Nicotine pre-exposure reduces stroke-induced glucose transporter-1 activity at the blood-brain barrier in mice.
Nicotine pre-exposure reduces stroke-induced glucose transporter-1 activity at the blood-brain barrier in mice.
复制标题
DOI：
10.1186/s12987-015-0005-y
复制
发表时间：
2015-04-29
影响因子：
7.3
通讯作者：
Abbruscato TJ
中科院分区：
文献类型：
--
作者：
Shah KK;Boreddy PR;Abbruscato TJ
随着电子烟在吸烟和非吸烟人群中的使用越来越多，需要进行严格的研究来调查尼古丁对生物系统的影响，以确定长期的健康后果。我们以前已经表明，尼古丁发挥特定的神经血管效应，影响血脑屏障（BBB）功能，以应对中风。在这项研究中，我们研究了尼古丁对载体介导的葡萄糖转运到缺血脑的影响。具体而言，本研究调查葡萄糖转运蛋白-1（GLUT 1）的功能和表达在BBB中的局灶性脑缺血模型的小鼠预先暴露于尼古丁。通过渗透泵以4.5 mg/kg/天的剂量皮下给予尼古丁1、7或14天，以反映吸烟者中观察到的血浆水平。采用短暂性大脑中动脉闭塞（tMCAO）1h再灌注24 h的方法，建立大鼠大脑中动脉缺血再灌注（IR）模型。采用放射性标记葡萄糖原位脑灌注技术检测葡萄糖转运，免疫荧光法检测脑血管GLUT 1表达。尼古丁预暴露（1、7和14天）导致D-葡萄糖穿过BBB的流入速率（Kin）显著降低，其中在14天尼古丁输注动物中降低49%。我们观察到，与盐水灌注的假手术动物相比，盐水灌注的tMCAO动物中载体介导的葡萄糖转运通过BBB增加了41%。有趣的是，在tMCAO组中，与盐水输注的tMCAO和假手术动物相比，预先暴露于尼古丁14天的动物的葡萄糖转运增加分别显著减弱了80%和38%。此外，脑微血管内皮中GLUT 1蛋白表达的免疫荧光研究证实，盐水灌注的tMCAO动物中也诱导GLUT 1，并且在tMCAO动物中，尼古丁预暴露14天后，该蛋白表达诱导显著降低（P < 0.01）。尼古丁预暴露降低了IR增强的GLUT 1转运蛋白功能和表达在局灶性脑缺血小鼠模型的血脑屏障。这些研究表明，中风前尼古丁暴露可能会在神经血管单位（NVU）产生增强的葡萄糖剥夺状态，并可能增加中风损伤的脆弱性。
With growing electronic cigarette usage in both the smoking and nonsmoking population, rigorous studies are needed to investigate the effects of nicotine on biological systems to determine long-term health consequences. We have previously shown that nicotine exerts specific neurovascular effects that influence blood brain barrier (BBB) function in response to stroke. In this study, we investigated the effects of nicotine on carrier-mediated glucose transport into ischemic brain. Specifically, the present study investigates glucose transporter-1 (GLUT1) function and expression at the BBB in a focal brain ischemia model of mice pre-exposed to nicotine. Nicotine was administrated subcutaneously by osmotic pump at the dose of 4.5 mg/kg/day for 1, 7, or 14 days to reflect the plasma levels seen in smokers. Ischemic-reperfusion (IR) injury was induced by 1 h transient middle cerebral artery occlusion (tMCAO) and 24 h reperfusion. Glucose transport was estimated using an in situ brain perfusion technique with radiolabeled glucose and brain vascular GLUT1 expression was detected with immunofluorescence. The nicotine pre-exposure (1, 7 & 14 day) resulted in significant reduction in D-glucose influx rate (Kin) across the BBB, with a 49% reduction in 14 day nicotine-infused animals. We observed a 41% increase in carrier-mediated glucose transport across the BBB in saline-infused tMCAO animals compared to saline-infused sham animals. Interestingly, in the tMCAO group of animals pre-exposed to nicotine for 14 days had significantly attenuated increased glucose transport by 80% and 38% compared to saline-infused tMCAO and sham animals respectively. Furthermore, immunofluorescence studies of GLUT1 protein expression in the brain microvascular endothelium confirmed that GLUT1 was also induced in saline-infused tMCAO animals and this protein expression induction was reduced significantly (P < 0.01) with 14 day nicotine pre-exposure in tMCAO animals. Nicotine pre-exposure reduced the IR-enhanced GLUT1 transporter function and expression at the BBB in a focal brain ischemia mouse model. These studies suggest that nicotine exposure prior to stroke could create an enhanced glucose deprived state at the neurovascular unit (NVU) and could provide an additional vulnerability to enhanced stroke injury.