Pentoxifylline inhibits replication of Japanese encephalitis virus: a comparative study with ribavirin

Abstract

Several investigations have shown that pentoxifylline possesses broad-spectrum antiviral activity against a range of RNA and DNA viruses. However, its ability to inhibit Japanese encephalitis virus (JEV) replication has not yet been studied. The present study was designed to investigate the antiviral activity of pentoxifylline against JEV in vitro and in vivo. The activity of pentoxifylline against JEV was evaluated in vitro using cytopathic effect inhibition and plaque reduction assays. Pentoxifylline was able to inhibit JEV replication in a dose-dependent manner at a 50% inhibitory concentration (IC(50)) of 50.3microg/mL (0.00018microM) and a therapeutic index (TI) of 10. Experiments to study the mechanism of antiviral action of pentoxifylline using in vitro translation of viral mRNA suggested that the drug did not interfere either with early or late protein synthesis but most likely exerted its action on virus assembly and/or release. Furthermore, the in vivo study showed that pentoxifylline at a concentration of 100mg/kg and 200mg/kg body weight was able to protect completely mice challenged with 50 x 50% lethal dose (LD(50)) of JEV.

Mycophenolic Acid Inhibits Replication of Japanese Encephalitis Virus

“…Ribavirin, a known inhibitor of Flavivirus replication, was used as a standard in this study to compare the results. Subsequently, the antiviral activity of ribavirin and mycophenolic acid against JEV was investigated using an in vitro cytopathic effect (CPE) inhibition assay in a 96-well plate as described earlier [9]. Briefly, monolayers of PS were inoculated with 1 multiple of infection (MOI) of virus (100 µl) and adsorbed for 2 h at 37°C.…”

“…In order to confirm the antiviral activity noted in the screening experiments, the compounds were subjected to plaque reduction assay as described earlier [9]. Briefly, PS cells were grown to a confluent monolayer, infected with 1 MOI of JEV and adsorbed for 2 h at 37°C.…”

“…The therapeutic potential and the specificity of action of the compounds were calculated as therapeutic index (TI), which is the ratio of CC 50 to IC 50 [9]. …”

“…Initially, a single replication cycle of JEV was established as described earlier [9]. Subsequently, a fresh monolayer of PS cells was infected with 1 MOI of JEV, and adsorbed for 1 h at 37°C.…”

Japanese Encephalitis, Recent Perspectives on Virus Genome, Transmission, Epidemiology, Diagnosis and Prophylactic Interventions

“…Supportive care directed to control convulsions and maintenance of airway, fluid and electrolyte balance plays a key role in treatment efficacy during the acute phase. Although, treatment with diethyldithiocarbamate (Saxena et al, 2003), Lipid-complexed small interfering RNA (siRNA) (Kumar et al, 2006), Rosmarinic acid (Swarup et al, 2007), Pentoxifylline (Sebastian et al, 2009), Arctigenin (a lignin derived from the Greater Burdock (Arctiumlappa) (Hayashi, 2010), Peptideconjugated phosphorodiamidatemorpholino oligomers (Anantpadma et al, 2010), Minocycline (semi-synthetic derivative of tetracycline) (Dutta & Basu, 2011), Tilapia hepcidin 1-5 (Antimicrobial peptide) (Huang et al, 2011), Griffithsin (Ishag et al, 2013), Bispidine (amino acid conjugate of 3,7-diazabicyclononane) (Haridas et al, 2013), Mycophenolic acid (Sebastian et al, 2011), Luteolin (Fan et al, 2016 and anti-miR301a therapy (Hazra et al, 2017) have been found as promising candidates against JE infection that were attempted and showed protective effect in laboratory models. Their efficacy in the hospital settings is a big challenge which needs further assessment and increased availability to the needful.…”