Developmental differences in the regulation and functional capacity of ABC efflux transporters at brain barrier interfaces

Abstract

The safety and potential risks of many medications used in treating pregnant women and newborn children are not well defined. This is, in part, due to limited knowledge of how readily drugs transfer into integral organs such as the brain early in development. The present Thesis investigated the expression, regulation and function of ATP-binding cassette (ABC) efflux transporters at brain, cerebrospinal fluid (CSF) and placental interfaces of the Sprague Dawley rat, highlighting age-dependent differences. The expression of eight main ABC efflux transporters (abcb1a/b, abcg2, abcc1-5) was described in the rat brain, choroid plexus and placenta, revealing distinct developmental profiles. Immunostaining of the interface between the ventricular CSF and the brain identified PGP and BCRP transporters at this interface in the newborn rat but not in the adult. Drugs (rhodamine-123, digoxin, cimetidine, paracetamol) entered the developing brain more than the adult brain. Chronic drug exposure (diallyl sulfide, digoxin, paracetamol) caused an up-regulation of efflux transporter expression and functional capacity at brain barriers in adult but not fetal (E19) or newborn (P4) rats. Fetal rats exposed chronically to paracetamol via the dam had increased transfer into the brain compared to acute treatment, with this result being dose-dependent. Transcriptomic analysis revealed that chronic paracetamol exposure caused a large inflammatory profile in the placenta, indicating potential toxicity of paracetamol use in pregnancy over extended periods. The results in this Thesis suggest that drug transport into the rat brain is higher during development for acute and chronic conditions and indicate aspects of a treatment regime that may need to be considered differently for the safe prescription of medications to patients of different ages.