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Journal of Zhejiang University SCIENCE B 2008 Vol.9 No.11 P.903-915


Cyclooxygenase-2 inhibitor inhibits hippocampal synaptic reorganization in pilocarpine-induced status epilepticus rats

Author(s):  Hai-ju ZHANG, Ruo-peng SUN, Ge-fei LEI, Lu YANG, Chun-xi LIU

Affiliation(s):  Department of Pediatrics, Renmin Hospital of Wuhan University, Wuhan 430060, China; more

Corresponding email(s):   streeg@sina.com

Key Words:  Epileptogenesis, Cyclooxygenase-2 (COX-2), Neurogenesis, Microglia, &gamma, -amino butyric acid (GABA), c-Fos, Mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK), Spontaneous recurrent seizure

Hai-ju ZHANG, Ruo-peng SUN, Ge-fei LEI, Lu YANG, Chun-xi LIU. Cyclooxygenase-2 inhibitor inhibits hippocampal synaptic reorganization in pilocarpine-induced status epilepticus rats[J]. Journal of Zhejiang University Science B, 2008, 9(11): 903-915.

@article{title="Cyclooxygenase-2 inhibitor inhibits hippocampal synaptic reorganization in pilocarpine-induced status epilepticus rats",
author="Hai-ju ZHANG, Ruo-peng SUN, Ge-fei LEI, Lu YANG, Chun-xi LIU",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Cyclooxygenase-2 inhibitor inhibits hippocampal synaptic reorganization in pilocarpine-induced status epilepticus rats
%A Hai-ju ZHANG
%A Ruo-peng SUN
%A Ge-fei LEI
%A Chun-xi LIU
%J Journal of Zhejiang University SCIENCE B
%V 9
%N 11
%P 903-915
%@ 1673-1581
%D 2008
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B0820018

T1 - Cyclooxygenase-2 inhibitor inhibits hippocampal synaptic reorganization in pilocarpine-induced status epilepticus rats
A1 - Hai-ju ZHANG
A1 - Ruo-peng SUN
A1 - Ge-fei LEI
A1 - Lu YANG
A1 - Chun-xi LIU
J0 - Journal of Zhejiang University Science B
VL - 9
IS - 11
SP - 903
EP - 915
%@ 1673-1581
Y1 - 2008
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B0820018

Objective: To examine modulations caused by cyclooxygenase-2 (COX-2) inhibitors on altered microenvironments and overbalanced neurotransmitters in pilocarpine-induced epileptic status rats and to investigate possible mechanisms. Methods: Celecoxib (a COX-2 inhibitor) was administered 45 min prior to pilocarpine administration. The effects of COX-2 inhibitors on mIPSCs (miniature GABAergic inhibitory postsynaptic currents) of CA3 pyramidal cells in the hippocampus were recorded. Expressions of COX-2, c-Fos, newly generated neurons, and activated microgliosis were analyzed by immunohistochemistry, and expressions of α-subunit of &gamma;-amino butyric acid (GABAA) receptors and mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) activity were detected by Western blotting. Results: Pretreatment with celecoxib showed protection against pilocarpine-induced seizures. Celecoxib prevented microglia activation in the hilus and inhibited the abnormal neurogenesis and astrogliosis in the hippocampus by inhibiting MAPK/ERK activity and c-Fos transcription. Celecoxib also up-regulated the expression of GABAA receptors. NS-398 (N-2-cyclohexyloxy-4-nitrophenyl-methanesulfonamide), another COX-2 inhibitor, enhanced the frequency and decay time of mIPSCs. Conclusion: The COX-2 inhibitor celecoxib decreased neuronal excitability and prevented epileptogenesis in pilocarpine-induced status epilepticus rats. Celecoxib regulates synaptic reorganization by inhibiting astrogliosis and ectopic neurogenesis by attenuating MAPK/ERK signal activity, mediated by a GABAergic mechanism.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1] Altar, C.A., Laeng, P., Jurata, L.W., Brockman, J.A., Lemire, A., Bullard, J., Bukhman, Y.V., Young, T.A., Charles, V., Palfreyman, M.G., 2004. Electroconvulsive seizures regulate gene expression of distinct neurotrophic signaling pathways. J. Neurosci., 24(11):2667-2677.

[2] Baik, E.J., Kim, E.J., Lee, S.H., Moon, C.H., 1999. Cyclooxygenase-2 selective inhibitors aggravate kainic acid induced seizure and neuronal cell death in the hippocampus. Brain Res., 843(1-2):118-129.

[3] Brock, S.C., Bonsall, J., Luskin, M.B., 1998. The neuronal progenitor cells of the forebrain subventricular zone: intrinsic properties in vitro and following transplantation. Methods, 16(3):268-281.

[4] Chen, C., Magee, J.C., Bazan, N.G., 2002. Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J. Neurophysiol., 87(12):2851-2857.

[5] Dashtipour, K., Tran, P.H., Okazaki, M.M., Nadler, J.V., Ribak, C.E., 2001. Ultrastructural features and synaptic connections of hilar ectopic granule cells in the rat dentate gyrus are different from those of granule cells in the granule cell layer. Brain Res., 890(2):261-271.

[6] Desjardins, P., Sauvageau, A., Bouthillier, A., Navarro, D., Hazell, A.S., Rose, C., Butterworth, R.F., 2003. Induction of astrocytic cyclooxygenase-2 in epileptic patients with hippocampal sclerosis. Neurochem. Int., 42(4):299-303.

[7] Dhir, A., Naidu, P.S., Kulkarni, S.K., 2006. Effect of cyclooxygenase-2 (COX-2) inhibitors in various animal models (bicuculline, picrotoxin, maximal electroshock-induced convulsions) of epilepsy with possible mechanism of action. Indian J. Exp. Biol., 44(2):286-291.

[8] Esclapez, M., Hirsch, J.C., Ben-Ari, Y., Bernard, C., 1999. Newly formed excitatory pathways provide a substrate for hyperexcitability in experimental temporal lobe epilepsy. J. Comp. Neurol., 408(4):449-460.

[9] Gass, P., Bruehl, C., Herdegen, T., Kiessling, M., Lutzenburg, M., Witte, O.W., 1997. Induction of FOS and JUN proteins during focal epilepsy: congruences with and differences to [14C] deoxyglucose metabolism. Brain Res. Mol. Brain Res., 46(1-2):177-184.

[10] Ivanov, A., Pellegrino, C., Rama, S., Dumalska, I., Salyha, Y., Ben-Ari, Y., Medina, I., 2006. Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of the extracellular signal-regulated kinases (ERK) activity in cultured rat hippocampal neurons. J. Physiol., 572(6):789-798.

[11] Jin, X., Prince, D.A., Huguenard, J.R., 2006. Enhanced excitatory synaptic connectivity in layer v pyramidal neurons of chronically injured epileptogenic neocortex in rats. J. Neurosci., 26(18):4891-4900.

[12] Jung, K.H., Chu, K., Kim, M., Jeong, S.W., Song, Y.M., Lee, S.T., Kim, J.Y., Lee, S.K., Roh, J.K., 2004. Continuous cytosine-b-D-arabinofuranoside infusion reduces ectopic granule cells in adult rat hippocampus with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Eur. J. Neurosci., 19(12):3219-3226.

[13] Kang, T.C., Kim, D.S., Kwak, S.E., Kim, J.E., Won, M.H., Kim, D.W., Choi, S.Y., Kwon, O.S., 2006. Epileptogenic roles of astroglial death and regeneration in the dentate gyrus of experimental temporal lobe epilepsy. Glia, 54(4):258-271.

[14] Kawaguchi, K., Hickey, R.W., Rose, M.E., Zhu, L., Chen, J., Graham, S.H., 2005. Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus. Brain Res., 1050(1-2):130-137.

[15] Kunz, T., Oliw, E.H., 2001. The selective cyclooxygenase-2 inhibitor rofecoxib reduces kainate-induced cell death in the rat hippocampus. Eur. J. Neurosci., 13(3):569-575.

[16] Lopez-Toledano, M.A., Shelanski, M.L., 2004. Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J. Neurosci., 24(23):5439-5444.

[17] Lukiw, W.J., Cui, J.G., Musto, A.E., Musto, B.C., Bazan, N.G., 2005. Epileptogenesis in diacylglycerol kinase epsilon deficiency up-regulates COX-2 and tyrosine hydroxylase in hippocampus. Biochem. Biophys. Res. Commun., 338(1):77-81.

[18] McIntyre, D.C., Poulter, M.O., Gilby, K., 2002. Kindling: some old and some new. Epilepsy Res., 50(1-2):79-92.

[19] Mikkonen, M., Soininen, H., Kalvianen, R., Tapiola, T., Ylinen, A., Vapalahti, M., Paljarvi, L., Pitkanen, A., 1998. Remodeling of neuronal circuitries in human temporal lobe epilepsy: increased expression of highly polysialylated neural cell adhesion molecule in the hippocampus and the entorhinal cortex. Ann. Neurol., 44(6):923-934.

[20] Morimoto, K., Fahnestock, M., Racine, R.J., 2004. Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog. Neurobiol., 73(1):1-60.

[21] Motte, J., Fernandes, M.J., Baram, T.Z., Nehlig, A., 1998. Spatial and temporal evolution of neuronal activation, stress and injury in lithium-pilocarpine seizures in adult rats. Brain Res., 793(1-2):61-72.

[22] Okada, K., Yuhi, T., Tsuji, S., Yamashita, U., 2001. Cyclooxygenase-2 expression in the hippocampus of genetically epilepsy susceptible El mice was increased after seizure. Brain Res., 894(2):332-335.

[23] Rothstein, J.D., Dykes-Hoberg, M., Pardo, C.A., Bristol, L.A., Jin, L., Kuncl, R.W., Kanai, Y., Hediger, M.A., Wang, Y., Schielke, J.P., Welty, D.F., 1996. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron, 16(3):675-686.

[24] Sankar, R., Shin, D., Liu, H., Katsumori, H., Wasterlain, C.G., 2000. Granule cell neurogenesis after status epilepticus in the immature rat brain. Epilepsia, 41(s6):S53-S56.

[25] Sasaki, T., Kitagawa, K., Sugiura, S., Omura-Matsuoka, E., Tanaka, S., Yagita, Y., Okano, H., Matsumoto, M., Hori, M., 2003. Implication of cyclooxygenase-2 on enhanced proliferation of neural progenitor cells in the adult mouse hippocampus after ischemia. J. Neurosci. Res., 72(4):461-471.

[26] Scharfman, H.E., Goodman, J.H., Sollas, A.L., 2000. Granule-like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: functional implications of seizure-induced neurogenesis. J. Neurosci., 20(9):6144-6158.

[27] Seibert, K., Zhang, Y., Leahy, K., Hauser, S., Masferrer, J., Perkins, W., Lee, L., Isakson, P., 1994. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc. Natl. Acad. Sci. USA, 91(25):12013-12017.

[28] Shafiq, N., Malhotra, S., Pandhi, P., 2003. Anticonvulsant action of celecoxib (alone and in combination with sub-threshold dose of phenytoin) in electroshock induced convulsion. Methods Find. Exp. Clin. Pharmacol., 25(2):87-90.

[29] Subbaramaiah, K., Zakim, D., Weksler, B.B., Dannenberg, A., 1997. Inhibition of cyclooxygenase: a novel approach to cancer prevention. Proc. Soc. Exp. Biol. Med., 216(2):201-210.

[30] Sweatt, J.D., 2004. Mitogen-activated protein kinases in synaptic plasticity and memory. Curr. Opin. Neurobiol., 14(3):311-317.

[31] Tashiro, A., Goldberg, J., Yuste, R., 2002. Calcium oscillations in neocortical astrocytes under epileptiform conditions. J. Neurobiol., 50(1):45-55.

[32] Torre, E.R., Lothman, E., Steward, O., 1993. Glial response to neuronal activity: GFAP-mRNA and protein levels are transiently increased in the hippocampus after seizures. Brain Res., 631(2):256-264.

[33] Tu, B., Bazan, N.G., 2003. Hippocampal kindling epileptogenesis upregulates neuronal cyclooxygenase-2 expression in neocortex. Exp. Neurol., 179(2):167-175.

[34] Willingale, H.L., Gardiner, N.J., McLymont, N., Giblett, S., Grubb, B.D., 1997. Prostanoids synthesized by cyclo-oxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability. Br. J. Pharmacol., 122(8):1593-1604.

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