizza, “The role of cytokines in the pathophysiology of epilepsy,” Brain Behav. Immunol., 22, 797-803 (2008).
M. Minami, Y. Kuraishi, and M. Satoh, “Effects of kainic acid on messenger RNA levels of IL-1 beta, IL-6, TNF alpha and LIF in the rat brain,” Biochem. Biophys. Res. Commun., 176, 593-598 (1991).
M. Minami, Y. Kuraishi, T. Yamaguchi, et al., “Convulsants induce interleukin-1 beta messenger RNA in rat brain,” Biochem. Biophys. Res. Commun., 171, 832-837 (1990).
C. R. Plata-Salaman, S. E. Ilyin, N. P. Turrin, et al., “Kindling modulates the IL-1β system, TNF-α, TGF-b1, and neuropeptide mRNA in specific brain regions,” Mol. Brain Res., 75, 248-258 (2000).
K. Rijkers, H. J. Majoie, G. Hoogland, et al., ”The role of interleukin-1 in seizures and epilepsy: a critical review,” Exp. Neurol., 216, 258-271 (2009).
A. A. Shandra, L. S. Godlevsky, R. S. Vastyanov, et al., “The role of TNF-α in amygdala kindled rats,” Neurosci. Res., 42, 147-153 (2002).
Y. Yuhas, L. Shulman, A. Weizman, et al., “Involvement of tumor necrosis factor alpha and interleukin-1beta in enhancement of pentylenetetrazole-induced seizures caused by Shigella dysenteriae,” Infect. Immunol., 67, 1455-1460 (1999).
J. L. Jankowsky and P. H. Patterson, “The role of cytokines and growth factors in seizures and their sequelae,” Prog. Neurobiol., 63, 125-149 (2001).
M. G. de Simoni, C. Perego, T. Ravizza, et al., “Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus,” Eur. J. Neurosci., 12, 2623-2633 (2000).
A. M. L. Coenen and E. L. J. M. van Luijtelaar, “Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats,” Behav. Genetics, 33, 635-655 (2003).
G. van Luijtelaar and E. Sitnikova, “Global and focal aspects of absence epilepsy: the contribution of genetic models,” Neurosci. Biobehav. Rev., 30, 983-1003 (2006).
A. M. Coenen and E. L. van Luijtelaar, ”The WAG/Rij rat model for absence epilepsy, age and sex factors,” Epilepsy Res., 1, 297-301 (1987).
E. L. J. M. van Luijtelaar and A. M. L. Coenen, “Two types of electrocortical paroxysms in an inbred strain of rats,” Neurosci. Lett., 70, 393-397 (1986).
N. M. de Bruin, E. L. van Luijtelaar, S. J. Jansen, et al., “Dopamine characteristics in different rat genotypes, the relation to absence epilepsy,” Neurosci. Res., 38, 165-173 (2000).
U. Schridde and G. van Luijtelaar, “The influence of strain and housing on two types of spike-wave discharges in rats,” Genes, Brain, Behav., 3, 1-7 (2004).
W. A. Banks, A. Moinuddin, and J. E. Morley, “Regional transport of TNF-α across the blood-brain barrier in young ICR and young and aged SAMP8 mice,” Neurobiol. Aging, 22, 671-676 (2001).
N. J. Rothwell and G.N. Luheshi, “Interleukin 1 in the brain, biology, pathology and therapeutic target,” Trends Neurosci., 23, 618-625 (2000).
J. Szelényi, “Cytokines and the central nervous system,” Brain Res. Bull., 54, 329-338 (2001).
J. M. Krueger, J. Fang, P. Taishi, et al., “Sleep – a physiological role for IL-1β and TNF-α,” Ann. N. Y. Acad. Sci., 856, 148-159 (1998).
A. M. L. Coenen, E. M. H. Blezer, and E. L. J. M. van Luijtelaar, “Effects of the GABA-uptake inhibitor tiagabine on electroencephalogram, spike-wave discharges and behavior of rats,” Epilepsy Res., 21, 89-94 (1995).
A. Depaulis and G. van Luijtelaar, “Genetic models of absence epilepsy in the rat,” in: Models of Seizures and Epilepsy, A. Pitkänen, P. A. Schwartkroin, and S. L. Moshé (eds.), Elsevier, Amsterdam (2006), pp. 233-248.
E. L. J. M. van Luijtelaar and A. M. L. Coenen, “Circadian rhythmicity in absence epilepsy in rats,” Epilepsy Res., 2, 331-336 (1998).
E. L. van Luijtelaar, R. Dirksen, T. B. Vree, and F. van Haaren, “Effects of acute and chronic cocaine administration on EEG and behavior in intact and castrated male and intact and ovariectomized female rats,” Brain Res. Bull., 40, 43-50 (1996).
L. P. Noldus, R. J. Trienes, A. H. Hendriksen, et al., “The Observer Video-Pro, new software for the collection, management, and presentation of time-structured data from videotapes and digital media files,” Behav. Res. Methods Instrum. Comput., 32, 197-206 (2000).
L. S. Godlevsky, E. V. Kobolev, and I. V. Smirnov, “Effect of bacterial lypopolysaccharide on penicillin-induced seizure activity in rats,”Neurophysiology, 40, No. 3, 199-203 (2008).
A. Vezzani, M. Conti, A. de Luigi, 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).
D. Shemi, A. N. Azab, and J. Kaplanski, “Time-dependent effect of LPS on PGE2 and TNF-alpha production by rat glial brain culture: influence of COX and cytokine inhibitors,” J. Endotoxin Res., 6, 377-381 (2000).
U. Schridde and G. van Luijtelaar, “Corticosterone increases spike-wave discharges in a dose- and time-dependent manner in WAG/Rij rats,” Pharmacol. Biochem. Behav., 78, 369-375 (2004).
E. A. Tolmacheva and G. van Luijtelaar, “The role of ovarian steroid hormones in the regulation of basal and stress induced absence seizures,” J. Steroid Biochem. Mol. Biol., 104, 281-288 (2007).
B. Przewlocka, W. Lason, J. Turchan, et al., “Anatomical and functional aspects of mu opioid receptors in epileptic WAG/Rij rats,” Epilepsy Res., 29, 167-173 (1998).
M. J. van der Meer, C. G. Sweep, G. J. Pesman, et al., “Synergism between IL-1 beta and TNF-α on the activity of the pituitary-adrenal axis and on food intake of rats,” Am. J. Physiol., 268, No. 4, 551-557 (1995).
A. M. Coenen, W. H. Drinkenburg, B. W. Peeters, et al., “Absence epilepsy and the level of vigilance in rats of the WAG/Rij strain,” Neurosci. Biobehav. Rev., 15, 259-263 (1991).
I. C. Hellstrom, M. Danik, G. N. Luheshi, and S. Williams, “Chronic LPS exposure produces changes in intrinsic membrane properties and a sustained IL-beta-dependent increase in GABAergic inhibition in hippocampal CA1 pyramidal neurons,” Hippocampus, 15, 656-664 (2005).
M. Inoue, B. W. Peeters, E. L. van Luijtelaar, et al., “Spontaneous occurrence of spike-wave discharges in five inbred strains of rats,” Physiol. Behav., 48, 199-201 (1990).
J. Peltola, M. Hurme, A. Miettinen, and T. Keränen, “Elevated levels of interleukin-6 may occur in cerebrospinal fluid from patients with recent epileptic seizures,” Epilepsy Res., 31, 129-133 (1998).
J. Peltola, J. Palmio, L. Korhonen, et al., “Interleukin-6 and interleukin-1 receptor antagonist in cerebrospinal fluid from patients with recent tonic-clonic seizures,” Epilepsy Res., 41, 205-211 (2000).
L. Marchetti, M. Klein, K. Schlett, et al., “Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-Daspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway,” J. Biol. Chem., 279, 32869-32881 (2004).
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Neirofiziologiya/Neurophysiology, Vol. 43, No. 6, pp. 554-563, November-December, 2011.
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van Luijtelaar, G., Lyashenko, S., Vastyanov, R. et al. Cytokines and Absence Seizures in a Genetic Rat Model. Neurophysiology 43, 478–486 (2012). https://doi.org/10.1007/s11062-012-9252-6
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DOI: https://doi.org/10.1007/s11062-012-9252-6