NMDA Channel Antagonist MK-801 Does Not Protect against Bilirubin Neurotoxicity

Abstract

Background: Bilirubin encephalopathy or kernicterus is a potentially serious complication of neonatal hyperbilirubinemia. The mechanism of bilirubin-induced neurotoxicity is not known. Many neurological insults are mediated through NMDA receptor activation. Objective: We assessed the effect of the NMDA channel antagonist, MK-801 on bilirubin neurotoxicity in vivo and in vitro. Methods: Bilirubin toxic ity in vitro was assessed using trypan blue staining. Sulfadimethoxine injected (i.p.) jaundiced Gunn rat pups ex hibit many neurological sequelae observed in human hyperbilirubinemia. Brainstem auditory-evoked potentials (BAEPs), a noninvasive sensitive tool to assess auditory dysfunction due to bilirubin neurotoxicity, were used to assess neuroprotection with MK-801 (i.p.) in vivo. Results: In primary cultures of hippocampal neurons, 20 min exposure to 64:32 µM bilirubin:human serum albumin reduced the cell viability by approximately 50% ten hours later. MK-801 treatment did not protect the cells. MK-801 pretreatment doses ranging from 0.1–4.0 mg/kg did not protect against BAEP abnormalities in Gunn rat pups 6 h after sulfadimethoxine injection. Conclusion: Our findings suggest that bilirubin neurotoxicity is not mediated through NMDA receptor activation.