Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport

Abstract

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 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 therapeutic implications for CNS malignancies.

Effects of Volatile Anesthetics versus Ketamine on Blood-Brain Barrier Permeability via Lipid-Mediated Alterations of Endothelial Cell Membranes

“…Acharya et al (Acharya et al, 2015) described enhanced leakage of endogenous IgG into the brain of rats undergoing 3 h of anesthesia with sevoflurane or isoflurane, as detected by immunohistochemistry, and endothelial cell damage in scanning electron microscopic images, alterations in tight junctional folds, and even occasional death of endothelial cells. In contrast, a recent study by Saher's group could not confirm alterations of tight junction protein expression in mouse brain under isoflurane (Spieth et al, 2021). In agreement with the latter, our ex vivo data did not show any significant changes in the immunofluorescence intensities of the tight junction proteins claudin-5, occludin and ZO-1 in isoflurane-anesthetized animals vs. naïve mice (Fig.…”

The Effects of Propofol on a Human in vitro Blood-Brain Barrier Model

“…Brain endothelium has a significantly reduced rate of transcytosis compared to peripheral endothelial cells ( Daneman et al, 2010 ). Isoflurane has been demonstrated to increase caveolar-dependent transcytosis, however, propofol exposure did not alter non-specific transcytosis in iPSC-derived BMECs ( Spieth et al, 2021 ).…”

Brain Waste Removal System and Sleep: Photobiomodulation as an Innovative Strategy for Night Therapy of Brain Diseases

“…Pilot studies on rats show that sleep and opened BBB are equally accompanied by BWRS activation, which has an identical effect on the EEG dynamics and makes it possible to identify EEG markers of increased BBB permeability [ 84 ]. Non-invasive technology for assessing the BBB using only EEG is important for monitoring BBB permeability during surgery in order to control the depth of anesthesia and for the analysis of the progression of a number of brain diseases, such as AD and Parkinson’s disease, brain trauma, diabetic and COVID-19 cerebrovascular injuries, and depression [ 16 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ].…”