Role of serine protease inhibitor, ulinastatin, in rat model of hepatic encephalopathy: aquaporin 4 molecular targeting and therapeutic implication

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Abstract
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.

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