Abstract
Kynurenine 3-monooxygenase (KMO) is a kind of rate-limiting enzyme in the kynurenine pathway. We investigated the change in KMO expression and intermediary metabolite levels after intracerebral hemorrhage (ICH) in neuronal injury. Treatment with thrombin to primary-cultured microglia increased the KMO expression through the p38 MAPK pathway. In the cultured medium, the ratio of quinolinic acid (QUIN), an N-methyl-D-aspartate receptor agonist, to kynurenic acid (KYNA), its antagonist, was increased, whereas the level of 3-hydroxykynurenine, a redox-active compound, showed no significant change. The increased QUIN/KYNA ratio was blocked by Ro61-8048, a KMO inhibitor. In the mouse ICH model, immunohistochemical staining showed that KMO was co-localized with neurons, microglia, and astrocytes. The QUIN/KYNA ratio was increased after ICH, but blocked by the intracerebroventricular injection of Ro61-8048 or liposomal clodronate, a microglia toxin. Ro61-8048 ameliorated the loss of neurons, as indicated by NeuN-immunopositive cells, at the perihematomal region and repaired their abnormal behaviors without affecting the hematoma size. In conclusion, thrombin-induced alterations of microglial KMO and intermediary metabolites of the kynurenine pathway were suggested to play important roles in neuronal injury after ICH.
