Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain

Abstract

Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs.

Acute effects of focused ultrasound-induced increases in blood-brain barrier permeability on rat microvascular transcriptome

“…Previous work by Cho et al . has shown that FUS induces a downregulation in immunodetection of P-gp 24 hrs post-sonication43. Results presented here are consistent with this finding, as there was a significant reduction in Abcb1a gene expression 6 hrs following FUS.…”

Physical blood-brain barrier disruption induced by focused ultrasound does not overcome the transporter-mediated efflux of erlotinib

“…Interestingly, several studies suggested that FUS may not restrict to the "physical" disruption, but might also impact BBB physiology [26]. Using similar conditions to ours, Cho and colleagues reported a decrease in ABCB1 expression at the BBB of the sonicated area, 24 h after FUS [28]. Aryal et al, confirmed this observation and showed that the effect was maximum 48 h post FUS (~50% decrease) [27].…”

“…It can be hypothesized that ABC-transporter function may be modulated by BBB integrity. Recent studies have reported an impact of FUS-induced BBB disruption on the rat microvascular transcriptome [26] and a delayed decrease in ABCB1 expression in the sonicated area, 24 to 48 h after FUS [27,28]. This suggests that erlotinib, which brain distribution is mainly governed by ABC-transporter mediated efflux at the BBB, may benefit from the immediate and/or delayed impact of FUSinduced BBB disruption as a strategy to locally improve its brain delivery.…”

A dynamic in-vitro model of the intestinal epithelium for the investigation of P-glycoprotein activity

“…It is also worth noticing that differing events regarding the modulation of the protein by the presence of uid ow have been reported not only in intestinal models. For instance, a study by Garcia-Polite et al demonstrated that the protein activity had a peak when endothelial cells were subjected to a shear stress of 1 Pa and that it decreased for a shear stress of 4 Pa (40); while there is a contrasting hypothesis that P-gp is down regulated in arterioles of rat brain in response to a higher shear stress (41,42). Nevertheless, the shear stress provided by the ow in the present study is below the mentioned ranges and suggests that these cells are highly sensitive to even low levels of mechanical stimuli.…”