Nobiletin-rich kososan, a Kampo formula, prevents the onset of apathy-like behavior and neuroinflammation in sickness behavior mouse model induced by increasing doses of lipopolysaccharide

Infectious diseases are often concomitant with symptoms of lassitude and emotional disturbances, including depression, the so-called sickness behavior. Kososan, a Kampo (traditional Japanese herbal) formula, has been clinically used for depressive mood, with demonstrated efficacy in stress-induced depressive-like behavior mouse models. Additionally, our previous study has shown that nobiletin-rich kososan (NKS) prevents aging-related depressive-like behaviors and neuroinflammation in mice. Here, we examined whether NKS alleviates depressive-like behavior and neuroinflammation in a mouse model of sickness behavior induced by lipopolysaccharide (LPS). Repeated oral administration of NKS and the positive control antidepressant paroxetine (Paro) significantly prevented this behavior. NKS and Paro significantly increased the anti-inflammatory milieu in the hippocampus and prefrontal cortex (PFC), as well as brain microglia, of LPS-injected mice. The expression of the vascular tight junction protein claudin-5 was also significantly increased by the treatment with NKS, but not with Paro, in the hippocampus and PFC of LPS-injected mice. In vitro analysis using brain microvascular endothelial cells (BMVECs) showed that incubation with 5% serum derived from mice orally administered NKS resulted in a significant increase in the expression of anti-inflammatory heme oxygenase 1 as well as autophagic flux markers. Moreover, the claudin-5 levels in BMVECs were also increased under LPS-stimulated conditions. These results suggest that NKS exerts prophylactic effects against the LPS-induced apathy-like behavior, partly mediated by the increase in the anti-inflammatory milieu and in the levels of tight junction proteins in the brain. This study provides scientific evidence supporting the potential efficacy of NKS in preventing post-infection depression.