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Cytokines and Absence Seizures in a Genetic Rat Model

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Neurophysiology Aims and scope

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 The action of tiagabine was potentiated by earlier IL-1β injection, even when IL-1β was no longer active.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

  1. 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).

    Article  PubMed  CAS  Google Scholar 

  2. N. C. Danbolt, “Glutamate uptake,” Prog. Neurobiol., 65, 1-105 (2001).

    Article  PubMed  CAS  Google Scholar 

  3. N. J. Rothwell and S. J. Hopkins, “Cytokines and the nervous system II, Actions and mechanisms of action,” Trends Neurosci., 18, 130-136 (1995).

    Article  PubMed  CAS  Google Scholar 

  4. A. Vezzani and T. Granata, “Brain inflammation in epilepsy, experimental and clinical evidence,” Epilepsia, 46, 1724-1743 (2005).

    Article  PubMed  CAS  Google Scholar 

  5. M. Hauf, R. Wiest, A. Nirkko, et al., “Dissociation of epileptic and inflammatory activity in Rasmussen Encephalitis,” Epilepsy Res., 83, 265-268 (2009).

    Article  PubMed  Google Scholar 

  6. 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).

    Article  PubMed  Google Scholar 

  7. 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).

    Article  PubMed  Google Scholar 

  8. 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).

    Article  PubMed  CAS  Google Scholar 

  9. 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).

    Article  PubMed  CAS  Google Scholar 

  10. A. Vezzani, S. Balosso, and T. Ravizza, “The role of cytokines in the pathophysiology of epilepsy,” Brain Behav. Immunol., 22, 797-803 (2008).

    Article  CAS  Google Scholar 

  11. 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).

    Article  PubMed  CAS  Google Scholar 

  12. 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).

    Article  PubMed  CAS  Google Scholar 

  13. 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).

    Article  PubMed  CAS  Google Scholar 

  14. 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).

    Article  PubMed  CAS  Google Scholar 

  15. 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).

    Article  PubMed  CAS  Google Scholar 

  16. 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).

    CAS  Google Scholar 

  17. 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).

    Article  PubMed  CAS  Google Scholar 

  18. 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).

    Article  PubMed  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. 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).

    Article  PubMed  Google Scholar 

  21. 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).

    Article  PubMed  CAS  Google Scholar 

  22. 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).

    Article  PubMed  Google Scholar 

  23. 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).

    Article  PubMed  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. 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).

    Article  PubMed  CAS  Google Scholar 

  26. N. J. Rothwell and G.N. Luheshi, “Interleukin 1 in the brain, biology, pathology and therapeutic target,” Trends Neurosci., 23, 618-625 (2000).

    Article  PubMed  CAS  Google Scholar 

  27. J. Szelényi, “Cytokines and the central nervous system,” Brain Res. Bull., 54, 329-338 (2001).

    Article  PubMed  Google Scholar 

  28. 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).

    Article  PubMed  CAS  Google Scholar 

  29. 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).

    Article  PubMed  CAS  Google Scholar 

  30. 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.

    Google Scholar 

  31. E. L. J. M. van Luijtelaar and A. M. L. Coenen, “Circadian rhythmicity in absence epilepsy in rats,” Epilepsy Res., 2, 331-336 (1998).

    Article  Google Scholar 

  32. 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).

    Article  PubMed  Google Scholar 

  33. 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).

    Article  PubMed  CAS  Google Scholar 

  34. 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).

    Article  CAS  Google Scholar 

  35. 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).

    PubMed  CAS  Google Scholar 

  36. 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).

    PubMed  CAS  Google Scholar 

  37. 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).

    Article  PubMed  CAS  Google Scholar 

  38. 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).

    Article  PubMed  CAS  Google Scholar 

  39. 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).

    Article  PubMed  CAS  Google Scholar 

  40. 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).

    Google Scholar 

  41. 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).

    Article  PubMed  CAS  Google Scholar 

  42. 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).

    Article  PubMed  CAS  Google Scholar 

  43. 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).

    Article  PubMed  CAS  Google Scholar 

  44. 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).

    Article  PubMed  CAS  Google Scholar 

  45. 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).

    Article  PubMed  CAS  Google Scholar 

  46. 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).

    Article  PubMed  CAS  Google Scholar 

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Correspondence to G. van Luijtelaar.

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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

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