Neuronal mdr-1 gene expression after experimental focal hypoxia: A new obstacle for neuroprotection?
Neuronal mdr-1 gene expression after experimental focal hypoxia: A new obstacle for neuroprotection?
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DOI：
10.1016/j.jns.2007.03.004
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发表时间：
2007-07-15
影响因子：
4.4
通讯作者：
Brusco, Alicia
中科院分区：
文献类型：
--
作者：
Lazarowski, Alberto;Caltana, Laura;Brusco, Alicia
中风相关脑缺氧后的神经元损伤是长期残疾和死亡的主要原因。脑缺血后 3 小时后神经保护治疗策略的无效性尚不清楚。 P-糖蛋白（P-gp）是多药耐药基因（MDR-1）的产物，通常在血脑屏障表达。 P-gp 神经元表达已在难治性癫痫和脑缺血后得到证实。在本报告中，我们研究了通过立体定位手术在雄性成年大鼠（Bregma - 1.30 mm）的额顶皮质局部注射CoCl2（1-200 mM）后缺氧诱导的神经元P-gp表达。使用特异性单克隆抗体分析脑切片的 P-gp 免疫染色，并使用特异性星形细胞和神经元标记物进行双重免疫标记。注射1 mM CoCl2 5天后，在神经元、毛细血管上的星形胶质细胞末端和血管上的内皮细胞中观察到病变部位周围的P-gp表达。较高的 CoCl2 剂量 (200 mM) 导致整个星形胶质细胞和神经元细胞质的额外 P-gp 免疫染色。电子显微镜 (EM) 研究显示，注射 CoCl2 后 6 小时，神经元就发生了变化。缺氧神经元和星形胶质细胞终足中的 P-gp 表达可能会损害药物进入脑实质，因此表明存在两种基于 P-gp 的泵系统（一种在星形胶质细胞中，另一种在缺氧神经元中），它们能够充当神经保护药理学策略的先前未被注意到的障碍。 (c) 2007 Elsevier B.V. 保留所有权利。
Neuronal damage after stroke-associated brain hypoxia is a leading cause of long-term disability and death. The refractoriness to therapeutic strategies for neuroprotection after 3 h post brain ischemia is poorly understood. P-glycoprotein (P-gp), the multidrug resistance gene (MDR-1) product is normally expressed at blood-brain-barrier. P-gp neuronal expression has been demonstrated in refractory epilepsy and after brain ischemia. In this report we investigated the hypoxia-induced neuronal P-gp expression after local injection of CoCl2 (1-200 mM) in the frontoparietal cortex of male adult rats (Bregma - 1.30 mm) by stereotaxic surgery. P-gp immunostaining of brain slides was analyzed using specific monoclonal antibodies and double immunolabeling was done with specific astrocytic and neuronal markers. Five days after injection of 1 mM CoCl2, P-gp expression surrounding the lesion site was observed in neurons, astrocytic end-foot on capillary blood vessels and endothelial cells on blood vessels. Higher CoCl2 doses (200 mM) resulted in additional P-gp immunostaining of the entire astrocytic and neuronal cytoplasm. Electron microscopy (EM) studies showed alterations in neurons as early as 6 h after the CoCl2, injection. P-gp expression in hypoxic neurons and astrocytic end-foot could potentially impair of drugs access to the brain parenchyma thus suggesting the presence of two P-gp-based pumping systems (one in astrocytes and other in the hypoxic neurons) that are able to behave as a previously unnoticed obstacle for pharmacological strategies of neuroprotection. (c) 2007 Elsevier B.V. All rights reserved.