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

Pedro Arend Guazzelli,Daniela Nogara,Mateus Grings,Jussemara S Da Silva,Leo Anderson Meira-Martins,Diogo O Souza,Fernanda U Fontella,Adriano Martimbianco De Assis,Gabriel S Lazzarotto,Giordano Fabricio Cittolin-Santos,Moacir Wajner,Yasmine Nonose,Guilhian Leipnitz

doi:10.3389/fnmol.2019.00327

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.

Highlights

Acute liver failure (ALF) is a syndrome characterized by sudden hepatic injury and dysfunction in patients with a previously healthy liver and is associated with high lethality and morbidity (Craig et al, 2010; Bernal, 2017)
ALF is a meaningful and potentially life-threatening syndrome that is caused by liver damage and substantial neurotoxin accumulation in the brain, such as ammonia (Bernal, 2017)
Blood ammonia elevation plays an essential role in the development of encephalopathy and leads to glutamatergic excitotoxicity, oxidative stress and astrocytic dysfunction (Ciecko-Michalska et al, 2012; Butterworth, 2015)

Summary

Introduction

Acute liver failure (ALF) is a syndrome characterized by sudden hepatic injury and dysfunction in patients with a previously healthy liver and is associated with high lethality and morbidity (Craig et al, 2010; Bernal, 2017). The characteristic features of this condition are impaired liver synthetic function (expressed as coagulopathy), hepatic encephalopathy (HE) and, in severe cases, multi-organ failure (Craig et al, 2010; Scott et al, 2013). The final stages of HE reach 20–25% of lethality due to cerebral edema and high intracranial pressure (Larsen and Wendon, 2008; Stravitz and Larsen, 2009) which demands rapid and aggressive treatment strategies such as liver transplantation (Acharya and Bajaj, 2018; Rajaram and Subramanian, 2018). Ammonia can cross the blood-brain barrier by diffusion (Cooper et al, 1985) and numerous studies have shown a positive correlation between its arterial concentration and intracranial hypertension in humans (Clemmesen et al, 1999; Bernal et al, 2007)

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