Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
J Pharm Sci. 2019 Jul;108(7):2247-2255. doi: 10.1016/j.xphs.2019.01.030. Epub 2019 Feb 7.
Previous studies have demonstrated that the ionophore clioquinol (CQ), in conjunction with the biometals copper and zinc, increases the expression of P-glycoprotein (P-gp) in human cerebral microvascular endothelial (hCMEC/D3) cells. As P-gp expression and function at the blood-brain barrier (BBB) is of great interest regarding CNS drug access and endogenous toxin trafficking (e.g., amyloid beta), the present study assessed the in vivo translation of these previous in vitro findings. Swiss outbred mice received an 11-day treatment of CQ (30 mg/kg) by oral gavage, after which brain microvessel-enriched fractions (MEFs) and surrounding interfaces (subcortical brain tissue and plasma) were extracted. P-gp expression was quantified in the MEF, and biometal concentrations in all 3 compartments were assessed via inductively coupled plasma mass spectrometry. CQ treatment did not modify the expression of P-gp, nor copper or zinc concentrations in the brain MEF under this treatment regime. Metallomic analysis revealed, however, that CQ reduced potassium and magnesium levels in the brain MEF and also lowered brain iron levels. This study has shown that under this dosing regimen, CQ does not increase BBB P-gp expression in Swiss outbred mice, but that CQ facilitates redistribution of certain metal ions within the brain MEF, plasma, and brain parenchyma.
先前的研究表明，载离剂氯碘羟喹（CQ）与生物金属铜和锌一起使用，可增加人脑血管内皮（hCMEC/D3）细胞中 P-糖蛋白（P-gp）的表达。由于血脑屏障（BBB）处 P-gp 的表达和功能与中枢神经系统药物进入和内源性毒素转运（如淀粉样β）密切相关，因此本研究评估了这些先前体外发现的体内转化情况。瑞士杂交小鼠通过口服灌胃接受了 11 天的 CQ（30mg/kg）治疗，之后提取富含脑微血管的脑微区（MEFs）和周围界面（皮质下脑组织和血浆）。通过电感耦合等离子体质谱法在 MEF 中定量 P-gp 的表达，并评估所有 3 个隔室中的生物金属浓度。在这种治疗方案下，CQ 处理并没有改变 MEF 中 P-gp 的表达，也没有改变铜或锌的浓度。金属组学分析显示，CQ 降低了脑 MEF 中的钾和镁水平，也降低了脑铁水平。本研究表明，在这种给药方案下，CQ 不会增加瑞士杂交小鼠 BBB 上的 P-gp 表达，但 CQ 可促进脑 MEF、血浆和脑实质中某些金属离子的再分布。
