Effect of bilirubin on expression and localization of PGP and Mrp1 in the central nervous system

Around 70% of children with kernicterus die within seven days, while the 30% survivors usually suffer irreversible sequels, including hearing loss, paralysis of upward gaze, mental retardation, and cerebral palsy with athetosis. Bilirubin encephalopathy is actually the leading cause of hospital readmission of newborns within the first month after birth. Historically the studies concerning the bilirubin entry the central nervous system have focused on the blood brain barrier (BBB), located at the level of the endothelial cells forming the brain micro vessels (MV), leading to the †œfree bilirubin theory†�. It consists in the idea that only the free unconjugated bilirubin, the part of bilirubin exceeding the binding ability of the serum albumin, is able to cross the cell membranes and diffuse in tissue. In brain a second blood brain barrier is present. It is located at the level of the epithelial cells forming the choroids plexuses, between the blood and the cerebrospinal fluid (blood-cerebrospinal fluid barrier, BCSFB). Despite the largest surface area available for the exchanges, the high blood flux, the strategically position between two circulating fluids and the more leaky phenotype, limited studies have been made concerning its role in limiting the bilirubin entry the brain. Two ATP dependent transporters, the Multidrug Resistance-associated Protein 1 (Mrp1) and the MultiDrug resistance Protein (Pgpor MDR1), appear to be actively involved in UCB trafficking. The transporters play an important role i