Neuroprotective effects of kynurenine-3-hydroxylase inhibitors in models of brain ischemia.
The neuroprotective effects of two kynurenine hydroxylase inhibitors, (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfona mide (Ro 61-8048), were studied in vitro and in vivo. In organotypic hippocampal slice cultures deprived of oxygen and glucose, these inhibitors significantly reduced neuronal damage. In gerbils subjected to bilateral carotid occlusion for 5 min, the administration of mNBA (400 mg/kg i.p., 3 times) or Ro 61-8048 (40 mg/kg i.p., 3 times) dramatically decreased the percentage of damaged pyramidal neurones in the hippocampal CA1 region. Finally, in rats with permanent occlusion of the middle cerebral artery, mNBA (200-400 mg/kg i.p.) and Ro 61-8048 (40 mg/kg i.p.) administration reduced the infarct volume. Our results demonstrate that ischemic neuronal damage may be significantly decreased by inhibiting kynurenine hydroxylase.
Moroni
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F
Department of Pharmacology, University of Florence, Firenze, Italy. moronif@stat.ds.unifi.it
Cozzi
A
A
Peruginelli
F
F
Carpenedo
R
R
Pellegrini-Giampietro
D E
DE
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D002544:Cerebral Infarction / Q000517:prevention & control*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D066298:In Vitro Techniques; D002546:Ischemic Attack, Transient / Q000503:physiopathology* / Q000517:prevention & control; D050601:Kynurenine 3-Monooxygenase; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; C086214:(3-nitrobenzoyl)alanine; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase; D000409:Alanine