Xanthohumol Attenuates Lipopolysaccharide-Induced Depressive Like Behavior in Mice: Involvement of NF-κB/Nrf2 Signaling Pathways

Depression is the most common psychiatric disorder associated with brain and immune system abnormalities. In recent years, xanthohumol (Xn) a bioactive prenylated flavonoid has received ample attention for its polypharmacological effects, therefore, here we aimed to explore the protective effects of Xn against the LPS-induced depressive-like symptoms mediated by inflammation and oxidative stress. We tested the effect of Xn against LPS-induced behavioural changes in mice by means of forced swimming test (FST), tail suspention test (TST), sucrose preference test (SPT) and open field test (OPT). Examined the neuroinflammation and oxido-nitrosative stress (O&NS) markers and analyze Nrf2 and NF-κB signalling pathways in the hippocampus. Our results indicated that peripheral repeated administration of lipopolysaccharides (LPS) (1 mg/kg, intra peritoneally) induced depressive-like behavior, neuroinflammation and O&NS in mice. Pretreatment with Xn (10 and 20 mg/kg, intra gastrically) reverse the behavioural impairments prophylactically as obvious in the FST and TST without effecting locomotion, however only 20 mg dose improve anhedonic behavior as observed in SPT. Similarly, Xn pretreatment in dose-dependent manner prevented the LPS induced neuro-inflammation and O&NS. Immunofluorescence analysis showed that Xn reduced activated gliosis via attenuation of Iba-1 and GFAP in hippocampus. In addition, Xn considerably reduced the expression of phospho-NF-κB and cleaved caspase-3 while enhanced Nrf2 and HO-1 expression in the hippocampus. To the best of our knowledge, this is the first study to examine the underlying beneficial prophylactic effects of the Xn in neuroinflammation and O&NS mediating depressive-like behaviors.