Kynurenine 3‐mono‐oxygenase inhibitors attenuate post‐ischemic neuronal death in organotypic hippocampal slice cultures

• Published in: Journal of neurochemistry 2002-09, Vol.82 (6), p.1465-1471
• Main Authors: Carpenedo, Raffaella, Meli, Elena, Peruginelli, Fiamma, Pellegrini‐Giampietro, Domenico E., Moroni, Flavio
• Format: Article
• Language: English
• Subjects: (m‐nitrobenzoyl)‐alanine; Alanine - analogs & derivatives; Alanine - pharmacology; Animals; Biological and medical sciences; Brain Ischemia - metabolism; Brain Ischemia - pathology; Cell Death - drug effects; Cell Hypoxia - physiology; Culture Media, Conditioned - chemistry; Culture Media, Conditioned - metabolism; Enzyme Inhibitors - pharmacology; Glucose - deficiency; Glucose - metabolism; Hippocampus - metabolism; Hippocampus - pathology; In Vitro Techniques; kynurenic acid; Kynurenic Acid - analysis; Kynurenic Acid - metabolism; Kynurenic Acid - pharmacology; Kynurenine - analogs & derivatives; Kynurenine - analysis; Kynurenine - metabolism; Kynurenine - pharmacology; Kynurenine 3-Monooxygenase; Medical sciences; Mixed Function Oxygenases - antagonists & inhibitors; Mixed Function Oxygenases - metabolism; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuropharmacology; neuroprotection; Neuroprotective agent; Neuroprotective Agents - pharmacology; oxygen–glucose deprivation; Pharmacology. Drug treatments; Pyramidal Cells - drug effects; Pyramidal Cells - pathology; quinolinic acid; Quinolinic Acid - pharmacology; Rats; Ro 61–8048; Sulfonamides - pharmacology; Thiazoles - pharmacology
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2002.01090.x

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 µm) or 3,4‐dimethoxy‐[‐N‐4‐(nitrophenyl)thiazol‐2yl]‐benzenesulfonamide (1–10 µm) 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 α7 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 µm) 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.