Effect of heat preconditioning on the uptake and permeability of R123 in brain microvessel endothelial cells during mild heat treatment
Effect of heat preconditioning on the uptake and permeability of R123 in brain microvessel endothelial cells during mild heat treatment
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DOI：
10.1002/jps.20015
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发表时间：
2004-04-01
影响因子：
3.8
通讯作者：
Tanguay, RL
中科院分区：
文献类型：
--
作者：
Ng, KY;Cho, CW;Tanguay, RL
本研究的目的是评估在血脑屏障（BBB）的细胞培养模型中，轻度加热和热预处理对P-糖蛋白（P-gp）底物罗丹明123（R123）的摄取和渗透性的影响。一个直接的目标是确定先前的轻度热处理是否可以使脑微血管内皮细胞对未来的热应激更具抵抗力，并通过未来的超声诱导的轻度热（USMH）处理影响BBB药物渗透。为了解决这一问题，研究了热预处理和未热预处理的牛脑微血管内皮细胞（BBMEC）单层中P-gp和热休克蛋白70（Hsp 70）两种蛋白的表达水平及其对R123摄取以及R123和[C-14] -蔗糖与温和加热和P-gp调节剂PSC 833联合使用的渗透性的影响。与对照组和PSC 833相比，轻度加热导致R123和[C-14] -蔗糖的BBB渗透性显著增加。暴露于热预处理BBMEC引起轻微的，但不显著的减少细胞摄取的R123在温和的热处理过程中和后立即。热预处理也引起轻微的，但不显著的降低R123和[C-14] -蔗糖在BBMEC单层的渗透性在温和的热处理。由于暴露于温和的热BBMEC单层不影响P-gp的表达，但略有影响Hsp 70的表达，热预处理，结果在BBB的加强而不是P-gp的表达增加的建议。然而，热预处理是不足以推翻温和的热的渗透增强作用，因为温和的热引起的R123的吸收和渗透性的R123和[C-14]-蔗糖在热预处理和热非条件细胞显着增加。由于已知Hsp 70在细胞修复和保护机制中起主要作用，因此我们的结果意味着温和热处理的相对良性性质。由于超声波产生的热量可以控制并定位在组织内的小体积内，因此目前的结果还表明USMH可以在治疗脑肿瘤和其他脑相关疾病中发挥关键作用。(C)2004 Wiley-Liss，Inc.和美国药学协会药物科学杂志93：896-907，2004。
The purpose of this study was to assess the effect of mild heat and heat preconditioning on the uptake and permeability of a P-glycoprotein (P-gp) substrate, rhodamine 123 (R123), in a cell culture model of the blood-brain barrier (BBB). An immediate goal was to determine whether prior mild heat treatment could render brain microvessel endothelial cells more resistant to future heat stress and affect BBB drug permeation by future ultrasound-induced mild heat (USMH) treatment. To address this issue, the expression level of two proteins, P-gp and heat shock protein 70 (Hsp70), and their effects on uptake of R123 and permeability of R123 and [C-14] -sucrose in combination with mild heat and P-gp modulator PSC833 during and after mild heat treatment in heat-preconditioned and heat-unconditioned bovine brain microvessel endothelial cell (BBMEC) monolayers were studied. Mild heat caused a significant increase in BBB permeability of R123 and [C-14] -sucrose when compared with control and PSC833. Exposure of BBMECs to heat preconditioning caused a slight but insignificant decrease in cellular uptake of R123 both during and immediately after mild heat treatment. Heat preconditioning also caused a slight but insignificant decrease in permeability of R123 and [C-14] -sucrose in BBMEC monolayers during mild heat treatment. Because exposure of BBMEC monolayers to mild heat did not affect P-gp expression but slightly affected Hsp70 expression, a heat preconditioning that results in a reinforcement of the BBB other than increased expression of P-gp is suggested. However, heat preconditioning is not sufficient to override the permeation-enhancing effects of mild heat because mild heat caused a significant increase in R123 uptake and permeability of R123 and [C-14]-sucrose in both heat-preconditioned and heat-unconditioned cells. Because Hsp70 is known to play a major role in cellular repair and protective mechanisms, our results would imply a relative benign nature of mild heat treatment. Because heating produced by ultrasonic waves can be controlled and localized to a small volume within the tissue, the present results also suggest that USMH could play a pivotal role in the treatment of brain tumors and other brain-related diseases. (C) 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:896-907, 2004.