A number of prostaglandins (PGs) are produced in the brain, each known to possess unique physiological functions. Inhibition of prostaglandin biosynthesis reduces the seizure threshold induced by chemical convulsants suggesting that the elevation in prostaglandin levels measured during seizure activity may help moderate neuronal firing and thereby influence seizure spread. However, investigations into which of the arachidonic acid metabolites might affect seizure propagation has been slowed because specific inhibitors have not been found that can alter the relative ratios of prostaglandins in brain. The discovery of two distinct forms of cyclooxygenase in brain, one form associated with prostaglandin E2 production (a potent anticonvulsant compound) and the second associated with prostaglandin F2 alpha biosynthesis, suggests that differential inhibition of prostaglandin biosynthesis is possible at the level of the cyclooxygenases. The regulation of the two cyclooxygenases is not known; nor is their distribution in brain (i.e. neurons or glia) and other body organs. This study will examine the two cyclooxygenase forms using biochemical and pharmacological methods. Isolation of the two cyclooxygenases will be conducted and their pH optimum, fatty acid substrate specificity and the effect of inhibitors on their activities will be addressed to ascertain distinguishing properties. The ability to selectively alter the ratio of prostaglandin metabolites in brain will be assessed in vivo using compounds that are known to affect arachidonic acid metabolism in vitro. These studies will serve to provide insight into a novel method for prostaglandin production and will determine which prostaglandins have significance in limiting the intensity and spread of convulsions. This line of investigation suggests that certain non-steroidal anti-inflammatory agents may be potential anti-convulsants by their ability to inhibit a select cylooxygenase.
