Thrombin increases kynurenine 3-monooxygenase expression in microglia

Kynurenine 3-monooxygenase (KMO) is an enzyme situated at the junction to kynurenic acid (KYNA), an antagonist of the N-methyl-D-aspartate (NMDA) receptor, or to quinolinic acid (QUIN), an agonist of it, in the kynurenine pathway. To reveal the role(s) of KMO after intracerebral hemorrhage, the effect of thrombin, a serine protease, on KMO expression was investigated using primary-cultured microglia. Thrombin increased the KMO mRNA level and the effect reached a peak at 6 h. The increased KMO mRNA was suppressed by the p38 MAPK inhibitor but not the ERK and JNK inhibitors. The KMO protein level was also increased by thrombin in a concentration-dependent manner and the increased protein tended to be suppressed by the p38 MAPK inhibitor. The ratio of QUIN/KYNA, indicating the intensity of NMDA stimulation, was increased in the conditioned medium and the increased QUIN/KYNA ratio was suppressed by Ro61-8048, a KMO inhibitor, in a concentration-dependent manner. The increase of QUIN/KYNA ratio by KMO in microglia may be involved in hemorrhagic brain injury.