ROLE OF GLUTAMATE RECEPTOR-MEDIATED EXCITOTOXICITY IN BILIRUBIN-INDUCED BRAIN INJURY IN THE GUNN RAT MODEL

Severe hyperbilirubinemia in neonates with prematurity and/or systemic illnesses such as hemolytic disease, acidosis, and hypoxemia enhances their risk for developing cerebral palsy, paralysis of ocular upgaze, and deafness, This neurologic syndrome has been associated with selec tive neuronal vulnerability in the basal ganglia, certain brainstem nu clei, and Purkinje cells. However, the mechanism by which bilirubin da mages neurons remains unclear. In these studies, we found that intrace rebral injection of N-methyl-D-aspartate (NMDA), an excitotoxic analog ue of glutamate, caused greater injury in jaundiced 7-day-old Gunn (jj ) rat pups than in nonjaundiced heterozgous (Nj) littermate controls. NMDA injection caused even greater injury when protein-bound bilirubin was displaced with the sulfonamide drug sulfadimethoxine in jaundiced homozygous pups, In additional experiments, the acute signs of biliru bin-mediated neuronal injury, induced in homozygous (jj) Gunn rats by treatment with sulfonamide, were reduced by concurrent treatment with the NMDA-type glutamate channel antagonist -10,11-dihydro-5H-dibenzo[a ,d]cyclohept-5,10-imine (MK-801, dizocilpine). The results suggest tha t bilirubin may cause encephalopathy and neuronal injury, at least in part, through an NMDA receptor-mediated excitotoxic mechanism. This co nclusion is consistent with clinical observations that bilirubin encep halopathy is synergistically worsened by hypoxemia, which also shares an excitotoxic mechanism of neuronal injury. (C) 1998 Academic Press.