Abstract
Kynurenine 3-mono-oxygenase (KMO) inhibitors facilitate kynurenic acid (KYNA) neosynthesis and reduce the formation of 30H-kynurenine (3-HK) and quinolinic acid (QUIN). They also attenuate post-ischemic brain damage and decrease glutamate (Glu) content in brain extracellular spaces.
To investigate KMO mechanism(s) of neuroprotection, we performed experiments in gerbils subjected to bilateral carotid occlusion and in organotypic rat hippocampal slice cultures exposed to oxygen and glucose deprivation (OGD). In gerbils, direct application of KYNA (100 nM, through reverse microdialysis in the hippocampus) completely prevented the increase in Glu output induced by transient (5 min) occlusion of the carotids. In rat hippocampal slices exposed for 30 min to OGD, KMO inhibitors (mnitrobenzoyl)-alanine (mNBA, 30-100.tM) or 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol2y1]-benzenesulfonamide (Ro 61-8048, 1-10 p.M) reduced post-ischemic neuronal death and increased KYNA concentrations in the incubation medium. KYNA may antagonize glycinesor a7 nicotinic acetylcholine receptors but the concentrations in the incubation medium never reached values that could efficiently antagonize receptor function. On the contrary, 3-HK (1-10 kiM) added to slices exposed to OGD in the presence of KMO inhibitors completely prevented the neuroprotective effects of the inhibitors.
Our findings suggest that KMO inhibitors reduce OGD-induced pyramidal cell death by decreasing 3-HK (and possibly QUIN) synthesis.
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Moroni, F., Carpenedo, R., Cozzi, A., Meli, E., Chiarugi, A., Pellegrini-Giampietro, D.E. (2003). Studies on the Neuroprotective Action of Kynurenine Mono-Oxygenase Inhibitors in Post-Ischemic Brain Damage. In: Allegri, G., Costa, C.V.L., Ragazzi, E., Steinhart, H., Varesio, L. (eds) Developments in Tryptophan and Serotonin Metabolism. Advances in Experimental Medicine and Biology, vol 527. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0135-0_15
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DOI: https://doi.org/10.1007/978-1-4615-0135-0_15
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