NMDA channel antagonist MK-801 does not protect against bilirubin neurotoxicity.
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 toxicity in vitro was assessed using trypan blue staining. Sulfadimethoxine injected (i.p.) jaundiced Gunn rat pups exhibit 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 microM 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.


CONCLUSIONS
Our findings suggest that bilirubin neurotoxicity is not mediated through NMDA receptor activation.
Shapiro
Steven M
SM
Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298-0599, USA.
Sombati
Sompong
S
Geiger
Angela
A
Rice
Ann C
AC
D000818:Animals; D000831:Animals, Newborn; D000890:Anti-Infective Agents; D001663:Bilirubin / Q000009:adverse effects*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000502:physiology; D006932:Hyperbilirubinemia / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology; D007565:Jaundice / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology; D007647:Kernicterus / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D011911:Rats, Gunn; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D013412:Sulfadimethoxine
D000890:Anti-Infective Agents; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D013412:Sulfadimethoxine; D016291:Dizocilpine Maleate; D001663:Bilirubin