Kynurenine 3-mono-oxygenase inhibitors attenuate post-ischemic neuronal death in organotypic hippocampal slice cultures.
Kynurenine 3-mono-oxygenase (KMO) inhibitors reduce 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) neosynthesis and facilitate kynurenine metabolism towards kynurenic acid (KYNA) formation. They also reduce tissue damage in models of focal or transient global cerebral ischemia in vivo. We used organotypic hippocampal slice cultures exposed to oxygen and glucose deprivation (OGD) to investigate KMO mechanism(s) of neuroprotective activity. Exposure of the slices to 30 min of OGD caused CA1 pyramidal cell death and significantly decreased the amount of KYNA released in the incubation medium. The KMO inhibitors (m-nitrobenzoyl)-alanine (30-100 micro m) or 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfonamide (1-10 micro m) reduced post-ischemic neuronal death and increased KYNA concentrations in slice incubation media. The maximal concentration of KYNA detected in the incubation media of slices treated with KMO inhibitors was approximately 50 nm and was too low to efficiently interact with alpha7 nicotinic acetylcholine receptors or with the glycineb site of N-methyl-d-aspartate (NMDA) receptors. On the other hand, the addition of either 3-HK or QUIN (1-10 micro m) to OGD-exposed hippocampal slices prevented the neuroprotective activity of KMO inhibitors. Our results suggest that KMO inhibitors reduce the neuronal death found in the CA1 region of organotypic hippocampal slices exposed to 30 min of OGD by decreasing the local synthesis of 3-HK and QUIN.
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D050601:Kynurenine 3-Monooxygenase; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D017378:Quinolinic Acid / Q000494:pharmacology; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; C086214:(3-nitrobenzoyl)alanine; C005045:3-hydroxykynurenine; D007737:Kynurenine; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase; D017378:Quinolinic Acid; D007736:Kynurenic Acid; D005947:Glucose; D000409:Alanine