Attenuated function and expression of P-glycoprotein at blood-brain barrier and increased brain distribution of phenobarbital in streptozotocin-induced diabetic mice
Attenuated function and expression of P-glycoprotein at blood-brain barrier and increased brain distribution of phenobarbital in streptozotocin-induced diabetic mice
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DOI：
10.1016/j.ejphar.2007.01.062
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发表时间：
2007-04-30
影响因子：
5
通讯作者：
Liu, Li
中科院分区：
文献类型：
--
作者：
Liu, HaiYan;Zhang, DongMei;Liu, Li
本研究旨在探讨糖尿病是否对链脲佐菌素诱导的3周糖尿病小鼠脑内P-糖蛋白的功能和表达以及苯巴比妥的分布有影响。通过测量非糖尿病小鼠和糖尿病小鼠中的罗丹明123（一种众所周知的P-糖蛋白底物）的脑与血浆浓度比来评估血脑屏障中的P-糖蛋白功能。用蛋白质印迹法检测脑皮质中P-糖蛋白的表达。糖尿病是否改变苯巴比妥（60 mg/kg，i. v.）测定小鼠脑中的分布，并研究分布的改变是否导致非糖尿病小鼠和糖尿病小鼠中苯巴比妥（80和100 mg/kg）诱导的翻正反射丧失的差异。结果显示，糖尿病小鼠脑/血浆罗丹明123浓度比值显著高于非糖尿病小鼠，western blot提示糖尿病3周小鼠脑P-糖蛋白水平显著低于非糖尿病小鼠，胰岛素治疗可恢复P-糖蛋白的损伤。糖尿病小鼠脑中苯巴比妥的暴露量是非糖尿病小鼠的1.30倍，而血浆中的暴露量是1.09倍。苯巴比妥在糖尿病小鼠脑中分布的增加显著增加了苯巴比妥诱导的翻正反射丧失的持续时间，并减少了翻正反射丧失的潜伏期。提示糖尿病小鼠脑内P-糖蛋白的功能和表达受损，苯巴比妥的脑内分布增加。(c)2007 Elsevier B. V.保留所有紧身衣。
The aim of the study was to investigate whether diabetes mellitus modulated the function and expression of P-glycoprotein and the distribution of phenobarbital in the brain of 3-week streptozotocin-induced diabetic mice. P-glycoprotein function in blood-brain barrier was assessed by measuring the brain-to-plasma concentration ratios of rodamine123, a well-known P-glycoprotein substrate, in non-diabetic mice and diabetic mice. P-glycoprotein expression in the brain cortex was evaluated with western blot. Whether diabetes mellitus changed the distribution of phenobarbital (60 mg/kg, i.v.) in brain of mice was measured, and whether the changed distribution caused the difference of phenobarbital (80 and 100 mg/kg)-induced loss of the righting reflex in non-diabetic and diabetic mice were also investigated. The results showed that the brain-to-plasma concentration ratio value of rodamine123 in diabetic mice was significantly higher than that of non-diabetic mice, western blot suggested that the protein level of P-glycoprotein in the brain of 3-week diabetic mice was significantly lower than that of non-diabetic mice, and insulin treatment restored the impairment of P-glycoprotein. The exposure of phenobarbital in brain of diabetic mice was 1.30-fold of that of non-diabetic mice, while in plasma the fold was 1.09. The increased distribution of phenobarbital in the brain of diabetic mice significantly increased the duration of Phenobarbital-induced loss of the righting reflex and reduced the latency time of loss of the righting reflex. All the results suggested that the function and expression of P-glycoprotein might be impaired and the brain distribution of phenobarbital was increased in brain of streptozotocin-induced diabetic mice. (c) 2007 Elsevier B.V. All tights reserved.