1. Imaging the impact of blood-brain barrier disruption induced by focused ultrasound on P-glycoprotein function.
- Author
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Goutal, Sébastien, Novell, Anthony, Leterrier, Sarah, Breuil, Louise, Selingue, Erwan, Gerstenmayer, Matthieu, Marie, Solène, Saubaméa, Bruno, Caillé, Fabien, Langer, Oliver, Truillet, Charles, Larrat, Benoît, and Tournier, Nicolas
- Subjects
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BLOOD-brain barrier , *P-glycoprotein , *MICROBUBBLE diagnosis , *POSITRON emission tomography , *CONTRAST-enhanced magnetic resonance imaging , *METOCLOPRAMIDE - Abstract
The P-glycoprotein (P-gp/ABCB1) is a major efflux transporter which impedes the brain delivery of many drugs across the blood-brain barrier (BBB). Focused ultrasound with microbubbles (FUS) enables BBB disruption, which immediate and delayed impact on P-gp function remains unclear. Positron emission tomography (PET) imaging using the radiolabeled substrate [11C]metoclopramide provides a sensitive and translational method to study P-gp function at the living BBB. A FUS protocol was devised in rats to induce a substantial and targeted disruption of the BBB in the left hemisphere. BBB disruption was confirmed by the Evan ' s Blue extravasation test or the minimally-invasive contrast-enhanced MRI. The expression of P-gp was measured 24 h or 48 h after FUS using immunostaining and fluorescence microscopy. The brain kinetics of [11C]metoclopramide was studied by PET at baseline, and both immediately or 24 h after FUS, with or without half-maximum P-gp inhibition (tariquidar 1 mg/kg). In each condition (n = 4–5 rats per group), brain exposure of [11C]metoclopramide was estimated as the area-under-the-curve (AUC) in regions corresponding to the sonicated volume in the left hemisphere, and the contralateral volume. Kinetic modeling was performed to estimate the uptake clearance ratio (R 1) of [11C]metoclopramide in the sonicated volume relative to the contralateral volume. In the absence of FUS, half-maximum P-gp inhibition increased brain exposure (+135.0 ± 12.9%, p < 0.05) but did not impact R 1 (p > 0.05). Immediately after FUS, BBB integrity was selectively disrupted in the left hemisphere without any detectable impact on the brain kinetics of [11C]metoclopramide compared with the baseline group (p > 0.05) or the contralateral volume (p > 0.05). 24 h after FUS, BBB integrity was fully restored while P-gp expression was maximally down-regulated (−45.0 ± 4.5%, p < 0.001) in the sonicated volume. This neither impacted AUC nor R 1 in the FUS + 24 h group (p > 0.05). Only when P-gp was inhibited with tariquidar were the brain exposure (+130 ± 70%) and R 1 (+ 29.1 ± 15.4%) significantly increased in the FUS + 24 h/tariquidar group, relative to the baseline group (p < 0.001). We conclude that the brain kinetics of [11C]metoclopramide specifically depends on P-gp function rather than BBB integrity. Delayed FUS-induced down-regulation of P-gp function can be detected. Our results suggest that almost complete down-regulation is required to substantially enhance the brain delivery of P-gp substrates. [Display omitted] • P-glycoprotein (P-gp) hinders the blood-brain barrier (BBB) passage of many drugs. • BBB disruption induced by focused ultrasound (FUS) enables targeted brain delivery. • P-gp function at the BBB can be studied in vivo using [11C]metoclopramide PET imaging. • Immediately after FUS, BBB disruption did not impact the P-gp-mediated efflux in rats. • P-gp expression was decreased 24 h to 48 h after FUS, with limited impact on function. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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