Neuronal overexpression of COX-2 results in dominant production of PGE2 and altered fever response.

Cyclooxygenases catalyze the first committed step in the formation of prostaglandins and thromboxanes from arachidonic acid. Cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is expressed in brain selectively in neurons of hippocampus, cerebral cortex, amygdala, and hypothalamus. Prostaglandins function in many processes in the CNS, including fever induction, nociception, and learning and memory, and are upregulated in paradigms of excitotoxic brain injury such as stroke and epilepsy. To address the varied functions of COX-2 and its prostaglandin products in brain, we have developed a transgenic mouse model in which COX-2 is selectively overexpressed in neurons of the CNS. COX-2 transgenic mice demonstrate elevated levels of all prostaglandins and thromboxane, albeit with a predominant induction of PGE(2) over other prostaglandins, followed by more modest inductions of PGI(2), and relatively smaller increases in PGF(2alpha),PGD(2), and TxB(2). We also examined whether increased neuronal production of prostaglandins would affect fever induction in response to the bacterial endotoxin lipopolysaccharide. COX-2 induction in brain endothelium has been previously determined to play an important role in fever induction, and we tested whether neuronal expression of COX-2 in hypothalamus also contributed to the febrile response. We found that in mice expressing transgenic COX-2 in anterior hypothalamus, the febrile response was significantly potentiated in transgenic as compared to non-transgenic mice, with an accelerated onset of fever by 1 2 hours after LPS administration, suggesting a role for neuronally derived COX-2 in the fever response.

Pharmacology of celecoxib in rat brain after kainate administration.

Prostaglandin E(2) (PGE(2)) 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, PGE(2) 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 PGE(2), PGF(2alpha), and PGD(2) production, with COX activity and PGE(2) 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 PGE(2) 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.