Miah Mohammad K, Bickel Ulrich, Mehvar Reza
Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
Clinical Pharmacology & Quantitative Pharmacology, CPSS, AstraZeneca, Boston, Massachusetts, USA.
Metab Brain Dis. 2024 Dec 5;40(1):53. doi: 10.1007/s11011-024-01486-6.
Contradictory results have been reported about the effects of liver diseases on the blood-brain barrier (BBB) permeability to markers. For instance, both an increase and no change in the BBB permeability to BBB markers sodium fluorescein and Evans blue have been reported in experimental cholestasis induced by bile duct ligation (BDL) in rats. These contradictory effects might be due to inherent limitations of these markers and/or methodological issues. Here, we investigated the time course of the impact of BDL in rats on BBB permeability using a recently developed stable isotope labeled marker [C]sucrose, which is expected to be devoid of limitations of other markers, such as sodium fluorescein. At various times (five days, two weeks, and four weeks) after BDL or sham surgery, the brain uptake clearance (K) of [C]sucrose was estimated using quantitation of the marker in plasma, blood, and brain by a specific LC-MS/MS analytical method. BDL caused substantial increases in the plasma concentrations of liver biochemical markers (bilirubin, total bile acids, ammonia, and cholesterol) and reduced liver cytochrome P450 content and metabolic activities. However, compared with the sham group, the plasma or blood AUC, brain concentrations, and K of [C]sucrose in BDL animals remained unchanged at all the studied times. Additionally, we observed a negative correlation between the sucrose K and plasma total bile acids concentrations in the BDL animals. It is concluded that cholestatic liver disease, induced by BDL surgery in rats, does not significantly affect the BBB permeability to sucrose up to 4 weeks after the surgery.
关于肝脏疾病对血脑屏障（BBB）对标志物通透性的影响，已有相互矛盾的报道。例如，在大鼠胆管结扎（BDL）诱导的实验性胆汁淤积中，已报道血脑屏障对血脑屏障标志物荧光素钠和伊文思蓝的通透性增加和无变化。这些相互矛盾的影响可能是由于这些标志物的固有局限性和/或方法学问题。在此，我们使用最近开发的稳定同位素标记标志物[C]蔗糖研究了BDL对大鼠血脑屏障通透性影响的时间进程，预计该标志物没有其他标志物（如荧光素钠）的局限性。在BDL或假手术后的不同时间（五天、两周和四周），通过特定的液相色谱-串联质谱（LC-MS/MS）分析方法对血浆、血液和脑中的标志物进行定量，以估计[C]蔗糖的脑摄取清除率（K）。BDL导致肝脏生化标志物（胆红素、总胆汁酸、氨和胆固醇）的血浆浓度大幅增加，并降低了肝脏细胞色素P450含量和代谢活性。然而，与假手术组相比，BDL动物在所有研究时间点的血浆或血液曲线下面积（AUC）、脑浓度和[C]蔗糖的K均保持不变。此外，我们观察到BDL动物中蔗糖K与血浆总胆汁酸浓度之间呈负相关。得出的结论是，大鼠BDL手术诱导的胆汁淤积性肝病在手术后4周内不会显著影响血脑屏障对蔗糖的通透性。
