Acute Liver Failure Induces Glial Reactivity, Oxidative Stress and Impairs Brain Energy Metabolism in Rats

Abstract

Acute liver failure (ALF) implies a severe and rapid liver dysfunction that leads to impaired liver metabolism and hepatic encephalopathy (HE). Recent studies have suggested that several brain alterations such as astrocytic dysfunction and energy metabolism impairment may synergistically interact, playing a role in the development of HE. The purpose of the present study is to investigate early alterations in redox status, energy metabolism and astrocytic reactivity of rats submitted to ALF. Adult male Wistar rats were submitted either to subtotal hepatectomy (92% of liver mass) or sham operation to induce ALF. Twenty-four hours after the surgery, animals with ALF presented higher plasmatic levels of ammonia, lactate, ALT and AST and lower levels of glucose than the animals in the sham group. Animals with ALF presented several astrocytic morphological alterations indicating astrocytic reactivity. The ALF group also presented higher mitochondrial oxygen consumption, higher enzymatic activity and higher ATP levels in the brain (frontoparietal cortex). Moreover, ALF induced an increase in glutamate oxidation concomitant with a decrease in glucose and lactate oxidation. The increase in brain energy metabolism caused by astrocytic reactivity resulted in augmented levels of reactive oxygen species (ROS) and Poly [ADP-ribose] polymerase 1 (PARP1) and a decreased activity of the enzymes superoxide dismutase and glutathione peroxidase (GSH-Px). These findings suggest that in the early stages of ALF the brain presents a hypermetabolic state, oxidative stress and astrocytic reactivity, which could be in part sustained by an increase in mitochondrial oxidation of glutamate.

Blood-brain barrier permeability and increased levels of amino acids in cerebrospinal fluid are associated with brain alterations in rats with acute liver failure

“…The amino acid pro le and albumin evaluation discussed above were performed 24h after subtotal hepatectomy -a result observed in previous studies carried out by our group [35,39]. Following 24h of surgery, most of the rats present signi cant neurological impairment and are not yet in the nal stages of HE, as the mean time of death is after 36 hours (Table 1).…”

“…A subtotal hepatectomy was performed as previously described [38,35,39], with minor modi cations. Anesthesia was induced and maintained with 3% iso urane at an oxygen ow rate of 1 L/min during the whole procedure.…”

“…CSF harvesting was performed according to previous reports from our group [39,35,41]. Animals were brie y anesthetized with 3% iso urane and positioned in a stereotaxic frame.…”

Genetic variants of IFIH1 and DHX58 affect the chronicity of hepatitis C in the Chinese Han population

“…AST also effectively inhibits the inflammatory response in the rat brain and down-regulates the expression of P2X7R (ATP-gated purinergic receptor). All these suggest that AST dysfunction and energy metabolism may have a synergistic interaction ( Guazzelli et al, 2019 ; Er et al, 2020 ; Wang et al, 2020 ) which in turn affects the ATP-dependent LGP2 and MDA5 to play a synergistic antiviral effect, but the specific mechanism is not clear and further research is needed.…”

Ameliorative Effect of Chitosan Oligosaccharides on Hepatic Encephalopathy by Reshaping Gut Microbiota and Gut–Liver Axis

“…Previous reports stated that HE emphasized abnormal amino acid metabolism and ammonia metabolism . Most ammonia is metabolized through the urea cycle in the liver, and thus, ammonia and false neurotransmitter bloodstream levels are enhanced in the circumstance of liver insufficiency . In cirrhotic patients, it has been elucidated that an imbalance exists among the aromatic amino acids (AAA) and branched-chain amino acids (BCAA), where the serum concentrations of AAA are enhanced but BCAA are reduced.…”