Liu Haiyan, Xu Xiao, Yang Zhihong, Deng Yuanxiong, Liu Xiaodong, Xie Lin
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Brain Res. 2006 Dec 6;1123(1):245-52. doi: 10.1016/j.brainres.2006.09.061. Epub 2006 Oct 30.
The aim was to investigate the effect of diabetes mellitus (DM) on P-glycoprotein (P-GP) function and expression in rat blood-brain barrier (BBB). P-GP function in BBB was assessed by measuring the brain-to-plasma concentration ratios (Kp values) of rhodamine 123 (Rho123) and vincristine (VCR), two well-known P-GP substrates, in control rats and 5-week streptozotocin (STZ)-induced diabetic rats. Evans blue (EB) dye was used as a BBB integrity indicator for examining the extravasation from the blood into the brain. P-GP expression in the brain cortex was evaluated with Western blot. The uptakes of Rho123 and VCR by cultured rat brain microvessel endothelial cells (rBMECs) incubated in diabetic and control rat serum for 72 h were also used to examine P-GP function, respectively. It was found that the Kp value of Rho123 (0.022+/-0.005 vs. 0.016+/-0.002 ml/g brain, p=0.033) and VCR (0.072+/-0.028 vs. 0.023+/-0.006 ml/g brain, p=0.006) in diabetic rats was significantly higher than that in control rats. The uptakes of Rho123 and VCR by cultured rBMECs incubated in the diabetic rat serum were higher than that in the control rat serum, respectively. No significant difference of the EB concentration in the brain cortex was found between the diabetic rats and control rats. Electron microscope examination of the brain cortex did not show a clear damage to the endothelial cells of microvessel in diabetic rats. In addition, the protein level of P-GP in the brains of the diabetic rats examined was significantly lower than that of control rats. These results suggested that the function and expression of P-GP might be impaired in the BBB of STZ-induced diabetic rats.
目的是研究糖尿病（DM）对大鼠血脑屏障（BBB）中P-糖蛋白（P-GP）功能和表达的影响。通过测量对照大鼠和5周链脲佐菌素（STZ）诱导的糖尿病大鼠中两种著名的P-GP底物罗丹明123（Rho123）和长春新碱（VCR）的脑-血浆浓度比（Kp值）来评估BBB中的P-GP功能。伊文思蓝（EB）染料用作BBB完整性指标，用于检查从血液到脑内的外渗情况。用蛋白质印迹法评估大脑皮质中P-GP的表达。分别用在糖尿病和对照大鼠血清中孵育72小时的培养大鼠脑微血管内皮细胞（rBMECs）对Rho123和VCR的摄取来检查P-GP功能。结果发现，糖尿病大鼠中Rho123的Kp值（0.022±0.005 vs. 0.016±0.002 ml/g脑，p = 0.033）和VCR的Kp值（0.072±0.028 vs. 0.023±0.006 ml/g脑，p = 0.006）显著高于对照大鼠。在糖尿病大鼠血清中孵育的培养rBMECs对Rho123和VCR的摄取分别高于对照大鼠血清中的摄取。糖尿病大鼠和对照大鼠大脑皮质中EB浓度无显著差异。糖尿病大鼠大脑皮质的电子显微镜检查未显示微血管内皮细胞有明显损伤。此外，所检测的糖尿病大鼠大脑中P-GP的蛋白水平显著低于对照大鼠。这些结果表明，STZ诱导的糖尿病大鼠BBB中P-GP功能和表达可能受损。
