Smith S E, Hodges H, Sowinski P, Man C M, Leach M J, Sinden J D, Gray J A, Meldrum B S
Department of Neurology, Institute of Psychiatry, Denmark Hill, London, UK.
Neuroscience. 1997 Apr;77(4):1123-35. doi: 10.1016/s0306-4522(96)00530-1.
4-Amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)pyrimidine (BW619C89) is a sodium channel antagonist which when administered parenterally reduces neurological deficit and infarct volume after middle cerebral artery occlusion in rats. We have investigated whether BW619C89 administered orally before middle cerebral artery occlusion is cerebroprotective when rats are assessed at one day after stroke, and whether cerebroprotection is long lasting and related to functional recovery. A cerebroprotective oral dose of BW619C89 (20 mg/kg) was used to determine whether reduction in infarct volume is long lasting and can be enhanced with continued therapy, and whether behavioural deficits occurring after middle cerebral artery occlusion such as disturbances in cognition and motor coordination are ameliorated by treatment with BW619C89. Rats received sham surgery or middle cerebral artery occlusion with a single treatment of BW619C89 (20 mg/kg) 1 h before middle cerebral artery occlusion, a double treatment group receiving 20 mg/kg BW619C89 1 h before and 10 mg/kg 5 h after middle cerebral artery occlusion, or continued treatment with BW619C89 for up to five days. Neurological deficit, assessed from days 1 to 21, and at 70 days after middle cerebral artery occlusion, was reduced to a similar extent in all three groups of rats treated with BW619C89, compared with vehicle-treated controls. At 70 days after middle cerebral artery occlusion, all groups performed at control level. Vehicle-treated rats were impaired in the Morris water maze and step-through passive avoidance paradigm five to eight weeks after middle cerebral artery occlusion, when neurological deficit was minimal. These deficits were partially alleviated, to a similar extent, by all of the three treatments with BW619C89. Total volumes of brain damage, assessed at 70 days after middle cerebral artery occlusion in Luxol Fast Blue- and Cresyl Violet-stained coronal sections, were reduced in all three groups of BW619C89-treated rats, to 46% in the single, 50% in the double and 58% in the continued treatment group, compared with vehicle-treated rats. Extent of brain damage correlated with extent of impairment of the rats in the water maze. These findings suggest that BW619C89 has long-lasting cerebroprotective effects with advantageous functional consequences after single oral administration in a rodent model of stroke. Prolonged treatment with BW619C89 did not significantly enhance the cerebroprotective effects. Deficits in performance of rats in the water maze and step-through passive avoidance tasks indicate sustained cognitive impairment after middle cerebral artery occlusion. The reductions in brain damage by BW619C89 correlated with significant long-term functional improvement.
4-氨基-2-(4-甲基-1-哌嗪基)-5-(2,3,5-三氯苯基)嘧啶(BW619C89)是一种钠通道拮抗剂，经肠胃外给药可减少大鼠大脑中动脉闭塞后的神经功能缺损和梗死体积。我们研究了在大脑中动脉闭塞前口服BW619C89，在中风后一天评估大鼠时是否具有脑保护作用，以及脑保护作用是否持久并与功能恢复相关。使用脑保护口服剂量的BW619C89(20mg/kg)来确定梗死体积的减小是否持久以及持续治疗是否可增强这种作用，以及大脑中动脉闭塞后出现的行为缺陷(如认知和运动协调障碍)是否可通过BW619C89治疗得到改善。大鼠接受假手术或大脑中动脉闭塞，其中一组在大脑中动脉闭塞前1小时单次给予BW619C89(20mg/kg)，双次治疗组在大脑中动脉闭塞前1小时给予20mg/kg BW619C89，在大脑中动脉闭塞后5小时给予10mg/kg，或持续用BW619C89治疗长达五天。与给予赋形剂的对照组相比，在大脑中动脉闭塞后第1天至第21天以及第70天评估的神经功能缺损，在所有三组接受BW619C89治疗的大鼠中均有相似程度的降低。在大脑中动脉闭塞后70天，所有组的表现均达到对照水平。给予赋形剂的大鼠在大脑中动脉闭塞后五至八周，当神经功能缺损最小时，在莫里斯水迷宫和穿梭式被动回避范式中表现受损。所有三种BW619C89治疗在相似程度上部分减轻了这些缺陷。在卢索尔坚牢蓝和甲酚紫染色的冠状切片中，在大脑中动脉闭塞后70天评估的脑损伤总体积，在所有三组接受BW619C89治疗的大鼠中均减小，单次治疗组为46%，双次治疗组为50%，持续治疗组为58%，而给予赋形剂的大鼠为对照。脑损伤程度与大鼠在水迷宫中的受损程度相关。这些发现表明，在啮齿动物中风模型中，单次口服BW619C89具有持久的脑保护作用，并具有有利的功能后果。延长BW619C89治疗并未显著增强脑保护作用。大鼠在水迷宫和穿梭式被动回避任务中的表现缺陷表明大脑中动脉闭塞后存在持续的认知障碍。BW619C89对脑损伤的减轻与显著的长期功能改善相关。
