Anti-inflammatory strategies for hepatic encephalopathy: preclinical studies

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TL;DR

This narrative review summarizes preclinical evidence that anti-inflammatory drugs, including minocycline, ibuprofen, infliximab, sildenafil, and natural compounds like cannabidiol and sulforaphane, reduce neuroinflammation and improve cognitive and motor function in animal models of hepatic encephalopathy. The findings support inflammation as a promising therapeutic target beyond traditional ammonia-lowering therapies. However, clinical translation remains limited, and future studies must address pharmacokinetic and safety issues in patients with liver disease.

Full summary

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**Background:** Hepatic encephalopathy (HE) is a common neuropsychiatric complication of acute or chronic liver disease, affecting 30–70% of cirrhotic patients. It is characterized by cognitive and motor dysfunction due to impaired blood detoxification. Current treatments focus on reducing ammonia absorption or increasing its metabolism, but they have limited efficacy, side effects, and poor tolerability. A growing body of evidence implicates both systemic and central nervous system (CNS) inflammation in HE pathogenesis. This narrative review summarizes preclinical studies evaluating anti-inflammatory strategies as potential therapeutic targets for HE.

**Methods:** The authors conducted a narrative review of preclinical studies investigating anti-inflammatory drugs, natural compounds, hormones, and supplements in animal models of HE. Models included thioacetamide (TAA) intoxication, bile duct ligation (BDL), portacaval shunt (PCS), hyperammonemic diet, and galactosamine-induced acute liver failure. Outcomes assessed included peripheral and central inflammatory markers, glial activation, behavioral tests (cognitive, motor, anxiety-like), and survival.

**Key Results:** Several FDA-approved drugs with anti-inflammatory properties showed beneficial effects in experimental HE: - **Minocycline** (tetracycline antibiotic) prevented microglial activation in the frontal cortex, thalamus, and hippocampus of rats after portocaval anastomosis with hepatic arterial ligation, decreasing brain IL-1β, IL-6, and TNF levels and retarding neurological symptom progression. - **Ibuprofen** (NSAID) improved learning ability and motor activity in PCS rats, restored brain prolyl oligopeptidase (PREP) levels, and decreased iNOS and COX activity. - **Etanercept** (TNF-neutralizing drug) attenuated liver and brain damage in azoxymethane-induced acute liver failure in mice, reducing plasma ALT, AST, ammonia, TNF, and IL-6, and decreasing microglial activation. - **Infliximab** (anti-TNF monoclonal antibody) modulated peripheral inflammation (reducing IL-6 and PGE2, increasing IL-10) and improved memory, learning, and motor coordination in PCS rats. - **Losartan and candesartan** (angiotensin II receptor antagonists) rescued liver parameters, reduced fibrosis, and candesartan improved motor function in chronic TAA-induced liver failure rats. - **Sildenafil and tadalafil** (PDE5 inhibitors) improved motor coordination, spatial learning, and memory in PCS and TAA models, associated with decreased microglial activation and reduced TNF, IL-1β, and IL-6 levels in cerebellum and hippocampus. - **Bicuculline** (GABA-A receptor antagonist) reduced astrocyte activation and IL-1β levels in the hippocampus, improving learning and memory and decreasing anxiety-like behavior in hyperammonemic rats.

Natural compounds and supplements also showed promise: - **Cannabidiol (CBD)** reduced behavioral changes, improved memory and motor function in BDL mice, increased hippocampal BDNF, decreased TNF-α levels and astrogliosis, and improved liver function (↓ AST, ALT, ammonia, bilirubin). - **Sulforaphane** promoted microglial polarization to the anti-inflammatory M2 phenotype in the cerebellum and hippocampus of hyperammonemic rats, increased IL-10 and IL-4, and improved spatial learning and motor coordination. - **Erythropoietin (EPO)** restored hepatic parameters, decreased neurodegeneration and gliosis in hippocampus and cerebellum, and improved motor function and spatial learning in BDL rats. - **Fibroblast growth factor-21 (FGF-21)** decreased serum and brain levels of CCL5, TNF-α, IL-1β, and IL-6, increased IL-10 mRNA, and improved cognitive and neurological scores in TAA-induced acute liver failure mice. - **Taurine** supplementation rescued motor coordination and locomotor activity in BDL rats, associated with reduced ammonia and increased antioxidant activity. - **Coenzyme Q10** improved liver parameters and reduced depressive-like behavior and locomotor activity deficits in TAA-induced acute liver failure rats.

**Clinical Implications:** Preclinical evidence strongly supports inflammation as a therapeutic target in HE. Anti-inflammatory strategies, including repurposed FDA-approved drugs and natural compounds, demonstrate neuroprotective effects by reducing neuroinflammation, glial activation, and oxidative stress, leading to improved cognitive and motor outcomes in animal models. However, clinical translation is lacking. Future studies must address pharmacokinetic challenges, optimal dosing, safety, and efficacy in patients with liver disease, particularly those with severe HE or immunosuppression. The review highlights the urgent need for translational research to bridge the gap between promising preclinical findings and clinical application.