Cerebellar neurodegeneration in a new rat model of episodic hepatic encephalopathy

Abstract

Hepatic encephalopathy has traditionally been considered a reversible disorder. However, recent studies suggested that repeated episodes of hepatic encephalopathy cause persistent impairment leading to neuronal loss. The aims of our study were the development of a new animal model that reproduces the course of episodic hepatic encephalopathy and the identification of neurodegeneration evidences. Rats with portacaval anastomosis underwent simulated episodes of hepatic encephalopathy, triggered by the regular administration of ammonium acetate, and/or lipopolysaccharide. The neurological status was assessed and neuronal loss stereologically quantified in motor areas. During the simulated episodes, ammonia induced reversible motor impairment in portacaval anastomosis rats. In cerebellum, stereology showed a reduction in Purkinje cell population in portacaval anastomosis and PCA+NH groups and morphological changes. An increase in astrocyte size in PCA+NH group and activated microglia in groups treated with ammonium acetate and/or lipopolysaccharide was observed. A modulation of neurodegeneration-related genes and the presence of apoptosis in Bergmann glia were observed. This new animal model reproduces the clinical course of episodic hepatic encephalopathy when ammonia is the precipitant factor and demonstrates the existence of neuronal loss in cerebellum. The persistence of over-activated microglia and reactive astrocytes could participate in the apoptosis of Bergmann glia and therefore Purkinje cell degeneration.

Bile‐duct ligation renders the brain susceptible to hypotension‐induced neuronal degeneration: Implications of ammonia

“…A decrease in neuronal count was evidenced in an animal model with a history of repeated or long episodes of HE and was suggested to be more prevalent in alcoholic cirrhosis (Butterworth, 2007; García‐Lezana et al., 2017). Described mechanisms of neural death in HE include excessive stimulation of the N‐methyl‐D‐aspartate (NMDA) receptor by glutamate, mitochondrial dysfunction, lactic acidosis, oxidative stress and inflammation (García‐Lezana et al., 2017; Jeong et al., 2018). In BDL rats with different degrees of hypotension, the degeneration of neurons was proportional to the degree of hypotension.…”

2021 ISHEN guidelines on animal models of hepatic encephalopathy

“…The use of PCA to shunt blood away from the liver to establish hepatic insufficiency prior to the administration of a secondary insult has similarly been extensively studied 79,119 . Although early studies sought to investigate impaired hepatic clearance of bacteria 120 post PCA, more recent studies have investigated episodic HE induced by repeated administration of endotoxin or ammonia which demonstrated neuronal loss and cerebral inflammation 121,122 . Other studies in this model have explored the effects of simulated esophageal bleeding 123 as a source of hyperammonemia, and the effects of superadded ammonia on other body systems 124,125 .…”

Brain Gray Matter Alterations in Hepatic Encephalopathy: A Voxel-Based Meta-Analysis of Whole-Brain Studies

“…These regions are more susceptible to plasma ammonia. New animal models using ammonia as a precipitation factor also confirmed cerebellar neuron loss ( García-Lezana et al, 2017 ). Gray matter loss reflects ammonia-related neurological changes.…”