Mediator / Acute seizures* / Chronic seizures‡ / Kindling / References
NFκB / + / n.a. / n.a. / 1–3
Interleukins / + / + / + / 1,2,4–13
Interferons / = / n.a. / + / 1,14
TNF / + / + / + / 1,8,10,11
Complement system / + / + / n.a. / 15–17
COX-2/PGs / + / + / + / 1,2,16,18–25
Chemokines / + / + / n.a. / 1,16,26–30
Adhesion molecules / + / + / + / 10,31–33
Plasminogen activator§ / + / + / + / 16,34–36
HMGB1 / + / + / n.a. / 37
TLR2/TLR4 / + / + / n.a. / 1,37
mTOR / + / + / n.a. / 38,39
*Acute seizures include both short discrete seizures and status epilepticus (i.e. seizure lasting over 30 min).‡Chronic seizures refer to spontaneous recurrent seizures in chronic epileptic rats or mice. §Tissue and urokinase plasminogen activators. Abbreviations: + or = means increase or no change compared with control specimens; n.a., data not available; COX-2, cyclooxygenase 2; HMGB1, high mobility group box 1; mTOR, mammalian target of rapamycin; NFκB, nuclear factor κB; PGs, prostaglandins; TLR, Toll-like receptor; TNF, tumor necrosis factor.
1. Turrin, N.P. & Rivest, S. Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy. Neurobiol. Dis.16, 321–334 (2004).
2.Voutsinos-Porche, B. et al. Temporal patterns of the cerebral inflammatory response in the rat lithium–pilocarpine model of temporal lobe epilepsy. Neurobiol. Dis.17, 385–402 (2004).
3.Unlap, T. & Jope, R.S. Inhibition of NFκB DNA binding activity by glucocorticoids in rat brain. Neurosci. Lett.198, 41–44 (1995).
4.Vezzani, A. et al. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc. Natl Acad. Sci. USA97, 11534–11539 (2000).
5.Ravizza, T. et al. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol. Dis.29, 142–160 (2008).
6.Minami, M., Kuraishi, Y. & Satoh, M. Effects of kainic acid on messenger RNA levels of IL-1β, IL-6, TNFα and LIF in the rat brain. Biochem. Biophys. Res. Commun.176, 593–598 (1991).
7.Vezzani, 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.19, 5054–5065 (1999).
8.De Simoni, M.G. et al. Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur. J. Neurosci.12, 2623–2633 (2000).
9.Eriksson, C., Tehranian, R., Iverfeldt, K., Winblad, B. & Schultzberg, M. Increased expression of mRNA encoding interleukin-1β and caspase-1, and the secreted isoform of interleukin-1 receptor antagonist in the rat brain following systemic kainic acid administration. J. Neurosci. Res.60, 266–279 (2000).
10.Dhote, F. et al. Prolonged inflammatory gene response following soman-induced seizures in mice. Toxicology238, 166–176 (2007).
11.Plata-Salaman, C.R. et al. Kindling modulates the IL-1β system, TNF-α, TGF-β1, and neuropeptide mRNAs in specific brain regions. Brain Res. Mol. Brain Res.75, 248–258 (2000).
12.Ravizza, T. et al. Interleukin Converting Enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production. Neurobiol. Dis.31, 327–333 (2008).
13.Balosso, S. et al. A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1β. Brain131, 3256–3265 (2008).
14.Luo, X. et al. Effect of intravenous immunoglobulin treatment on brain interferon-γ and interleukin-6 levels in a rat kindling model. Epilepsy Res.88, 162–167 (2010).
15.Aronica, E. et al. Complement activation in experimental and human temporal lobe epilepsy. Neurobiol. Dis.26, 497–511 (2007).
16.Gorter, J.A. et al. Potential new antiepileptogenic targets indicated by microarray analysis in a rat model for temporal lobe epilepsy. J. Neurosci.26, 11083–11110 (2006).
17.Rozovsky, I. et al. Selective expression of clusterin (SGP-2) and complement C1qB and C4 during responses to neurotoxins in vivo and in vitro. Neuroscience62, 741–758 (1994).
18.Takemiya, T. et al. Inducible brain COX-2 facilitates the recurrence of hippocampal seizures in mouse rapid kindling. Prostaglandins Other Lipid Mediat.71, 205–216 (2003).
19.Naffah-Mazzacoratti, M.G., Bellissimo, M.I. & Cavalheiro, E.A. Profile of prostaglandin levels in the rat hippocampus in pilocarpine model of epilepsy. Neurochem. Int.27, 461–466 (1995).
20.Jung, K.H. et al. Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neurobiol. Dis.23, 237–246 (2006).
21.Lee, B., Dziema, H., Lee, K.H., Choi, Y.S. & Obrietan, K. CRE-mediated transcription and COX-2 expression in the pilocarpine model of status epilepticus. Neurobiol. Dis.25, 80–91 (2007).
22.Polascheck, N., Bankstahl, M. & Loscher, W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp. Neurol.224, 219–233(2010).
23.Holtman, L. et al. Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy. Epilepsy Res.84, 56–66 (2009).
24.Yoshikawa, K., Kita, Y., Kishimoto, K. & Shimizu, T. Profiling of eicosanoid production in the rat hippocampus during kainic acid-induced seizure: dual phase regulation and differential involvement of COX-1 and COX-2. J. Biol. Chem.281, 14663–14669 (2006).
25.Tanaka, S. et al. Stage- and region-specific cyclooxygenase expression and effects of a selective COX-1 inhibitor in the mouse amygdala kindling model. Neurosci. Res.65, 79–87 (2009).
26.Xu, J.H. et al. CCR3, CCR2A and macrophage inflammatory protein (MIP)-1a, monocyte chemotactic protein-1 (MCP-1) in the mouse hippocampus during and after pilocarpine-induced status epilepticus (PISE). Neuropathol. Appl. Neurobiol.35, 496–514 (2009).
27.Foresti, M.L. et al. Chemokine CCL2 and its receptor CCR2 are increased in the hippocampus following pilocarpine-induced status epilepticus. J. Neuroinflammation6, 40 (2009).
28.Manley, N.C., Bertrand, A.A., Kinney, K.S., Hing, T.C. & Sapolsky, R.M. Characterization of monocyte chemoattractant protein-1 expression following a kainate model of status epilepticus. Brain Res.1182, 138–143 (2007).
29.Wu, Y. et al. Expression of monocyte chemoattractant protein-1 in brain tissue of patients with intractable epilepsy. Clin. Neuropathol.27, 55–63 (2008).
30.Liu, J.X., Cao, X., Tang, Y.C., Liu, Y. & Tang, F.R. CCR7, CCR8, CCR9 and CCR10 in the mouse hippocampal CA1 area and the dentate gyrus during and after pilocarpine-induced status epilepticus. J. Neurochem.100, 1072–1088 (2007).
31.Fabene, P.F. et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nature Med.14, 1377–1383 (2008).
32.Hansen, A., Jorgensen, O.S., Bolwig, T.G. & Barry, D.I. Hippocampal kindling alters the concentration of glial fibrillary acidic protein and other marker proteins in rat brain. Brain Res.531, 307–311 (1990).
33.Sato, K., Iwai, M., Nagano, I., Shoji, M. & Abe, K. Changes of localization of highly polysialylated neural cell adhesion molecule (PSA-NCAM) in rat hippocampus with exposure to repeated kindled seizures. Brain Res.946, 323–327 (2002).
34.Lukasiuk, K., Kontula, L. & Pitkanen, A. cDNA profiling of epileptogenesis in the rat brain. Eur. J. Neurosci.17, 271–279 (2003).
35.Lahtinen, L. et al. Urokinase-type plasminogen activator regulates neurodegeneration and neurogenesis but not vascular changes in the mouse hippocampus after status epilepticus. Neurobiol. Dis.37, 692–703 (2010).
36.Qian, Z., Gilbert, M.E., Colicos, M.A., Kandel, E.R. & Kuhl, D. Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature361, 453–457 (1993).
37.Maroso, M. et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nature Med.16, 413–419 (2010).
38.Zeng, L.H., Rensing, N.R. & Wong, M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J. Neurosci.29, 6964–6972 (2009).
39.Huang, X. et al. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol. Dis. 40, 193–199 (2010).