The Acute Impact of Propofol on Blood–Brain Barrier Integrity in Mice

• Published in: Pharmaceutical research 2024-08, Vol.41 (8), p.1599-1611
• Main Authors: Nozohouri, Ehsan, Ahn, Yeseul, Zoubi, Sumaih, Patel, Dhavalkumar, Archie, Sabrina Rahman, Akter, Khondker Ayesha, Siddique, Muhammad Bilal, Huang, Juyang, Abbruscato, Thomas J., Bickel, Ulrich
• Format: Article
• Language: English
• Subjects: Anesthesia; Anesthetics; Anesthetics, Intravenous - administration & dosage; Anesthetics, Intravenous - pharmacokinetics; Anesthetics, Intravenous - pharmacology; Animals; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood levels; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain - drug effects; Brain - metabolism; Ethylenediaminetetraacetic acid; Ketamine; Ketamine - administration & dosage; Ketamine - pharmacokinetics; Ketamine - pharmacology; Lipophilic; Male; Medical Law; Membrane permeability; Mice; Mice, Inbred C57BL; Original Research Article; Permeability; Permeability - drug effects; Pharmacology/Toxicology; Pharmacy; Phenols; Plasma; Propofol; Propofol - administration & dosage; Propofol - pharmacokinetics; Propofol - pharmacology; Proteins; Sucrose; Sucrose - administration & dosage; Xylazine; Xylazine - pharmacology; γ-Aminobutyric acid A receptors
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-024-03735-w

Purpose We investigated whether short term infusion of propofol, a highly lipophilic agonist at GABA A receptors, which is in widespread clinical use as anesthetic and sedative, affects passive blood–brain barrier (BBB) permeability in vivo . Methods Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine followed by a continuous IV infusion of propofol in lipid emulsion through a tail vein catheter. Control groups received ketamine/xylazine anesthesia and an infusion of Intralipid, or ketamine/xylazine anesthesia only. [ 13 C 12 ]sucrose as a permeability marker was injected as IV bolus 15 min after start of the infusions. Brain uptake clearance, K in , of sucrose was calculated from the brain concentrations at 30 min and the area under the plasma-concentration time curve. We also measured the plasma and brain concentration of propofol at the terminal time point. Results The K in value for propofol-infused mice was significantly higher, by a factor of 1.55 and 1.87, compared to the Intralipid infusion and the ketamine/xylazine groups, respectively, while the control groups were not significantly different. No difference was seen in the expression levels of tight junction proteins in brain across all groups. The propofol plasma concentration at the end of infusion (10.7 µM) matched the clinically relevant range of blood concentrations reported in humans, while concentration in brain was 2.5-fold higher than plasma. Conclusions Propofol at clinical plasma concentrations acutely increases BBB permeability, extending our previous results with volatile anesthetics to a lipophilic injectable agent. This prompts further exploration, potentially refining clinical practices and ensuring safety, especially during extended propofol infusion schemes.