LAT1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels

Congratulations to the team for a new publication, corresponded by the Ph.D. student Ahmed Montaser! Great job with a difficult task! Meaning that we had a nice study with our brain-targeted prodrug of a non-steroidal anti-inflammatory drug (NSAID), ketoprofen, that we have previously demonstrated to utilize L-type amino acid transporter 1 (LAT1) at the blood-brain barrier (BBB) and brain parenchymal cells. This has improved the delivery of ketoprofen into the site of action, where cyclooxygenase (COX) enzymes are located in the brain. So this was expected to decrease the prostaglandin E2 (PGE2) production in the brain after inflammation induction. However, the doses that were given were so high that no significant difference was observed between the ketoprofen and the prodrug groups. However, the results showed that prodrug was efficiently delivered into the brain parenchymal cells and that the release of ketoprofen was just slow, giving an extended-release profile to the prodrug. Together with lower systemic and hepatic exposure compared to ketoprofen itself, this prodrug can be considered as an efficient tool to study chronic administration of ketoprofen (in its LAT1-utilizing prodrug form) in the treatment of neurodegenerative diseases while avoiding their peripheral adverse effects.

Nevertheless, Ahmed wrote a nice story from the results and above all, he was able to develop our methodology for the future. For example, now on we don't have to buy expensive COX-activity assay kits, instead, we can isolate the enzyme from the cells and do the assay using arachidonic acid as an original electron donor (via prostaglandin G2, PGG2) to oxidize Amplex Red to resorufin in the presence of hemin. If COX inhibitor, such as ketoprofen is added, then this reaction slows down. We also have now a really specific liquid chromatography-tandem mass (LC-MS/MS) method for PGE2 quantification, thanks to another Ph.D. student Janne Tampio! More about this method will be published later on, in his publications.

The publication was published in Pharmaceuticals and it is open access, so you can read more about that study from the following link: (click-me)