Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion
Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion
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DOI：
10.1016/j.brainres.2004.02.037
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发表时间：
2004-05-22
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;Institóris, A;Bari, F
慢性脑灌注不足是一种轻度缺血性疾病，与年龄增长和痴呆的严重程度有关;然而，尚未建立一致的治疗方法来缓解相关的神经系统症状。我们对大鼠（n = 18）的颈总动脉进行永久性双侧闭塞，以产生脑灌注不足。手术后连续5天腹腔注射线粒体ATP敏感性K+通道开放剂二氮嗪（DZ，5 mg/kg）或其溶剂二甲基亚砜（DMSO）（0.25 ml）。假手术动物（n = 18）作为手术对照，而未处理大鼠作为处理对照。在脑灌注不足发作三个月后，大鼠在一个与大脑皮层相关的学习范例中进行测试，即Morris水迷宫。随后，处死动物，用免疫细胞化学标记背侧海马中的神经元、星形胶质细胞和小胶质细胞。DMSO和溶解于DMSO中的二氮嗪恢复了脑灌注不足相关的学习功能障碍，并防止了齿状回中环氧合酶-2阳性神经元的丢失。脑灌注不足导致星形胶质细胞增殖减少，这并不明显受到治疗的影响。小胶质细胞的激活大大增强脑灌注不足，这是完全防止二氮嗪溶解在DMSO中，但不是由DMSO单独。我们的结论是，二氮嗪可以通过抑制小胶质细胞活化来减轻缺血相关的神经炎症。此外，我们认为DMSO是一种在缺血条件下具有神经保护作用的化学物质，在实验动物模型中必须谨慎地用作水不溶性化合物的溶剂。(C)2004 Elsevier B. V.保留所有权利。
Chronic cerebral hypoperfusion, a mild ischemic condition is associated with advancing age and severity of dementia; however, no unanimous therapy has been established to alleviate related neurological symptoms. We imposed a permanent, bilateral occlusion of the common carotid arteries of rats (n = 18) to create cerebral hypoperfusion. A mitochondrial ATP-sensitive K+ channel opener diazoxide (DZ, 5 mg/kg) or its solvent dimethyl sulphoxide (DMSO) were administered i.p. (0.25 ml) on five consecutive days after surgery. Sham-operated animals (n = 18) served as control for the surgery, while nontreated rats were used as control for the treatments. Three months after the onset of cerebral hypoperfusion, the rats were tested in a hippocampus-related learning paradigm, the Morris water maze. Subsequently, the animals were sacrificed and neurons, astrocytes and microglia were labeled with immunocytochemistry in the dorsal hippocampus. DMSO and diazoxide dissolved in DMSO restored cerebral hypoperfusion-related learning dysfunction and prevented cyclooxygenase-2-positive neuron loss in the dentate gyrus. Cerebral hypoperfusion led to reduced astrocyte proliferation, which was not clearly affected by the treatment. Microglia activation was considerably enhanced by cerebral hypoperfitsion, which was completely prevented by diazoxide dissolved in DMSO, but not by DMSO alone. We conclude that diazoxide can moderate ischemia-related neuroinflammation by suppressing microglial activation. Furthermore, we suggest that DMSO is, a neuroprotective chemical in ischemic conditions, and it must be considerately used as a solvent for water-insoluble compounds in experimental animal models. (C) 2004 Elsevier B.V. All rights reserved.