Kinetic deterioration of short memory in rat with acute hepatic encephalopathy: Involvement of astroglial and neuronal dysfunctions

Abstract

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome resulting from acute or chronic hepatic impairments. The clinical features of HE include attention as well as a mild cognitive deficits associated with impaired attentional and executive networks in patients as well as in animal models of HE. The underlining pathomechanism of memory impairment in HE patients is still not fully understood; however, it may involve a possible gliopathy as well as neuropathy. The aim of the present investigation is to assess progression of short working memory deterioration in acute HE and to delineate the glial and the neuronal alteration which may underlie such cognitive impairment. The study was carried out in male Sprague-Dawley rats with acute liver failure induced by thioacetamide (TAA). The study was performed on different stages of acute HE; 12 h, 24 h and 36 h following administration of TAA. The liver functions were assessed via different biochemical markers (ALT, AST, bilirubin, urea and creatinine) and an histopathological examination of the liver tissue. While for the behavioral study, we used T-Maze test to assess short working memory using the percentage of alternation behavior, together with an immunohistochemical analysis of the Glial Fibrillary Acidic Protein (GFAP) as the key marker of astrocytes in the hippocampus, as well as serotonin (5-HT) for 5-HTergic neurons within the dorsal Raphe nucleus (DRN). Our data revealed a progressive loss of liver tissue integrity with inflammation and hepatocytes degeneration which was associated to obvious loss of the liver function. In parallel, we observed a gradual alteration of the alternation behavior, as a sign of altered short working memory in the acute HE rats. At the central level, the immunohistochemical study showed a time dependent region-specific changes of GFAP-immunoreactive astrocytes within the hippocampus. While within the DRN, serotonin levels declined progressively in a time-dependant manner. Our data revealed for the first time, a gradual loss of short memory function in acute HE, resulting from liver dysfunction. Such cognitive deterioration may involve a possible gliopathy as well as a 5-HTergic dysfunction which could be considered as a new key element for understanding the basis of memory and attention loss in HE patients.

Keywords: Acute hepatic encephalopathy; Dorsal raphe nucleus; GFAP; Hippocampus; Rat; Serotonin; Short working memory; T-maze.