The kynurenine pathway and neurologic disease. Therapeutic strategies.

The neurotoxic effects of QUIN have been well established. Clinical conditions have been identified where substantial elevations in CNS QUIN levels occur. There is a relationship between the severity of neurologic impairments and macrophage activation, with the magnitude of the increases in QUIN. The magnitude of QUIN increases in experimental immune activation, and macrophages in vitro, are highest in non-human primates, intermediate in gerbils and guinea pigs, and lowest in mice and rats. Macrophages in vitro are a useful screening system to evaluate potential inhibitors of the kynurenine pathway. Several models of CNS inflammation are available, including brain injury in post-ischemic gerbils and spinal cord injury in guinea pigs. 4-Chloro-3-hydroxyanthranilate is a potent inhibitor of QUIN production by macrophages and reduces QUIN accumulations in spinal cord injury. Such reductions are associated with significant neurologic improvements in the early post-injury period. The results support further investigation of QUIN as a mediator of neurologic dysfunction and damage in neurologic diseases.