MORPHOFUNCTIONAL CHANGES IN AN EXPERIMENTAL MODEL OF MINIMAL HEPATIC ENCEPHALOPATHY

TALLIS S; CALTANA L; SOUTO P; BRUSCO HA; PERAZZO JC

Greena

Simposio; 16th ISHEN Symposium; 2012

International Society on Hepatic Encephalopathy and Nitrogen Metabolism

Prehepatic portal hypertensive rats due to partial portal vein stricture displays morphological and functional damage of hippocampal mitochondrion, blood-brain barrier breakdown and induce a minimal hepatic encephalopathy (MHE). Recently, in this model, we showed the presence of apoptosis in the hippocampus. The aim of this study was to evaluate in a rat MHE model the morphofunctional features of different neural cells focusing in brain cortical parietal neuronal layer V and hippocampal CA1, regions closely interrelated to cognitive abilities. Methods: Two groups of rats were used: MHE and Sham operated group. Astrocytes were studied by immunolabelling with the glial fibrillary acidic protein (GFAP) and S100β protein, an astrogial derived neurotrophic factor. Neurons were assessed with neuronal nuclear marker (NeuN) and microtubule associated protein-2 (MAP-2) a neuron-specific cytoskeletal protein found mainly in dendrites. Neuronal filaments 200 kDa (Nf-200) present in the cell body and axonal and dendritic processes were also studied. The capillary vessels were labelled with specific antibodies against Nestin. The hypoxia induced factor -1α (HIF-1α), a transcription factor involved in oxygen homeostasis, and two of it downstream proteins, the P-glycoprotein (P-gp) and the erythropoietin receptor (Epo-R), were evaluated in both brain areas. Results: GFAP showed an increased area and number of hippocampal astrocytes but not in the cortex of MHE animals, meanwhile S100 β relative optical density was increased in both brain areas. The neuronal number did not differ in the studied areas, but MAP-2 and Nf-200 were significantly decreased in both areas, suggesting a reduction of neuronal processes. Also, the neuronal cytoskeleton showed qualitative and structural changes in the cerebral cortex of the MHE group. Both MAP-2 and Nf-200 fibers rendered waving-shape corkscrew-like images. The increased of the capillaries area in MHE animals, Nestin-immunoreactivity, in the hippocampal CA1 area was also observed. We also found high expression of HIF-1 α in cortex neurons of the MHE animals demonstrate by double immunostaining. P-gp and Epo-R expressions are in agree with the HIF-1 α expression. The hypoxic tissue state was not accompanied with hypoxemia. New data showing specific morphofunctional neuronal, astroglial and in capillaries in a model of MHE is presented. On the other hand could be proposed that a hypoxic tissue state is developing by occupying the binding domain of HIF-1 α, through ammonia, manganese or both, thereby avoiding its degradation and inducing its stabilization leading to the overexpression of P-gp and the Epo-R.