Etodolac Enhances the Blood-Brain Barrier Integrity and Clearance of Amyloid-Beta

Abstract

The interface between the blood circulation and the neural tissue features unique characteristics that are encompassed by the blood-brain barrier (BBB). The main functions of this barrier are maintenance of brain homeostasis, regulation of influx and efflux transport, and protection from harmful circulating endogenous and exogenous neurotoxins. These functions are determined by the BBB specialized multicellular structure. Every constituent cell type makes an indispensable contribution to the BBB integrity. Several reports indicated that the BBB is compromised in Alzheimer's disease (AD) which affects its integrity and functional activity. Furthermore, these changes in the BBB correlated well with dysfunction in the clearance of As across the BBB and formation of As plaques. Several hit compounds that were able to enhance the BBB integrity were identified from the high-throughput screening assay developed in our laboratory. Among these compounds etodolac, an NSAID drug, has shown to enhance the BBB model integrity measured by its ability to decrease the paracellular permeability markers Lucifer Yellow and inulin. Moreover, our data suggested that etodolac enhanced the active transport of amyloid-beta (As42) across the BBB model. In conclusion, the NSAID etodolac could be a promising drug for the treatment of Alzheimer's disease. In vivo studies are in progress to investigate etodolac effect in AD mouse model.