The impact of depressive disorders and treatment with an antidepressant on the activity of P-glycoprotein at the blood-brain barrier

ABSTRACTAmphotericin B (AMB) has been a mainstay therapy for fungal infections of the central nervous system, but its use has been limited by its poor penetration into the brain, the mechanism of which remains unclear. In this study, we aimed to investigate the role of P-glycoprotein (P-gp) in AMB crossing the blood-brain barrier (BBB). The uptake of AMB by primary brain capillary endothelial cellsin vitrowas significantly enhanced after inhibition of P-gp by verapamil. The impact of two model P-gp inhibitors, verapamil and itraconazole, on brain/plasma ratios of AMB was examined in both uninfected CD-1 mice and those intracerebrally infected withCryptococcus neoformans. In uninfected mice, the brain/plasma ratios of AMB were increased 15 min (3.5 versus 2.0;P< 0.05) and 30 min (5.2 versus 2.8;P< 0.05) after administration of verapamil or 45 min (6.0 versus 3.9;P< 0.05) and 60 min (5.4 versus 3.8;P< 0.05) after itraconazole administration. The increases in brain/plasma ratios were also observed in infected mice treated with AMB and P-gp inhibitors. The brain tissue fungal CFU in infected mice were significantly lower in AMB-plus-itraconazole or verapamil groups than in the untreated group (P< 0.005), but none of the treatments protected the mice from succumbing to the infection. In conclusion, we demonstrated that P-gp inhibitors can enhance the uptake of AMB through the BBB, suggesting that AMB is a P-gp substrate.

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Inhibition of P-glycoprotein at the blood brain barrier by phytochemicals derived from traditional Chinese medicine

Planta Medica ◽

10.1055/s-0029-1234258 ◽

2009 ◽

Vol 75 (09) ◽

Cited By ~ 1

Author(s):

T Efferth

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Blood Brain Barrier ◽

Brain Barrier ◽

P Glycoprotein ◽

Blood Brain

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Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Pharmaceutics ◽

10.3390/pharmaceutics13060892 ◽

2021 ◽

Vol 13 (6) ◽

pp. 892

Author(s):

Elisa L. J. Moya ◽

Elodie Vandenhaute ◽

Eleonora Rizzi ◽

Marie-Christine Boucau ◽

Johan Hachani ◽

...

Keyword(s):

Drug Discovery ◽

Blood Brain Barrier ◽

Early Stage ◽

Molecular Transport ◽

Brain Barrier ◽

Blood Brain ◽

Cns Drugs ◽

The Impact ◽

The Brain

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.

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Tailoring of P-glycoprotein for effective transportation of actives across blood-brain-barrier

Journal of Controlled Release ◽

10.1016/j.jconrel.2021.05.046 ◽

2021 ◽

Author(s):

Nazneen Pathan ◽

Pravin Shende

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

P Glycoprotein ◽

Blood Brain

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CdSe/ZnS Core-Shell-Type Quantum Dot Nanoparticles Disrupt the Cellular Homeostasis in Cellular Blood–Brain Barrier Models

International Journal of Molecular Sciences ◽

10.3390/ijms22031068 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1068

Author(s):

Katarzyna Dominika Kania ◽

Waldemar Wagner ◽

Łukasz Pułaski

Keyword(s):

Gene Expression ◽

Quantum Dot ◽

Blood Brain Barrier ◽

Protein Gene ◽

Brain Barrier ◽

Core Shell ◽

Cellular Homeostasis ◽

Blood Brain ◽

Shell Type ◽

The Impact

Two immortalized brain microvascular endothelial cell lines (hCMEC/D3 and RBE4, of human and rat origin, respectively) were applied as an in vitro model of cellular elements of the blood–brain barrier in a nanotoxicological study. We evaluated the impact of CdSe/ZnS core-shell-type quantum dot nanoparticles on cellular homeostasis, using gold nanoparticles as a largely bioorthogonal control. While the investigated nanoparticles had surprisingly negligible acute cytotoxicity in the evaluated models, a multi-faceted study of barrier-related phenotypes and cell condition revealed a complex pattern of homeostasis disruption. Interestingly, some features of the paracellular barrier phenotype (transendothelial electrical resistance, tight junction protein gene expression) were improved by exposure to nanoparticles in a potential hormetic mechanism. However, mitochondrial potential and antioxidant defences largely collapsed under these conditions, paralleled by a strong pro-apoptotic shift in a significant proportion of cells (evidenced by apoptotic protein gene expression, chromosomal DNA fragmentation, and membrane phosphatidylserine exposure). Taken together, our results suggest a reactive oxygen species-mediated cellular mechanism of blood–brain barrier damage by quantum dots, which may be toxicologically significant in the face of increasing human exposure to this type of nanoparticles, both intended (in medical applications) and more often unintended (from consumer goods-derived environmental pollution).

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