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

Abstract

Two kynurenine hydroxylase inhibitors, ( m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfonamide (Ro 61-8048), have been tested as neuroprotective agents on brain lesions induced by bilateral carotid occlusion in gerbils or by middle cerebral artery occlusion in rats. The percentage of lesioned pyramidal neurones found in the hippocampal CA1 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 minutes after occlusion) or to 10±11% after Ro 61-8048 (40 mg/kg intraperitoneally, three times). A significant reduction in infarct volumes also was found when the kynurenine hydroxylase inhibitors were given to rats after permanent middle cerebral artery occlusion (from 207 ± 111 mm 3 in vehicle-treated rats to 82 ± 18 and to 62 ± 57 mm 3 in rats treated with mNBA, 400 mg/kg intraperitoneally, or with Ro 61-8048, 40 mg/kg intraperitoneally, respectively). The administration of mNBA (400 mg/kg intraperitoneally) or Ro 61-8048 (40 mg/kg intraperitoneally) to gerbils with a dialysis probe in their dorsal hippocampus or to rats with a dialysis probe in their parietal cortex significantly increased kynurenic acid concentration in the dialysates. The data suggest that inhibition of kynurenine hydroxylase could be a new avenue to reduce neuronal loss in brain ischemia.