Lena Spieth, Stefan A. Berghoff, Sina K. Stumpf, Jan Winchenbach, Thomas Michaelis, Takashi Watanabe, Nina Gerndt, Tim Düking, Sabine Hofer, Torben Ruhwedel, Ali H. Shaib, Katrin Willig, Katharina Kronenberg, Uwe Karst, Jens Frahm, Jeong Seop Rhee, Susana Minguet, Wiebke Möbius, Niels Kruse, Christian von der Brelie, Peter Michels, Christine Stadelmann, Petra Hülper, Gesine Saher
- Background
Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood–brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery.
Methods
Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis.
Results
Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightnessBackground
Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood–brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery.
Methods
Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis.
Results
Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy.
Conclusions
Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching ther…
