Changes in CNS cells in hyperammonemic portal hypertensive rats

Rats with pre-hepatic portal hypertension because of partial portal vein ligation develop minimal hepatic encephalopathy (MHE) with hyperammonemia, impaired blood-brain barrier, mild brain edema, and severe mitochondrial changes in the hippocampus. The aim of this study was to evaluate changes of different neural cells in the cerebral cortex and the hippocampus. Animals were divided into two groups, MHE and sham. Astrocytes were studied by immunostaining with glial fibrillary acidic protein and S100β protein; neurons were immunostained with neuronal nuclear marker, microtubule associated protein-2, and NF-200 and capillaries with Nestin. The hypoxia-inducible factor 1α (HIF-1α) and its downstream proteins, P-glycoprotein (P-gp) and erythropoietin receptor (Epo-R), were also evaluated. Astrocytes were increased in area and number only in the hippocampus, while S100β increased in both brain areas in MHE animals. Microtubule associated protein-2 and NF-200 immunoreactivities (-ir) were significantly reduced in both areas. Hippocampal Nestin-ir was increased in MHE animals. These cellular changes were similar to those described in ischemic conditions, thus HIF-1α, P-gp, and Epo-R were also evaluated. A high expression of HIF-1α in cortical neurons was observed in the MHE group. It is likely that this hypoxia-like state is triggered via ammonia occupying the binding domain of HIF-1α and thereby preventing its degradation and inducing its stabilization, leading to the over-expression of P-gp and the Epo-R.