Rutin Attenuates Virus Entry and Replication and Exerts Neuroprotection in Experimental Models of Japanese Encephalitis.

Japanese encephalitis virus (JEV), which belongs to the virus family of Flaviviridae, is a threat to more than three billion people globally. There are no antiviral agents against JEV despite the availability of vaccines. This study considered the need for an effective drug against JEV by evaluating the antiviral and neuroprotective potentials of Chicoric Acid (CA) and Rutin in the in vitro and in vivo models of JE. In the in vitro study, CA and Rutin exhibited variable antiviral potency with IC50 values ranging from 11.03 to 24.04 µM and 16.45 to 26.84 µM in different treatment approaches. These agents demonstrated significant antiviral effects via viricidal activity and inhibiting the virus's entry into the host cells. In addition, treatment of JEV-infected SH-SY5Y cells with these compounds significantly reduced the intracellular viral load, the proportion of apoptotic cells, and the ROS level in a dose-dependent manner. In the in vivo studies, Rutin (50 mg/kg) significantly increased the survival rate and attenuated the encephalitis symptoms in the JEV-infected mice compared to other doses. Rutin (25 and 50 mg/kg) significantly reduced infectious viral particles, viral RNA, and viral NS3 protein expression in the mice's brains. Additionally, Rutin significantly mitigated JEV-induced neuroinflammation by decreasing microglial activation, inflammasome formation, proinflammatory cytokine, and ROS levels. In conclusion, Rutin exhibits non-specific viricidal activity, reduced viral load, and inflammatory cytokines; thus, it could be a potential therapeutic option in managing JE, subject to future investigations.