Pharmacology of celecoxib in rat brain after kainate administration

Paola Ciceri, Yan Zhang, Alex F. Shaffer, Kathleen M. Leahy, Mark B. Woerner, Walter G. Smith, Karen Seibert, Peter C. Isakson

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Abstract

Prostaglandin E2 (PGE2) is the major prostaglandin produced both centrally and in the periphery in models of acute and chronic inflammation, and its formation in both locations is blocked by cyclooxygenase-2 (COX-2) inhibitors such as celecoxib. In animal models of inflammation, PGE2 inhibition in the brain may occur secondarily to a peripheral action by inhibiting local PG formation that elicits increased firing of pain fibers and consequent activation of PG synthesis in the central nervous system (CNS), Celecoxib was studied in the kainate-induced seizure model in the rat, a model of direct central prostaglandin induction, to determine whether it can act directly in the CNS. In the kainate-treated rat brain there was increased PGE2,PGF, and PGD2 production, with COX activity and PGE2 formation increased about 7-fold over normal. We quantitated mRNA levels for enzymes involved in the prostaglandin biosynthetic pathways and found that both COX-2 and PGE synthase (PGEs) mRNA levels were increased in the brain; no changes were found for expression of COX-1 or PGD synthase mRNA. By Western blot analysis, COX-2 and PGEs were induced in total brain, hippocampus, and cortex, but not in the spinal cord. Immunohistological studies showed that COX-2 protein expression was enhanced in neurons. Dexamethasone treatment reduced the expression of both COX-2 and PGEs in kainate-treated animals. Celecoxib reduced the elevated PGE2 levels in brain of kainate-treated rats and inhibited induced COX activity, demonstrating the ability of this compound to act on COX-2 in CNS. Doses of celecoxib that inhibited brain COX-2 were lower than those needed for anti-inflammatory activity in adjuvant arthritis, demonstrating a potent direct central action of the compound.

Original languageEnglish
Pages (from-to)846-852
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume302
Issue number3
DOIs
StatePublished - Sep 1 2002

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    Ciceri, P., Zhang, Y., Shaffer, A. F., Leahy, K. M., Woerner, M. B., Smith, W. G., Seibert, K., & Isakson, P. C. (2002). Pharmacology of celecoxib in rat brain after kainate administration. Journal of Pharmacology and Experimental Therapeutics, 302(3), 846-852. https://doi.org/10.1124/jpet.302.3.846