In Vitro Models of the Human Blood–Brain Barrier Utilising Human Induced Pluripotent Stem Cells: Opportunities and Challenges

Pervaiz, Iqra; Al‐Ahmad, Abraham

doi:10.1007/978-1-0716-2289-6_3

Cited by 1 publication

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“…Among other factors affecting the quality and reproducibility of the model are culture media and supplements used during iPSC expansion and differentiation, and the tendency to de-differentiate from the hBMEC phenotype within a few days in culture. A recent review discusses these challenges (Pervaiz and Al-Ahmad, 2022).…”

Section: Discussionmentioning

confidence: 99%

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

Noorani¹,

Chowdhury²,

Alqahtani³

et al. 2023

J Pharmacol Exp Ther

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The purpose of this study was to investigate the effects of volatile anesthetic agents isoflurane and sevoflurane, at clinically relevant concentrations, on the fluidity of lipid membranes and permeability of the blood-brain barrier (BBB). We analyzed the in vitro effects of isoflurane or ketamine using erythrocyte ghosts (sodium fluorescein permeability) monolayers of brain microvascular endothelial cells ([ 13 C]sucrose and fluorescein permeability), or liposomes (fluorescence anisotropy). Additionally, we determined the effects of 30-min exposure of mice to isoflurane on the brain tight junction proteins.Finally, we investigated in vivo brain uptake of [ 13 C]mannitol and [ 13 C]sucrose after IV administration in mice under anesthesia with isoflurane, sevoflurane, or ketamine/xylazine in addition to the awake condition. Isoflurane at 1-and 5-mM concentrations increased fluorescein efflux from the erythrocyte ghosts in a concentration-dependent manner. Similarly, in endothelial cell monolayers exposed to 3% (v/v) isoflurane, permeability coefficients rose by about 25% for fluorescein and 40% for [ 13 C]sucrose, while transendothelial resistance and cell viability remained unaffected. Whereas isoflurane caused a significant decrease in liposomes anisotropy values, ketamine/xylazine did not show any effects. Brain uptake clearance (apparent K in ) of the passive permeability markers in vivo in mice approximately doubled under isoflurane or sevoflurane anesthesia, compared to either ketamine/xylazine anesthesia or the awake condition. In vivo exposure of mice to isoflurane did not change any of the brain tight junction proteins. Our data support membrane permeabilization rather than loosening of intercellular tight junctions as an underlying mechanism for increased permeability of the endothelial cell monolayers and the BBB in vivo. Significance Statement:The BBB controls the entry of endogenous substances and xenobiotics from the circulation into the central nervous system. Volatile anesthetic agents like isoflurane alter the lipid structure of cell membranes, transiently facilitating the brain uptake of otherwise poorly permeable, hydrophilic small molecules. Clinical implications may arise when potentially neurotoxic drugs gain enhanced access to the CNS under inhalational anesthetics.

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Section: Discussionmentioning

confidence: 99%