Inhibition of the infectivity and inflammatory response of influenza virus by Arbidol hydrochloride in vitro and in vivo (mice and ferret)

Abstract

Influenza virus infections are the main contagious respiratory disease with high levels of morbidity and mortality worldwide. Antiviral drugs are indispensable for the prophylaxis and treatment of influenza and other respiratory viral infections. In this study, the Arbidol hydrochloride (ARB), which has been licensed in Russia and China, is used to investigate its anti-viral and anti-inflammatory efficacy in vitro and in vivo. The antiviral results in vitro showed that ARB had a better inhibition on Influenza virus A/PR/8/34 (H1N1), A/Guangdong/GIRD07/09 (H1N1), A/Aichi/2/68 (H3N2), A/HK/Y280/97 (H9N2) with IC₅₀ ranging from 4.4 to 12.1μM. The further mechanisms study demonstrated that ARB is able to inhibit hemagglutinin-mediated hemolysis at concentration of 3.91-15.63μg/mL. The anti-inflammatory efficacy in vitro indicated that IL-6, IP-10, MCP-1, RANTES and TNF-α levels were diminished by ARB at concentrations of 22.6 and 18.8μM. The in vivo results in mice model displayed that the survival rates of mice administered 25mg/mL and 45mg/mL ARB were 40% and 50% respectively. And also, ARB can inhibit the decrease of body weight at 45mg/mL and inhibit the increase of mice lung index at 25mg/mL and 45mg/mL comparing to virus group. In ferret model, the ARB-treated ferrets showed a fever that peaked at 2 dpi and gradually decreased beginning at 3 dpi while relatively high temperatures were observed until 4 dpi in the virus group. The ARB-treated group scored 0-1 in the activity level at 2 dpi and 3 dpi at all time points. The transcription levels of cytokines in the respiratory tract of ferrets were detected at 3 dpi. Several proinflammatory cytokines induced by influenza (IL-10, TNF-α, IL-8 and IL-6) were down-regulated by post-treatment with ARB. The histopathological results of ferret lung displayed that ARB can alleviate the influenza virus induced lung lesions. Our results clarified the activity of ARB in both suppressing virus propagation and modulating the expression of inflammatory cytokines in vitro and in vivo, it can be as an effective drug to treat the influenza virus infection.

Keywords: Anti-inflammatory; Anti-viral; Arbidol hydrochloride; Influenza virus.