Lactoferrin averts neurological and behavioral impairments of thioacetamide-induced hepatic encephalopathy in rats via modulating HGMB1/TLR-4/MyD88/Nrf2 pathway.

Hepatic encephalopathy (HE) is a life-threatening disease caused by acute or chronic liver failure manifested by aberrant CNS changes. In the present study, we aimed to explore the neuroprotective effect of lactoferrin (LF) against thioacetamide (TAA)-induced HE in rats. Animals were divided into four groups, control, LF control, TAA-induced HE, and LF treatment, where LF was administered (300 mg/kg, p.o.) for 15 days in groups 2 and 4 meanwhile, TAA (200 mg/kg, i.p.) was given as two injections on days 13 and 15 for the 3rd and 4th groups. Pretreatment with LF significantly improved liver function observed as a marked decline in serum AST, ALT, and ammonia, together with lowering brain ammonia and enhancing motor coordination as well as cognitive performance. Restoration of brain oxidative status was also noted in the LF-treated group, where lipid peroxidation was hampered, and antioxidant parameters, Nrf2, HO-1, and GSH, were increased. Additionally, LF downregulated HMGB1, TLR-4, MyD88, and NF-κB signaling pathways, together with reducing inflammatory cytokine, TNF-α, and enhancing brain BDNF levels. Moreover, the histopathology of brain and liver tissues revealed that LF alleviated TAA-induced liver and brain deficits. In conclusion, the promising results of LF in attenuating HMGB1/TLR-4/MyD88 signaling highlight its neuroprotective role against HE associated with acute liver injury via ameliorating neuroinflammation, oxidative stress, and stimulating neurogenesis.