Hepatic encephalopathy (HE) is a devastating neuropsychiatric presentation of the advanced
hepatic insufficiency. It is associated with high morbidity and mortality. Aquaporin-4 (AQP4), the principal astrocyte
water channel, is primarily involved in
brain edema development.
Ulinastatin (ULI) is a potent
protease inhibitor, extracted from fresh human urine. We hypothesized that ULI could be neuroprotective in acute HE through molecular targeting of brain AQP4, which is known to be upregulated in HE. To induce
acute liver failure (ALF), the rats were acutely intoxicated with
thioacetamide (TAA). Animals were randomized into HE- and ULI-treated HE groups, with control normal group. Total
bilirubin,
albumin, serum aminotransferases, and serum/brain
ammonia/proinflammatory
cytokines, blood-brain barrier (BBB) integrity/
tight junction proteins, brain water content, and neurological scores were assessed. Additionally, brain AQP4 and α-
Syntrophin mRNA expression and
protein levels were evaluated by quantitative real-time PCR and
enzyme-linked
immunosorbent assay, respectively. Brain and liver tissues were stripped and processed for further microscopic and histological analyses. ULI exerted potent dual neuro/hepato protective potential, improved neurological score, animals' survival, ameliorated
brain edema, probably via anti-inflammatory activity, preserved BBB integrity, down-regulated AQP4 expression, and membrane polarization by decreased α-
syntrophin level, with rescued brain bioenergetics. ULI could be tooled as a possible therapeutic option in HE in ALF.Graphical abstract The possible ULI mediated protection in TAA-induced HE rat model.