Hepatoprotective and anti-inflammatory profile of sokeikakketsuto and makyoyokukanto in primary cultured rat hepatocytes

Abstract

Background: Sokeikakketsuto (SOK) is a Kampo medicine that can mitigate several types of pain, including arthralgia, neuralgia, low back pain, and myalgia, which may be introduced for the treatment of neuropathic pain in anti-cancer therapy. Considering that several Kampo medicines are known to have hepatoprotective and anti-inflammatory effects, we investigated the pharmacological mechanism of SOK in hepatocytes. Additionally, we examined another Kampo medicine, makyoyokukanto (MAK), as a reference as it has been reported to have similar efficacy for neuropathic pain.Methods: SOK or MAK was incubated with rat primary cultured hepatocytes treated with interleukin (IL)-1β. The induction of inducible nitric oxide synthase (iNOS), nitric oxide (NO) production, iNOS signaling pathways, and the expression of other inflammatory mediators was investigated.Results: IL-1β activated iNOS induction, followed by NO production. SOK and MAK reduced the expression of iNOS mRNA and its protein and decreased NO production. SOK and MAK also decreased the levels of tumor necrosis factor (TNF)-α and increased the levels of IL-6 and IL-1β. Transfection experiments with iNOS promoter-luciferase constructs revealed that MAK reduced iNOS mRNA synthesis and stability; however, SOK only reduced mRNA synthesis. Both medicines suppressed the activation of nuclear factor (NF)-κB but did not block the upregulation of type I IL-1 receptor in two essential signaling pathways.Conclusions: SOK and MAK could prevent NO production by inhibiting iNOS gene expression, partly through NF-κB activation, in inflamed hepatocytes. However, both medicines may have different mechanisms of action in the treatment of injured organs.