In vitro and in vivo studies have suggested that reduced astrocytic uptake of neuronally released
glutamate, alterations in expression of
glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP-4) contribute to
brain edema in
acute liver failure (ALF). However, there is no evidence to date to suggest that these alterations occur in patients with ALF. We analyzed the
mRNA expression of
excitatory amino acid transporters (EAAT-1, EAAT-2), GFAP, and AQP-4 in the cerebral cortex obtained at autopsy from eight patients with ALF and from seven patients with no evidence of hepatic or
neurological disorders by real-time PCR, and
protein expression was assessed using immunoblotting and immunohistochemistry. We demonstrated a significant decrease in GFAP
mRNA and
protein levels in ALF patients compared to controls. While the loss of EAAT-2
protein in ALF samples was post-translational in nature, EAAT-1
protein remained within normal limits. Immunohistochemistry confirmed that, in all cases, the losses of EAAT-2 and GFAP were uniquely astrocytic in their localization. AQP-4
mRNA expression was significantly increased and its immunohistochemistry demonstrated increased AQP-4 immunoreactivity in the glial end-feet process surrounding the microvessels. These findings provide evidence of selective alterations in the expression of genes coding for key astrocytic
proteins implicated in central nervous system (CNS) excitability and
brain edema in human ALF. We investigated the gene expression of astrocytic
proteins involved in astrocyte swelling causing
brain edema in autopsied brain tissues of patients with
acute liver failure. This study demonstrated loss of GFAP expression and up-regulation of AQP-4
protein expression leading to
cerebral edema, and loss of EAAT-2 expression implicated in excitatory neurotransmission. These findings may provide new
drug targets against CNS complications of
acute liver failure.