Abstract
Many pregnant women and prematurely born infants require medication for clinical conditions including cancer, cardiac defects and psychiatric disorders. In adults drug transfer from blood into brain is mostly restricted by efflux mechanisms (ATP-binding cassette, ABC transporters). These mechanisms have been little studied during brain development. Here expression of eight ABC transporters (abcb1a, abcb1b, abcg2, abcc1, abcc2, abcc3, abcc4, abcc5) and activity of conjugating enzyme glutathione-s-transferase (GST) were measured in livers, brain cortices (blood-brain-barrier) and choroid plexuses (blood-cerebrospinal fluid, CSF, barrier) during postnatal rat development. Controls were compared to animals chronically injected (4 days, 200 mg/kg/day) with known abcb1a inducer diallyl sulfide (DAS). Results reveal both tissue- and age-dependent regulation. In liver abcb1a and abcc3 were up-regulated at all ages. In cortex abcb1a/b, abcg2 and abcc4/abcc5 were up-regulated in adults only, while in choroid plexus abcb1a and abcc2 were up-regulated only at P14. DAS treatment increased GST activity in livers, but not in cortex or choroid plexuses. Immunocytochemistry of ABC transporters at the CSF-brain interface showed that PGP and BCRP predominated in neuroepithelium while MRP2/4/5 were prominent in adult ependyma. These results indicate an age-related capacity of brain barriers to dynamically regulate their defence mechanisms when chronically challenged by xenobiotic compounds.
Highlights
Most clinicians adopt a cautious approach when prescribing medications to pregnant women due to concerns that these compounds may reach the fetus, where they could adversely affect specific organs such as the brain[1]
For Real-time quantitative polymerase chain reaction (RT-qPCR), genes will be listed with common protein names in brackets, e.g. abcc[1] (MRP1), whereas for immunohistochemistry the protein will be listed with associated gene in brackets, e.g. major choroid plexus transporter abcc1 (MRP1)
We refer to the treatment regime as chronic when the animals are injected over several consecutive days
Summary
Most clinicians adopt a cautious approach when prescribing medications to pregnant women due to concerns that these compounds may reach the fetus, where they could adversely affect specific organs such as the brain[1]. At the blood-brain barrier interface in adults the main efflux transporters that have been identified are P-glycoprotein (PGP, abcb[1], MDR1), breast cancer resistance protein (BCRP, abcg2) and multidrug resistance-associated proteins 2 and 4 (MRP2, abcc[2]; MRP4, abcc4)[4,8]. A large-scale investigation in mice of 15 compounds has highlighted diallyl sulfide (DAS) as the most prominent inducer of abcb1a/b (PGP) expression at this barrier[12]. Both ex vivo and in vivo adult mouse models have revealed an increase in abcg[2] (BCRP) expression in the mouse blood brain barrier in response to clofibrate administration[13]. It is possible that not all stages of development have the same capacity to dynamically regulate efflux transporters, meaning that repeat drug exposure may pose a greater risk at certain developmental stages
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