Excessive intragastric alcohol administration exacerbates hepatic encephalopathy and provokes neuronal cell death in male rats with chronic liver disease
Article [Version of Record]
Is part of
Journal of neuroscience research ; vol. 102, no. 5.Publisher(s)
WileyAuthor(s)
Abstract(s)
Hepatic encephalopathy (HE) is defined as decline in neurological function during
chronic liver disease (CLD). Alcohol is a major etiological factor in the pathogenesis of
fibrosis/cirrhosis and has also been documented to directly impact the brain. However,
the role of alcohol in the development of HE in CLD remains unclear. Here, we investigated the impact of excessive alcohol administration on neurological deterioration in
rats with CLD. Starting day 7 post-BDL surgery, rats were administered alcohol twice
daily (51% v/v ethanol, 3 g/kg, via gavage) for 4 weeks. Motor coordination was assessed weekly using rotarod and anxiety-like behavior was evaluated with open field
and elevated plus maze at 5 weeks. Upon sacrifice, brains were collected for western
blot and immunohistochemical analyses to investigate neuronal integrity and oxidative stress status. Alcohol worsened motor coordination performance and increased
anxiety-like behavior in BDL rats. Impairments were associated with decreased
neuronal markers of NeuN and SMI311, increased apoptotic markers of cleaved/
pro-caspase-3 and Bax/Bcl2, increased necroptosis markers of pRIP3 and pMLKL,
decreased total antioxidant capacity (TAC), and increased 4-hydroxynonenal (4-HNE)
modified proteins in the cerebellum of BDL-alcohol rats when compared to respective
controls. Immunofluorescence confirmed the colocalization of cleaved caspase-3 and
pMLKL in the granular neurons of the cerebellum of BDL-alcohol rats. Excessive alcohol consumption exacerbates HE which leads to associated apoptotic and necroptotic
neuronal loss in the cerebellum of BDL-alcohol rats. Additionally, higher levels of 4-
HNE and decreased TAC in the cerebellum of BDL-alcohol rats suggest oxidative stress
is the triggering factor of apoptotic and necroptotic neuronal loss/injury.