Thrombin-induced kynurenine 3-monooxygenase causes variations in the kynurenine pathway, leading to neurological deficits in a murine intracerebral hemorrhage model.

The purpose of the present study is to investigate changes in the kynurenine pathway after intracerebral hemorrhage (ICH) and its effects on ICH-induced injury. The exposure of a primary rat microglial culture to thrombin increased the mRNA level of kynurenine 3-monooxygenase (KMO), and this increase was attenuated by a p38 MAPK inhibitor. Thrombin also increased the protein level of KMO. In the cultured medium, the ratio of quinolinic acid (QUIN), an N-methyl-d-aspartate receptor (NMDAR) agonist, to kynurenic acid (KYNA), its antagonist, increased. The increase in the QUIN/KYNA ratio was blocked by Ro61-8048, a KMO inhibitor. The mRNA expression of KMO increased in an in vivo murine ICH model. Immunohistochemical staining showed that increased KMO co-localized with neurons, microglia, and astrocytes. The QUIN/KYNA ratio increased after ICH but was blocked by Ro61-8048 or clodronate, a microglia toxin. Ro61-8048 ameliorated brain edema; however, this effect was masked by MK-801, an NMDAR antagonist. Ro61-8048 protected against neuron loss in the perihematomal region and repaired neurological deficits assessed using the corner turn and pole tests. In conclusion, thrombin-induced changes in KMO in microglia mainly and intermediary metabolites of the kynurenine pathway appear to play crucial roles in neuronal injury after ICH.