Colostomy Delays Cell Loss in the Brain and Improves Juvenile Survival in a Neonatal Rat Model of Hirschsprung's Disease.

Hirschsprung's disease is a congenital malformation characterized by the absence of enteric ganglia in the distal intestine and gut obstruction. Our previous study indicates the brain pathology during the disease progression. A subpopulation of Hirschsprung's disease patients is also associated with anomalies of the central nervous system. In the investigation, we studied a rat model of Hirschsprung's disease, known as spotting lethal ( sl / sl ) ET B -/- rats, which carries a spontaneous deletion in endothelin receptor B (human gene name: EDNRB ) and manifests a similar phenotype as humans with Hirschsprung's disease. Homozygous mutant sl / sl rats were successfully rescued from premature death by performing colostomy and dramatically survived to their juvenile age. By the body weight measured, their body growth was not revealed to be significantly different between ET B -/- and wildtype ET B +/+ or heterozygous (+/ sl ) ET B +/- groups while all underwent the same colostomy. Cell loss was investigated in several brain regions by using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay (TUNEL) in ET B +/+ , ET B -/- , and ET B +/- rats. Number of TUNEL-positive cells in the cerebellum and the hippocampus of ET B -/- rats was significantly increased compared with that of the ET B +/+ and ET B +/- rats. TUNEL-positive cells were observed in the molecular layer and granular cell layers of the cerebellum. In contrast, no significant difference in the density of TUNEL-positive cells was revealed in the cerebral cortex. These results suggest that either endothelin receptor B sl mutation or colostomy has predominant lasting effects on the cell survival/loss in the cerebellum and hippocampus of adult ET B -/- rats. Our findings provide the information on cellular changes in the brains of patients with Hirschsprung's disease due to congenital EDNRB mutation as well as clinically relevant interventions.