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Significance of lipid composition in a blood-brain barrier-mimetic PAMPA assay.

ABSTRACT: Endothelial cells forming the blood-brain barrier limit drug access into the brain, due to tight junctions, membrane drug transporters, and unique lipid composition. Passive permeability, thought to mediate drug access, is typically tested using porcine whole-brain lipid. However, human endothelial cell lipid composition differs. This investigation evaluated the influence of lipid composition on passive permeability across artificial membranes. Permeability of CNS-active drugs across an immobilized lipid membrane was determined using three lipid models: crude extract from whole pig brain, human brain microvessel lipid, and microvessel lipid plus cholesterol. Lipids were immobilized on polyvinylidene difluoride, forming donor and receiver chambers, in which drug concentrations were measured after 2 h. The log of effective permeability was then calculated using the measured concentrations. Permeability of small, neutral compounds was unaffected by lipid composition. Several structurally diverse drugs were highly permeable in porcine whole-brain lipid but one to two orders of magnitude less permeable across human brain endothelial cell lipid. Inclusion of cholesterol had the greatest influence on bulky amphipathic compounds such as glucuronide conjugates. Lipid composition markedly influences passive permeability. This was most apparent for charged or bulky compounds. These results demonstrate the importance of using species-specific lipid models in passive permeability assays.

SUBMITTER: Campbell SD

PROVIDER: S-EPMC4078735 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Significance of lipid composition in a blood-brain barrier-mimetic PAMPA assay.

Campbell Scott D SD Regina Karen J KJ Kharasch Evan D ED

Journal of biomolecular screening 20130814 3

Endothelial cells forming the blood-brain barrier limit drug access into the brain, due to tight junctions, membrane drug transporters, and unique lipid composition. Passive permeability, thought to mediate drug access, is typically tested using porcine whole-brain lipid. However, human endothelial cell lipid composition differs. This investigation evaluated the influence of lipid composition on passive permeability across artificial membranes. Permeability of CNS-active drugs across an immobili ...[more]

PMID: 23945876

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Project description:Essentials Potential neurodevelopmental side effects of thrombopoietin mimetics need to be considered. The effects of eltrombopag (ELT) on neuronal iron status and dendrite development were assessed. ELT crosses the blood-brain barrier and causes iron deficiency in developing neurons. ELT blunts dendrite maturation, indicating a need for more safety studies before neonatal use.SummaryBackground Thrombocytopenia is common in sick neonates. Thrombopoietin mimetics (e.g. eltrombopag [ELT]) might provide an alternative therapy for selected neonates with severe and prolonged thrombocytopenia, and for infants and young children with different varieties of thrombocytopenia. However, ELT chelates intracellular iron, which may adversely affect developing organs with high metabolic requirements. Iron deficiency (ID) is particularly deleterious during brain development, impairing neuronal myelination, dopamine signaling and dendritic maturation and ultimately impairing long-term neurological function (e.g. hippocampal-dependent learning and memory). Objective To determine whether ELT crosses the blood-brain barrier (BBB), causes neuronal ID and impairs hippocampal neuron dendrite maturation. Methods ELT transport across the BBB was assessed using primary bovine brain microvascular endothelial cells. Embryonic mouse primary hippocampal neuron cultures were treated with ELT or deferoxamine (DFO, an iron chelator) from 7 days in vitro (DIV) through 14 DIV and assessed for gene expression and neuronal dendrite complexity. Results ELT crossed the BBB in a time-dependent manner. 2 and 6 μm ELT increased Tfr1 and Slc11a2 (iron-responsive genes involved in neuronal iron uptake) mRNA levels, indicating neuronal ID. 6 μm ELT, but not 2 μm ELT, decreased BdnfVI, Camk2a and Vamp1 mRNA levels, suggesting impaired neuronal development and synaptic function. Dendrite branch number and length were reduced in 6 μm ELT-treated neurons, resulting in blunted dendritic arbor complexity that was similar to DFO-treated neurons. Conclusions Eltrombopag treatment during development may impair neuronal structure as a result of neuronal ID. Preclinical in vivo studies are warranted to assess ELT safety during periods of rapid brain development.

Dataset Information

Significance of lipid composition in a blood-brain barrier-mimetic PAMPA assay.

Publications

Significance of lipid composition in a blood-brain barrier-mimetic PAMPA assay.

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