Hepatic encephalopathy (HE) is a neuropsychiatric complex syndrome, ranging from subtle behavioral abnormalities to deep coma and death. Hepatic encephalopathy emerges as the major complication of acute or chronic liver failure. Multiplicity of factors are involved in its pathophysiology, such as central and neuromuscular neurotransmission disorder, alterations in sleep patterns and cognition, changes in energy metabolism leading to cell injury, an oxidative/nitrosative state and a neuroinflammatory condition. Moreover, in acute HE, a condition of imminent threat of death is present due to a deleterious astrocyte swelling. In chronic HE, changes in calcium signaling, mitochondrial membrane potential and long term potential expression, N-methyl-D-aspartate-cGMP and peripheral benzodiazepine receptors alterations, and changes in the mRNA and protein expression and redistribution in the cerebral blood flow can be observed. The main molecule indicated as responsible for all these changes in HE is ammonia. There is no doubt that ammonia, a neurotoxic molecule, triggers or at least facilitates most of these changes. Ammonia plasma levels are increased two-to three-fold in patients with mild to moderate cirrhotic HE and up to ten-fold in patients with acute liver failure. Hepatic and inter-organ trafficking of ammonia and its metabolite, glutamine (GLN), lead to hyperammonemic conditions. Removal of hepatic ammonia is a differentiated work that includes the hepatocyte, through the urea cycle, converting ammonia into GLN via glutamine synthetase. Under pathological conditions, such as liver damage or liver blood by-pass, the ammonia plasma level starts to rise and the risk of HE developing is high. Knowledge of the pathophysiology of HE is rapidly ex-HE is rapidly ex-HE is rapidly expanding and identification of focally localized triggers has led the development of new possibilities for HE to be considered. This editorial will focus on issues where, to the best of our knowledge, more research is needed in order to clarify, at least partially, controversial topics.

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 S100b protein; neurons were immunostained with neuronal nuclear marker, microtubule associated protein-2, and NF-200 and capillaries with Nestin. The hypoxia-inducible factor 1a (HIF-1a) 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 S100b 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-1a, P-gp, and Epo-R were also evaluated. A high expression of HIF-1a 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-1a and thereby preventing its degradation and inducing its stabilization, leading to the over-expression of P-gp and the Epo-R.

The mechanism of acetaminophen (AAP) hepatotoxicity involves glutathione depletion, oxidative stress and mitochondrial dysfunction leading to necrosis. Recently, glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) was highlighted as a mediator of cell death.AimTo evaluate GAPDH expression and subcellular distribution in liver of AAP acute intoxicated rats.M&MMale Wistar rats were injected i.p. with 1 g/kg b.w. of AAP (AAP group) or vehicle (C group) (n=4). After 24 h, liver GAPDH expression (mRNA and protein) was studied by RT‐PCR and Western‐Blot (WB). Nuclear, mitochondrial, and cytosolic GAPDH content was evaluated in hepatic subcellular fractions by WB. Results were expressed as mean±SD and statistically analized with Student‐t‐test (* p<0.05 vs C).ResultsGAPDH mRNA (AAP:408±221*; C:100±26) and protein expression (AAP:292±127*; C:100±7) were significantly increased in treated rats. Subcellular distribution of GAPDH changed for nucleus (AAP:232±95*; C:100±49) but not for mitochondrial and cytosolic fractions.ConclusionAAP acute intoxication increased GAPDH expression due to a transcriptional mechanism, which questions its use as a housekeeping gene for either RT‐PCR or WB studies. Under AAP overdose, the GAPDH increase its content in the nucleus sugesting a role in AAP toxicity.

No abstract

Brain damage in acetaminophen (AP) overdose is associated with liver failure but its direct effects has not been evaluated.AimTo study the effect of toxic and non‐toxic doses of AP on astrocyte and oligodendrocyte precursor cell (OPC) viability in a primary mixed glial cell culture.MYMPrimary cultures of mixed glial cells were carried out according to McCarthy and de Vellis (1980). Cells were treated with vehicle (DMSO) or AP (1 and 20 mM). After 48 hs cell viability was assessed; astrocyte marker (GFAP) and OPC marker (PDGFR‐alpha) expression was evaluated by western‐blot (WB) and immunocytochemistry.ResultsThe 1 mM dose of AP did not produce significant differences in cell viability, while 20 mM exposure decreased in 40% cell viability (P<0.001). The 20 mM dose produced the death of the 90% of the OPC in the culture and a decrease of 89% of PDGFR‐alpha expression (P<0.001) with an increase in GFAP optical density/cell and WB expression (47% and 97% respectively) (P<0.05). The 1mM dose did not produce significant changes in GFAP but produce a 25% significant decreased in PDGFR‐alpha expression (p<0.05).ConclusionAP produces direct toxic effects on glial cells characterized by oligodendrocyte death and the induction of reactive astroglia.