Improved l-Type amino acid transporter 1 (LAT1)-mediated delivery of anti-inflammatory drugs into astrocytes and microglia with reduced prostaglandin production

Non-steroidal anti-inflammatory drugs (NSAIDs) can have protective effects in the brain by inhibition of cyclooxygenases (COX). However, the delivery into the brain across the blood-brain barrier (BBB) and particularly into the brain parenchymal cells is hindered. Therefore, in the present study, we developed four l-type amino acid transporter 1 (LAT1)-utilizing prodrugs of flurbiprofen, ibuprofen, naproxen, and ketoprofen, since LAT1 is expressed on both, the BBB endothelial cells as well as parenchymal cells. The cellular uptake and utilization of LAT1 by novel prodrugs were studied in mouse cortical primary astrocytes and immortalized microglia (BV2), and the release of the parent NSAID in several tissue and cell homogenates. Finally, the effects of the studied prodrugs on prostaglandin E₂ (PGE₂) production and cell viability were explored. The gained results showed that all four prodrugs were carried into their target cells via LAT1. They also released their parent NSAIDs via carboxylesterases (CES) and most likely also other un-identified enzymes, which need to be carefully considered when administrating these compounds orally or intravenously. Most importantly, all the studied prodrugs reduced the PGE₂ production in astrocytes and microglia after lipopolysaccharide (LPS)-induced inflammation by 29-94% and without affecting the cell viability with the studied concentration (20 µM).