Journal of Functional Foods (Nov 2022)
Juglanin ameliorates depression-like behavior in chronic unpredictable mild stress-induced mice by improving AMPK signaling
Abstract
Depression is a widespread mental disorder with extremely complex pathogenesis, and its effective treatment still requires to be solved. Juglanin (Jug) is a natural compound with anti-inflammatory, antioxidant and anti-tumor effects, but whether it shows neuroprotective effects for depression treatment is largely unknown. In the present study, the chronic unpredictable mild stress (CUMS) mouse model and lipopolysaccharide (LPS)-stimulated cells were constructed to explore the regulatory potential of Jug on depression in vivo and in vitro, respectively. Numerous behavioral tests at first revealed that Jug supplementation significantly ameliorated anxiety/depression-like behavior and cognitive impairment in CUMS mice. CUMS-induced abnormal releases of stress-related markers in serum or hippocampus were strongly reversed in mice co-treated with Jug. Furthermore, neuronal death in hippocampus triggered by CUMS was highly abolished by Jug administration through increasing protein kinase B (AKT) activation and Caspase-3 blockage. We also found that glial activation due to CUMS was evidently ameliorated by Jug, as evidenced by the decreased CD11b and glial fibrillary acidic protein (GFAP) expression. Consistently, hippocampal neuroinflammation caused by CUMS was also considerably mitigated upon Jug consumption by prohibiting nuclear factor-kappa B (NF-κB) signaling. These neuroprotective and anti-inflammatory effects of Jug were confirmed in LPS-stimulated mouse hippocampal neurons and microglial cells via the same mechanisms. Importantly, we found that Jug treatment remarkably rescued AMP-activated protein kinase (AMPK) phosphorylation in hippocampus of CUMS mice, which was also observed in neurons and microglial cells under inflammatory conditions. Surprisingly, our in vitro experiments showed that AMPK deletion almost diminished the function of Jug to improve neuron survival and restrain neuroinflammation in LPS-exposed neurons and microglial cells, respectively, which were accompanied by AKT blockage and NF-κB activation recovery. These data suggested that the neuroprotective and anti-inflammatory capacity of Jug was AMPK-dependent. Collectively, we provided evidence that Jug might be a novel therapeutic strategy for depression treatment by improving AMPK activation.
