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

Abstract

Kainic acid (KA)-induced seizure in rat involves eicosanoid production in the brain, but their production mechanism and biological functions are poorly understood. We profiled the eicosanoid production during KA-induced seizure by a comprehensive lipidomics analysis using liquid chromatography-tandem mass spectrometry. Systemic KA administration caused production of large amounts of prostaglandin (PG) F(2alpha) and PGD(2) in the hippocampus, with smaller amounts of other PGs and hydroxyeicosatetraenoic acids. The production was biphasic, which consisted of an initial burst in the first 30 min and a sustained late phase production. The initial phase was specific to the hippocampus and was blocked by intracerebroventricular administration of KA receptor antagonists. A selective cyclooxygenase (COX)-2 inhibitor, NS398, completely inhibited the initial phase productions, except for PGD(2) and thromboxane B(2), whose productions were also dependent on COX-1. These results suggest that KA signals directly stimulate the arachidonic acid cascade in the initial phase and that COX-1 and COX-2, both constitutively expressed at low levels, differentially contribute to PG productions. In the late phase, a sustained PG production in hippocampus appears due to the increased COX-2 levels even with a limited arachidonic acid supply. The present study demonstrates a dual phase regulatory mechanism of eicosanoid production during KA-induced seizure, providing a biochemical basis for understanding the biosynthesis and roles of eicosanoids in the brain.