Hochuekkito reversed poly(I:C)-induced anxiety-like behavior and reductions in hippocampal BDNF expression in mice

We investigated the effects of hochuekkito (HET), a traditional Japanese herbal medicine, on anxiety-like behavior induced by the intraperitoneal administration of polyinosinic-polycytidylic acid (poly(I:C)), a synthetic double-stranded RNA that is widely used to mimic viral infection-associated inflammation, in mice. HET (1 g/kg) was orally administered to the mice once daily for two weeks prior to the injection of poly(I:C). Anxiety-like behavior was assessed for 24 h after the poly(I:C) injection using the light-dark box test. The repeated administration of HET significantly attenuated poly(I:C)-induced anxiety-like behavior. Diazepam failed to exert significant effects in poly(I:C)-treated mice. Poly(I:C) significantly increased serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentrations, as well as Il6 and Tnfa mRNA expression levels in the hippocampus and frontal cortex. HET significantly suppressed the poly(I:C)-induced elevation of serum IL-6 and TNF-α concentrations; however, it did not affect the poly(I:C)-induced increases in Il6 and Tnfa mRNA expression in the hippocampus and frontal cortex. Furthermore, poly(I:C) significantly reduced the hippocampal brain-derived neurotrophic factor (BDNF) concentration, and this reduction was significantly reversed by HET treatment. In addition, the administration of 7,8-dihydroxyflavone, a tropomyosin receptor kinase B receptor agonist, significantly increased the time spent in the light compartment in the light-dark box test and ameliorated poly(I:C)-induced anxiety-like behavior. These findings suggest that the anxiolytic-like effects of HET may be associated with the suppression of peripheral inflammatory cytokine responses and restoration of hippocampal BDNF signaling under conditions mimicking viral infection-induced inflammation.