ATP-dependent potassium channel blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats
ATP-dependent potassium channel blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats
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DOI：
10.1016/j.expneurol.2012.02.010
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发表时间：
2012-05-01
影响因子：
5.3
通讯作者：
Rodriguez, M. J.
中科院分区：
文献类型：
--
作者：
Ortega, F. J.;Gimeno-Bayon, J.;Rodriguez, M. J.
中风导致CNS损伤，与作为炎症反应的一部分的强烈快速小胶质细胞活化相关。在大鼠中风模型中，磺脲类药物受体阻断剂格列本脲可减少脑水肿和梗死体积。我们推测，在中风早期给予格列本脲可能通过ATP敏感性钾（K-ATP）通道阻滞促进神经保护性小胶质细胞活性。我们在体外发现，BV 2细胞系在对促炎信号的反应中表现出K-ATP通道亚基的表达上调，格列本脲增加了小胶质细胞的反应性形态、吞噬能力和TNF α释放。此外，在短暂性大脑中动脉闭塞后6、12和24 h给予大鼠格列本脲可改善神经功能结局，并在再灌注后3天保留损伤核心中的神经元。免疫组化显示，坏死区的主要细胞群为变形样小胶质细胞，这些细胞是神经元、星形胶质细胞、小胶质细胞和淋巴细胞。这些反应性小胶质细胞表达在功能性K-ATP通道中组装的SUR 1、SUR 2B和Kir6.2蛋白。这些发现提供了K-ATP通道在控制小胶质细胞反应性中的关键作用的证据，与格列本脲对缺血性脑的小胶质细胞作用一致，并表明小胶质细胞在卒中早期具有神经保护作用。(C)2012 Elsevier Inc. All rights reserved.
Stroke causes CNS injury associated with strong fast microglial activation as part of the inflammatory response. In rat models of stroke, sulphonylurea receptor blockade with glibenclamide reduced cerebral edema and infarct volume. We postulated that glibenclamide administered during the early stages of stroke might foster neuroprotective microglial activity through ATP-sensitive potassium (K-ATP) channel blockade. We found in vitro that BV2 cell line showed upregulated expression of K-ATP, channel subunits in response to pro-inflammatory signals and that glibenclamide increases the reactive morphology of microglia, phagocytic capacity and TNF alpha release. Moreover, glibenclamide administered to rats 6, 12 and 24 h after transient Middle Cerebral Artery occlusion improved neurological outcome and preserved neurons in the lesioned core three days after reperfusion. Immunohistochemistry with specific markers to neuron, astroglia, microglia and lymphocytes showed that resident amoeboid microglia are the main cell population in that necrotic zone. These reactive microglial cells express SUR1, SUR2B and Kir6.2 proteins that assemble in functional K-ATP channels. These findings provide that evidence for the key role of K-ATP channels in the control of microglial reactivity are consistent with a microglial effect of glibenclamide into the ischemic brain and suggest a neuroprotective role of microglia in the early stages of stroke. (C) 2012 Elsevier Inc. All rights reserved.