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.

抑郁症是与大脑和免疫系统异常相关的最常见的精神疾病。近年来，黄腐酚（Xn）是一种具有生物活性的异戊二烯化黄酮类化合物，因其多药理作用而受到广泛关注，因此，我们旨在探讨Xn对LPS诱导的炎症和氧化应激介导的抑郁样症状的保护作用。我们通过强迫游泳试验（FST）、悬尾试验（TST）、蔗糖偏好试验（SPT）和旷场试验（OPT）来测试Xn对LPS诱导的小鼠行为变化的影响。检查神经炎症和氧化亚硝化应激 (O&NS) 标记物并分析海马中的 Nrf2 和 NF-κB 信号通路。我们的结果表明，外周重复给予脂多糖（LPS）（1 mg/kg，腹膜内）诱导小鼠抑郁样行为、神经炎症和 O&NS。Xn 预处理（10 和 20 mg/kg，胃内注射））预防性地扭转了 FST 和 TST 中明显的行为障碍，而不影响运动，但只有 20 mg 剂量才能改善 SPT 中观察到的快感缺乏行为。同样，Xn 预处理以剂量依赖性方式预防 LPS 诱导的神经炎症和 O&NS。免疫荧光分析表明，Xn 通过减弱海马中的 Iba-1 和 GFAP 来减少活化的神经胶质细胞增生。此外，Xn 显着降低了海马中磷酸-NF-κB 和裂解 caspase-3 的表达，同时增强了 Nrf2 和 HO-1 的表达。据我们所知，这是第一项研究 Xn 对神经炎症和 O&NS 介导的抑郁样行为的潜在有益预防作用。