Grant: Project Grant

Multidrug transporters in the fetal blood-brain barrier (BBB) protect the brain from factors in the fetal blood. Protection of the brain is very important as 99% of all nerve cells in the adult brain develop during fetal life. These transporters limit the transfer of a spectrum of factors (steroids, cytokines), drugs (anticancer/HIV drugs, antibiotics, statins) and toxins (pesticides) into the brain. However, very little is known as to how they are regulated in the developing brain and how they are modified in common pregnancy complications. It is estimated that approximately 75% of pregnant people are prescribed drugs, many of which can be transported by the multidrug transporters. Further, many of the drugs most administered to babies born preterm are normally prevented from entering the brain by these transporters. However, due to reduced levels of these transporters in the preterm infant brain, there is increased risk of neurotoxicity. We have recently shown that maternal treatment with antenatal corticosteroids (ACS; which are given to people at risk of delivering preterm) results in long-term effects on drug transporter function at the BBB in offspring after birth. In the present proposal, we will; 1) determine how ACS treatment modifies development of drug transporters at the BBB from fetal to adult life using state-of-the-art imaging techniques in our established guinea pig model; and, 2) identify the mechanistic pathways by which these changes occur. New knowledge generated will be foundational in development of targeted strategies to optimize protection of the vulnerable fetal and infant brain, and support life-long brain health.