Abstract
Oxidative stress induced by high ammonia, which leads to astrocyte edema, is the key to acute hepatic encephalopathy (AHE). Nuclear factor erythroid 2-related factor 2 (NRF2) has been implicated in oxidative stress, but the mechanism of NRF2 against ammonia-induced astrocytes edema has not been fully studied. We confirmed that the NRF2 pathway is related to brain edema caused by AHE and found that Xiaochaihutang (XCHT) could effectively activate the NRF2 pathway to treat AHE. The model of AHE was established with thioacetamide (TAA) in rats. Rat behaviors were observed, brain water content, blood ammonia levels, glutamine synthetase (GS), malondialdehyde (MDA), and total superoxide dismutase (T-SOD) were determined after XCHT treatment. Furthermore, the expression of NRF2 pathway proteins and mRNA, glial fibrillary acidic protein (GFAP) and aquaporins 4 (AQP4) were examined. In order to determine whether XCHT has a direct effect on cerebral edema caused by high ammonia, we examined the effect of XCHT compound serum on cortical astrocytes in the presence of ammonia, through microscopic observation and immunofluorescence (IF). Results showed that AHE induced by TAA changed the behavior of the rats, and increased brain water content, blood ammonia levels, GS and MDA content meanwhile decreasing T-SOD, but these symptoms were improved by treatment with XCHT. XCHT protected brain edema by activating the NRF2 pathway and increasing the expression of downstream proteins and genes. Astrocytes treated with 5 mM ammonia also showed an increase in the AQP4 protein expression but a decrease in XCHT compound serum and ammonia-induced cell edema groups. This study demonstrates that the NRF2 pathway is involved in the brain edema in AHE, and XCHT may represent a useful prescription for the treatment of AHE.
Highlights
Hepatic Encephalopathy (HE) is a series of neuropsychological abnormalities secondary to liver dysfunction after excluding other known brain diseases, such as behavioral, intellectual and cognitive changes (Ferenci et al, 2002)
We investigated whether XCHT has a potentially protective effect on brain edema associated with acute hepatic encephalopathy (AHE), which works by activating the Nuclear factor erythroid 2-related factor 2 (NRF2) pathway
To clarify the effect of XCHT on brain edema caused by AHE, we performed in vivo and vitro experiments respectively and detected the expression of glial fibrillary acidic protein (GFAP), aquaporins 4 (AQP4) involved in astrocyte edema as well as the NRF2 pathway (Nucl-NRF2, Cyto-NRF2, HO-1, NQO-1, GCLC and GCLM)
Summary
Hepatic Encephalopathy (HE) is a series of neuropsychological abnormalities secondary to liver dysfunction after excluding other known brain diseases, such as behavioral, intellectual and cognitive changes (Ferenci et al, 2002). Acute liver failure (ALF) is called fulminant hepatic failure (FHF), which refers to various causes leading to severe acute liver injury, causing some potential and reversible diseases such as electrolyte metabolic disorder, jaundice, HE, etc (Trey and Davidson, 1970). The diseases are potentially reversible, they are all based on the loss of the detoxification function of the liver. One of the main components of ALF is the development of brain edema, which leads to increased intracranial pressure and brain herniation, eventually leading to death (Blei, 2010).
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