Kynurenine hydroxylase inhibitors reduce ischemic brain damage: Studies with (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2YL]-benzenesulfonamide (Ro 61-8048) in models of focal or global brain ischemia

Two kynurenine hydroxylase inhibitors, (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfonamide (Ro 61-804 8), have been tested as neuroprotective agents on brain lesions induced by bilateral carotid occlusion in gerbils or by middle cerebral artery occlusi on in rats. The percentage of lesioned pyramidal neurones found in the hipp ocampal CAI region of gerbils subjected to bilateral carotid occlusion for 5 minutes decreased from 92 +/- 10% in vehicle-treated animals to 7 +/- 6% after mNBA (400 mg/kg intraperitoneally, three times at 1, 30, and 180 minu tes after occlusion) or to 10 +/- 11% after Ro 61-8048 (40 mg/kg intraperit oneally, three times). A significant reduction in infarct volumes also was found when the kynurenine hydroxylase inhibitors were given to rats after p ermanent middle cerebral artery occlusion (from 207 +/- 111 mm(3) in ve hid e-treated rats to 82 +/- 18 and to 62 +/- 57 mm(3) in rats treated with mNB A, 400 mg/kg intraperitoneally, or with Ro 61-8048, 40 mg/kg intraperitonea lly, respectively). The administration of mNBA (400 mg/kg intraperitoneally ) or Ro 61-8048 (40 mg/kg intraperitoneally) to gerbils with a dialysis pro be in their dorsal hippocampus or to rats with a dialysis probe in their pa rietal cortex significantly increased kynurenic acid concentration in the d ialysates. The data suggest that inhibition of kynurenine hydroxylase could be a new avenue to reduce neuronal loss in brain ischemia.