Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolitesincrease in the spinal cord of rats with experimental allergic encephalomyelitis

Kynurenine 3-mono-oxygenase, one of the hey enzymes of the "kynurenine path way", catalyses the formation of 3-hydroxykynurenine and may direct the neo -synthesis of quinolinic and kynurenic acids. While 3-hydroxykynurenine and quinolinic acid have neurotoxic properties, kynurenic acid antagonizes exc itotoxic neuronal death. Here we report that the expression and activity of kynurenine 3-mono-oxygenase significantly increased in the spinal cord of rats with experimental allergic encephalopathy, an experimental model of mu ltiple sclerosis. As a consequence of this increase, the spinal cord conten t of 3-hydroxykynurenine and quinolinic acid reached neurotoxic levels. We also report that systemic administration of Ro 61-8048, a selective kynuren ine 3-mono-oxygenase inhibitor, reduced the increase of both 3-hydroxykynur enine and quinolinic acid, and caused accumulation of kynurenic acid. In th e brain and spinal cord of the controls, kynurenine 3-mono-oxygenase immuno reactivity was located in granules (probably mitochondria) present in the c ytoplasm of both neurons and astroglial cells. In the spinal cord of rats w ith experimental allergic encephalopathy, however, cells with a very intens e kynurenine 3-mono-oxygenase immunoreactivity, also able to express class II major histocompatibility complex and inducible nitric oxide synthase, we re found in perivascular, subependymal and subpial locations. These cells ( most probably macrophages) were responsible for the large increase in 3-hyd roxykynurenine and quinolinic acid found in the spinal cords of affected an imals. The results show that cells of the immune system are responsible for the in creased formation of 3-hydroxykynurenine and quinolinic acid, two neurotoxi c metabolites that accumulate in the central nervous system of rats with ex perimental allergic encephalomyelitis. They also demonstrate that selective kynurenine 3-mono-oxygenase inhibitors reduce the neo-synthesis of these t oxins. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserve d.