Acute or chronic liver injury is closely related to
hyperammonemia, which will result in oxidative stress and damage to nerve cells, and these factors are vital to the development of anxiety and depression. In this study, the effect of
Nootkatone (NKT) on the anxiety- and depression-like behavioral changes in mice induced by liver injury was investigated. Liver injury was induced by D-
galactosamine (D-GalN; 350 mg/kg) three times a week for 4 weeks. NKT (5 mg/kg or 10 mg/kg) was given as co-treatment daily for 4 weeks. NKT (5 mg/kg) co-treatment remarkably ameliorates D-GalN-induced anxiety- and depression-like behaviors as evident from the results of
sucrose preference test, forced swimming test, tail suspension test, and novelty suppressed feeding test. Results showed that NKT could induce an elevation in serum
alanine transaminase and
aspartate transaminase level, alleviate the oxidative stress induced by
hyperammonemia through activating Keap1/Nrf2/HO-1
antioxidant pathways, decrease the expression of
inducible nitric oxide synthase and NOX2 in hippocampus and prefrontal cortex, enhance the vitality of
superoxide dismutase,
catalase, and
glutathione levels in serum, liver, and brain, and significantly reduce the generation of
malondialdehyde. At the same time, NKT also reduces the level of
ammonia in serum and brain and upgrades the activity of
glutamine synthetase in the hippocampus and prefrontal cortex. Taken together, the present results suggested that NKT has a significant
antidepressant effect through modulation of oxidative stress induced by D-GalN administration.