Anxiolytic-like effects of hochuekkito in lipopolysaccharide-treated mice involve interleukin-6 inhibition

Abstract

Hochuekkito (HET) is a Kampo medicine used to treat postoperative and post-illness general malaise and decreased motivation. HET is known to regulate immunity and modulate inflammation. However, the precise mechanism and effects of HET on inflammation-induced central nervous system disorders remain unclear. This study aimed to assess the effect of HET on inflammation-induced anxiety-like behavior and the mechanism underlying anxiety-like behavior induced by lipopolysaccharide (LPS). Institute of Cancer Research mice were treated with LPS (300 μg/kg, intraperitoneally), a bacterial endotoxin, to induce systemic inflammation. The mice were administered HET (1.0 g/kg, orally) once a day for 2 weeks before LPS treatment. The light-dark box test and the hole-board test were performed 24 h after the LPS injection to evaluate the effects of HET on anxiety-like behaviors. Serum samples were obtained at 2, 5, and 24 h after LPS injection, and interleukin-6 (IL-6) levels in serum were measured. Human and mouse macrophage cells (THP-1 and RAW264.7 cells, respectively) were used to investigate the effect of HET on LPS-induced IL-6 secretion. The repeated administration of HET prevented anxiety-like behavior and decreased serum IL-6 levels in LPS-treated mice. HET significantly suppressed LPS-induced IL-6 secretion in RAW264.7 and THP-1 cells. Similarly, glycyrrhizin, one of the chemical constituents of HET, suppressed LPS-induced anxiety-like behaviors. Our study revealed that HET ameliorated LPS-induced anxiety-like behavior and inhibited IL-6 release in vivo and in vitro. Therefore, we postulate that HET may be useful against inflammation-induced anxiety-like behavior.

Comparative study of the effects of the three kinds of Kampo-hozai: Ninjinyoeito, Hochuekkito, and Juzentaihoto on anxious and low sociability behavior using NPY-knockout zebrafish

“…In addition, schisandrin rescues depression-like behaviors via the GDNF/ERK1/2/ROS and PI3K/AKT/NOX signaling pathways in mice ( Wan et al, 2017 ). HET improves LPS-induced anxiety in mice, and the active herb is identified as glycyrrhiza ( Ushio et al, 2022 ). The glycyrrhiza amount in HET was 1.5 times higher than in NYT ( Kiyomi et al, 2021 ).…”

“…Kampo has attracted attention as an important therapeutic agent in clinical practice ( Kiyomi et al, 2021 ). It can be used to treat a variety of conditions ranging from mental illnesses to physical frailty ( Ushio et al, 2022 ). In fact, 70%–90% of Japanese physicians regularly prescribe Kampo ( Kiyomi et al, 2021 ).…”

“…HET is commonly used to treat malaise, anorexia, night sweats, and fever ( Ohsawa et al, 2021 ). It also improves depressive symptoms, anorexia ( Tohda and Mingmalairak, 2013 ), and anxiety-like behavior in LPS-induced inflammation in mice ( Ushio et al, 2022 ). JTT is used to prevent anemia, loss of appetite, dry mouth, and side effects of cancer treatment such as anorexia and fatigue ( Chino et al, 2005 ; Ohsawa et al, 2021 ).…”