Therapeutic determinants of melatonin in hepatitis caused by coxsackievirus B3 infection

Coxsackievirus B (CVB) is the most recognized enteroviruses associated with acute hepatitis in neonates. It may develop into life-threatening fulminant hepatitis and disseminated intravascular coagulation. Melatonin is a potential agent against infection by modulating inflammation, apoptosis, and oxidative stress. The effect of melatonin on CVB3 replications, cytokine and chemokine productions, and liver damage in CVB3-infected Huh-7 and HepG2 cells were determined. A CVB3-infected hepatitis mouse model was used to explore antiviral, anti-inflammatory, anti-apoptotic, and immunomodulatory responses of melatonin treatment. Melatonin administration reduced viral proteins and viral titers in CVB3-infected cell lines. The expressions of Nrf2 and MST1 were increased, and the levels of cleaved caspase-9 and interleukin (IL)-1β were decreased after melatonin treatment. Melatonin decreased the mortality rate and clinical scores and improved liver damage markers in CVB3-infected mice. Melatonin treatment significantly decreased the viral loads in the liver, spleen, brain, and brain stem of CVB3-infected mice. In the liver of CVB3-infected mice, the expression of Nrf2 and MST1 was increased. Melatonin increased the levels of interferon (IFN)-γ and decreased the levels of IL-1β, IL-6, TNF-α, IL-10, RANTES, and MCP-1 in the serum of CVB3-infected mice. The monocyte expressions were increased after the melatonin treatment of CVB3-infected mice initially. The expressions of the T cells, NK cells, and dendritic cells were attenuated after melatonin treatment through course. Melatonin highlighted the antiviral, anti-inflammatory, anti-oxidative and immune regulatory responses against CVB3-infected hepatitis in vitro and in vivo. The clinical potential efficacy of melatonin treatment in CVB3-infected hepatitis is positive and convinced.