Abstract
The aim of this work was to conduct a comprehensive study about the transport properties of NSAIDs across the blood-brain barrier (BBB) in vitro. Transport studies with celecoxib, diclofenac, ibuprofen, meloxicam, piroxicam and tenoxicam were accomplished across Transwell models based on cell line PBMEC/C1-2, ECV304 or primary rat brain endothelial cells. Single as well as group substance studies were carried out. In group studies substance group compositions, transport medium and serum content were varied, transport inhibitors verapamil and probenecid were added. Resulted permeability coefficients were compared and normalized to internal standards diazepam and carboxyfluorescein. Transport rankings of NSAIDs across each model were obtained. Single substance studies showed similar rankings as corresponding group studies across PBMEC/C1-2 or ECV304 cell layers. Serum content, glioma conditioned medium and inhibitors probenecid and verapamil influenced resulted permeability significantly. Basic differences of transport properties of the investigated NSAIDs were similar comparing all three in vitro BBB models. Different substance combinations in the group studies and addition of probenecid and verapamil suggested that transporter proteins are involved in the transport of every tested NSAID. Results especially underlined the importance of same experimental conditions (transport medium, serum content, species origin, cell line) for proper data comparison.
Highlights
The blood-brain barrier (BBB) maintains the homeostasis between blood circulation and the central nervous system (CNS)
Three different models were used to study the transport of several non-steroidal anti-inflammatory drugs (NSAIDs) across the blood-brain barrier in vitro
The models based either on porcine cell line PBMEC/C1-2, on human cell line ECV304 or on a co-culture system consisting of primary rat brain microvascular endothelial cells (RBMEC) and astrocytes (AST)
Summary
The blood-brain barrier (BBB) maintains the homeostasis between blood circulation and the central nervous system (CNS). It consists of brain microvascular endothelial cells with distinct different features in comparison to the peripheral endothelium. Major brain endothelium specific properties are the lack of fenestrae, reduced endocytosis and restricted paracellular transport [1]. The barrier functionality comprises a physical, a transporter and a metabolic component. Lipophilic substances could permeate by passive diffusion across the cell membranes or by being shuttled via transporter proteins. Hydrophilic molecules such as glucose need transporters such as glut to overcome the BBB and reach the CNS. Shear stress by the bloodstream applied onto endothelial cells was shown to tighten the barrier in vitro [2,3,4]
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