Acute Bilirubin Encephalopathy Induced with Sulfadimethoxine in Gunn Rats

Abstract

Acute bilirubin encephalopathy was induced in young Gunn rats with a sulfonamide (sulfadimethoxine), which acts by competitive displacement of bilirubin from albumin binding sites, in order to study the differences between the spontaneously occurring neuronal degeneration described in Gunn rats (18) and the acute neurotoxic effects of bilirubin. Thirty 14 day old homozygous Gunn rats were injected with sulfadimethoxine, 50 mg/kg twice daily s.c. All treated rats developed signs of neurotoxicity within a few hours and were sacrificed by intracardiac perfusion with fixative after 6–12 hours (4 rats), 13–24 hours (12 rats), 25–48 hours (9 rats) and 49–103 hours (5 rats). The brains of fourteen treated animals showed regional yellow staining. Microscopic examination showed two different types of lesions: (1) all brains showed neuronal degeneration with accumulation of PAS-positive material and formation of membranous bodies (MB's) which was most marked in the areas with localized yellow staining, (2) acute necrotic lesions were present in the hippocampal formation, inferior colliculi, globus pallidus and in the ponto-medullary tegmentum in 8 of 13 animals which were sacrificed no less than 24 hours after the first injection. Ultrastructural examination of these acute necrotic lesions showed enlarged extracellular spaces, swelling of astrocytic processes and two types of neuronal cytolysis: (a) large ‘watery’ neurons with swollen cell bodies and (b) small neurons with shrunken cytoplasm, loss of organelles and electron-dense nuclei. The brains of control rats (5 untreated and 6 asphyxiated homozygous rats and 10 treated heterozygous litter-mates of the experimental rats) showed no abnormalities other than neuronal degeneration with MB formation. It is concluded that both processes, the neuronal degeneration with MB formation and acute necrotic lesions with neuronal cytolysis, represent two different tissue responses to the toxic effect of bilirubin. Neuronal degeneration with MB formation appears to result from prolonged exposure to relatively low concentrations of tissue bilirubin. The acute focal necrotic lesions are