Brain edema and associated astrocyte swelling leading to increased intracranial pressure are hallmarks of
acute liver failure (ALF). Elevated blood and brain levels of
ammonia have been implicated in the development of
brain edema in ALF. Cultured astrocytes treated with
ammonia have been shown to undergo cell swelling and such swelling was associated with an increase in the plasma membrane expression of aquaporin-4 (
AQP4) protein. Further, silencing the AQP4 gene in cultured astrocytes was shown to prevent the
ammonia-induced cell swelling. Here, we examined the evolution of
brain edema in AQP4-null mice and their wild type counterparts (WT-mice) in different models of ALF induced by
thioacetamide (TAA) or
acetaminophen (
APAP). Induction of ALF with TAA or
APAP significantly increased brain water content in WT mice (by 1.6% ± 0.3 and 2.3 ± 0.4%, respectively).
AQP4 protein was significantly increased in brain plasma membranes of WT mice with ALF induced by either TAA or
APAP. In contrast to WT-mice, brain water content did not increase in AQP4-null mice. Additionally, AQP4-null mice treated with either TAA or
APAP showed a remarkably lesser degree of neurological deficits as compared to WT mice; the latter displayed an inability to maintain proper gait, and demonstrated a markedly reduced exploratory behavior, with the mice remaining in one corner of the cage with its head tilted downwards. These results support a central role of AQP4 in the
brain edema associated with ALF.