Cozzi A, Carpenedo R, Moroni F
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
J Cereb Blood Flow Metab. 1999 Jul;19(7):771-7. doi: 10.1097/00004647-199907000-00007.
Two kynurenine hydroxylase inhibitors, (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfona mide (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 mm3 in vehicle-treated rats to 82+/-18 and to 62+/-57 mm3 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.
两种犬尿氨酸羟化酶抑制剂，（间硝基苯甲酰基）-丙氨酸（mNBA）和3,4-二甲氧基-[ -N-4-（硝基苯基）噻唑-2-基]-苯磺酰胺（Ro 61-8048），已作为神经保护剂在沙土鼠双侧颈动脉闭塞或大鼠大脑中动脉闭塞诱导的脑损伤模型上进行了测试。在沙土鼠双侧颈动脉闭塞5分钟后，在海马CA1区发现的受损锥体神经元百分比，从溶剂处理组动物的92±10%，在给予mNBA（腹腔注射400mg/kg，在闭塞后1、30和180分钟给药三次）后降至7±6%，或在给予Ro 61-8048（腹腔注射40mg/kg，给药三次）后降至10±11%。当在大鼠永久性大脑中动脉闭塞后给予犬尿氨酸羟化酶抑制剂时，也发现梗死体积显著减小（从溶剂处理组大鼠的207±111mm³，分别降至腹腔注射400mg/kg mNBA或40mg/kg Ro 61-8048处理组大鼠的82±18mm³和62±57mm³）。对背侧海马植入透析探针的沙土鼠或对顶叶皮质植入透析探针的大鼠腹腔注射mNBA（400mg/kg）或Ro 61-8048（40mg/kg），显著增加了透析液中犬尿酸的浓度。数据表明，抑制犬尿氨酸羟化酶可能是减少脑缺血中神经元损失的一条新途径。
