The effect of pre- and posttreatment with diazoxide on the early phase of chronic cerebral hypoperfusion in the rat
The effect of pre- and posttreatment with diazoxide on the early phase of chronic cerebral hypoperfusion in the rat
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DOI：
10.1016/j.brainres.2006.02.134
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发表时间：
2006-05-04
期刊：
影响因子：
2.9
通讯作者：
Bari, F
中科院分区：
文献类型：
--
作者：
Farkas, E;Instit贸ris, A;Bari, F
二氮嗪已被证实是一种线粒体依赖的K+通道开放剂，在缺血条件下是一种潜在的神经保护化合物。我们开始在慢性脑低灌流的大鼠模型中表征二氮卓不同治疗策略的结果。永久性双侧颈总动脉结扎(2VO，n=36)造成大鼠脑低灌注，假手术组(Sham，n=29)作为对照。二氮嗪或其赋形剂于术前或术后每日ip(5×0.5 mg/kg/0.25ml)或团注(5 mg/kg/0.25ml)。2VO后1周在Morris迷宫评估大鼠的空间学习成绩。在甲酚紫染色的切片上评估海马锥体细胞的丢失，同时用免疫细胞化学标记胶质细胞的反应性。每日或团注二氮卓预处理可显著改善2VO相关的学习障碍，而后处理无效。2VO可减少CA1区锥体神经元的数量，而二氮嗪重复或团注可阻止这一作用。与假手术组比较，二氮嗪可促进2VO大鼠海马CA1区星形胶质细胞的增殖和小胶质细胞的激活。这些数据表明，二氮嗪的神经保护作用依赖于缺血开始时的给药时间；该化合物被证明在慢性脑低灌流时具有神经保护作用，但不是在治疗后。因此，二氮卓预处理为脑缺血的治疗提供了广阔的前景。(C)2006爱思唯尔B.V.保留所有权利。
Diazoxide has been identified as a mitochondrial, ATP-dependent K+ channel opener, and a potentially neuroprotective compound under ischemic conditions. We set out to characterize the consequences of various treatment strategies with diazoxide in a rat model of chronic cerebral hypoperfusion. Cerebral hypoperfusion was induced by permanent, bilateral occlusion of the common carotid arteries (2VO, n = 36), sham-operated rats serving as controls (SHAM, n = 29). Diazoxide or its vehicle was administered i. p. daily (5 x 0.5 mg/kg/0.25 ml) or as a bolus injection (5 mg/kg/0.25 ml) before surgery or daily after surgery (5 x 0.5 mg/kg/0.25 ml). Spatial learning performance was assessed 1 week after 2VO in the Morris maze. Hippocampal pyramidal cell loss was assessed on cresyl violet-stained sections, while glial reactivity was labeled immunocytochemically. Daily or bolus pretreatment with diazoxide significantly improved 2VO-related learning impairment, whereas posttreatment was ineffective. The number of CA1 pyramidal neurons was reduced by 2VO, which was prevented by repeated or bolus pretreatment with diazoxide. Astrocyte proliferation and microglial activation were enhanced by posttreatment with diazoxide in the hippocampus CA1 area of 2VO animals as compared with SHAM. These data demonstrate that the neuroprotective effect exerted by diazoxide depends on the time of administration with respect to the onset of ischemia; pretreatment but not posttreatment with the compound has proved to be neuroprotective in chronic cerebral hypoperfusion. Thus, pretreatment with diazoxide offers therapeutical prospects for the treatment of cerebral ischemia. (c) 2006 Elsevier B.V. All rights reserved.