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Coadministration of Hedera helix L. Extract Enabled Mice to Overcome Insufficient Protection against Influenza A/PR/8 Virus Infection under Suboptimal Treatment with Oseltamivir.

Hong EH, Song JH, Shim A, Lee BR, Kwon BE, Song HH, Kim YJ, Chang SY, Jeong HG, Kim JG, Seo SU, Kim H, Kwon Y, Ko HJ - PLoS ONE (2015)

Bottom Line: Oral administration of ivy extract with suboptimal oseltamivir increased the antiviral activity of oseltamivir.Ivy extract and its compounds, particularly hedrasaponin F, significantly reduced the cytopathic effect in PR8-infected A549 cells in the presence of oseltamivir.Inflammatory cytokines and chemokines, including tumor necrosis factor-alpha and chemokine (C-C motif) ligand 2, were reduced by treatment with oseltamivir and the fraction of ivy extract.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.

ABSTRACT
Several anti-influenza drugs that reduce disease manifestation exist, and although these drugs provide clinical benefits in infected patients, their efficacy is limited by the emergence of drug-resistant influenza viruses. In the current study, we assessed the therapeutic strategy of enhancing the antiviral efficacy of an existing neuraminidase inhibitor, oseltamivir, by coadministering with the leaf extract from Hedera helix L, commonly known as ivy. Ivy extract has anti-inflammatory, antibacterial, antifungal, and antihelminthic properties. In the present study, we investigated its potential antiviral properties against influenza A/PR/8 (PR8) virus in a mouse model with suboptimal oseltamivir that mimics a poor clinical response to antiviral drug treatment. Suboptimal oseltamivir resulted in insufficient protection against PR8 infection. Oral administration of ivy extract with suboptimal oseltamivir increased the antiviral activity of oseltamivir. Ivy extract and its compounds, particularly hedrasaponin F, significantly reduced the cytopathic effect in PR8-infected A549 cells in the presence of oseltamivir. Compared with oseltamivir treatment alone, coadministration of the fraction of ivy extract that contained the highest proportion of hedrasaponin F with oseltamivir decreased pulmonary inflammation in PR8-infected mice. Inflammatory cytokines and chemokines, including tumor necrosis factor-alpha and chemokine (C-C motif) ligand 2, were reduced by treatment with oseltamivir and the fraction of ivy extract. Analysis of inflammatory cell infiltration in the bronchial alveolar of PR8-infected mice revealed that CD11b+Ly6G+ and CD11b+Ly6Cint cells were recruited after virus infection; coadministration of the ivy extract fraction with oseltamivir reduced infiltration of these inflammatory cells. In a model of suboptimal oseltamivir treatment, coadministration of ivy extract fraction that includes hedrasaponin F increased protection against PR8 infection that could be explained by its antiviral and anti-inflammatory activities.

No MeSH data available.


Related in: MedlinePlus

Determination of the effective dose of ivy extract in combination with oseltamivir.The survival rate (A) and body weight (B) of PR8-infected mice administered oseltamivir (*P<0.05; **P<0.01; ***P<0.001, two-tailed unpaired t-test). C: Survival rate of PR8-infected mice that received ivy extract or vehicle (PBS). D: Survival rate of PR8-infected mice that received oral coadministration of ivy extract and oseltamivir (*P<0.05, log-rank analysis of Mantel-Cox data) E: Body weight of PR8-infected mice that received oral coadministration of ivy extract and oseltamivir (*P<0.05, one-way ANOVA with Tukey’s post hoc test).
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pone.0131089.g001: Determination of the effective dose of ivy extract in combination with oseltamivir.The survival rate (A) and body weight (B) of PR8-infected mice administered oseltamivir (*P<0.05; **P<0.01; ***P<0.001, two-tailed unpaired t-test). C: Survival rate of PR8-infected mice that received ivy extract or vehicle (PBS). D: Survival rate of PR8-infected mice that received oral coadministration of ivy extract and oseltamivir (*P<0.05, log-rank analysis of Mantel-Cox data) E: Body weight of PR8-infected mice that received oral coadministration of ivy extract and oseltamivir (*P<0.05, one-way ANOVA with Tukey’s post hoc test).

Mentions: We adopted a novel strategy to screen extracts or chemical compounds eliciting antiviral activity under suboptimal oseltamivir against PR8 virus. Firstly, we determined the suboptimal dose of oseltamivir in PR8-infected mice. PR8-infected mice treated with 25 mg/kg of oseltamivir showed complete recovery from PR8 infection, while mice treated with 5 mg/kg showed 50% recovery (Fig 1A). Mice that survived the PR8 infection recovered their body weight within 8 days of infection; however, there were significant delays in recovery compared with mice receiving 5 mg/kg of oseltamivir treatment (Fig 1B). Thus, we decided to use 5 mg/kg oseltamivir for the combined treatment with candidate plant extracts in mice. We assumed that this dose of oseltamivir would enable us to assess the additive anti-influenza effects of plant extract in circumstances of incomplete removal of PR8 virus. Among the plant extracts tested during preliminary experiments, we found that 30% EtOH extract of ivy leaf (ivy extract) showed significant antiviral activity when combined with oseltamivir in vitro (data not shown). To confirm an anti-influenza virus effect of ivy extract in vivo, mice were intranasally infected with 5 x 103 PFU of PR8 at day 0 and treated with 30 mg/kg of ivy extract for 5 days starting from day 2. Although the administration of ivy extract alone on PR8-infected mice increased the survival rate of mice, the effect was only marginal and statistically insignificant (Fig 1C).


Coadministration of Hedera helix L. Extract Enabled Mice to Overcome Insufficient Protection against Influenza A/PR/8 Virus Infection under Suboptimal Treatment with Oseltamivir.

Hong EH, Song JH, Shim A, Lee BR, Kwon BE, Song HH, Kim YJ, Chang SY, Jeong HG, Kim JG, Seo SU, Kim H, Kwon Y, Ko HJ - PLoS ONE (2015)

Determination of the effective dose of ivy extract in combination with oseltamivir.The survival rate (A) and body weight (B) of PR8-infected mice administered oseltamivir (*P<0.05; **P<0.01; ***P<0.001, two-tailed unpaired t-test). C: Survival rate of PR8-infected mice that received ivy extract or vehicle (PBS). D: Survival rate of PR8-infected mice that received oral coadministration of ivy extract and oseltamivir (*P<0.05, log-rank analysis of Mantel-Cox data) E: Body weight of PR8-infected mice that received oral coadministration of ivy extract and oseltamivir (*P<0.05, one-way ANOVA with Tukey’s post hoc test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476699&req=5

pone.0131089.g001: Determination of the effective dose of ivy extract in combination with oseltamivir.The survival rate (A) and body weight (B) of PR8-infected mice administered oseltamivir (*P<0.05; **P<0.01; ***P<0.001, two-tailed unpaired t-test). C: Survival rate of PR8-infected mice that received ivy extract or vehicle (PBS). D: Survival rate of PR8-infected mice that received oral coadministration of ivy extract and oseltamivir (*P<0.05, log-rank analysis of Mantel-Cox data) E: Body weight of PR8-infected mice that received oral coadministration of ivy extract and oseltamivir (*P<0.05, one-way ANOVA with Tukey’s post hoc test).
Mentions: We adopted a novel strategy to screen extracts or chemical compounds eliciting antiviral activity under suboptimal oseltamivir against PR8 virus. Firstly, we determined the suboptimal dose of oseltamivir in PR8-infected mice. PR8-infected mice treated with 25 mg/kg of oseltamivir showed complete recovery from PR8 infection, while mice treated with 5 mg/kg showed 50% recovery (Fig 1A). Mice that survived the PR8 infection recovered their body weight within 8 days of infection; however, there were significant delays in recovery compared with mice receiving 5 mg/kg of oseltamivir treatment (Fig 1B). Thus, we decided to use 5 mg/kg oseltamivir for the combined treatment with candidate plant extracts in mice. We assumed that this dose of oseltamivir would enable us to assess the additive anti-influenza effects of plant extract in circumstances of incomplete removal of PR8 virus. Among the plant extracts tested during preliminary experiments, we found that 30% EtOH extract of ivy leaf (ivy extract) showed significant antiviral activity when combined with oseltamivir in vitro (data not shown). To confirm an anti-influenza virus effect of ivy extract in vivo, mice were intranasally infected with 5 x 103 PFU of PR8 at day 0 and treated with 30 mg/kg of ivy extract for 5 days starting from day 2. Although the administration of ivy extract alone on PR8-infected mice increased the survival rate of mice, the effect was only marginal and statistically insignificant (Fig 1C).

Bottom Line: Oral administration of ivy extract with suboptimal oseltamivir increased the antiviral activity of oseltamivir.Ivy extract and its compounds, particularly hedrasaponin F, significantly reduced the cytopathic effect in PR8-infected A549 cells in the presence of oseltamivir.Inflammatory cytokines and chemokines, including tumor necrosis factor-alpha and chemokine (C-C motif) ligand 2, were reduced by treatment with oseltamivir and the fraction of ivy extract.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.

ABSTRACT
Several anti-influenza drugs that reduce disease manifestation exist, and although these drugs provide clinical benefits in infected patients, their efficacy is limited by the emergence of drug-resistant influenza viruses. In the current study, we assessed the therapeutic strategy of enhancing the antiviral efficacy of an existing neuraminidase inhibitor, oseltamivir, by coadministering with the leaf extract from Hedera helix L, commonly known as ivy. Ivy extract has anti-inflammatory, antibacterial, antifungal, and antihelminthic properties. In the present study, we investigated its potential antiviral properties against influenza A/PR/8 (PR8) virus in a mouse model with suboptimal oseltamivir that mimics a poor clinical response to antiviral drug treatment. Suboptimal oseltamivir resulted in insufficient protection against PR8 infection. Oral administration of ivy extract with suboptimal oseltamivir increased the antiviral activity of oseltamivir. Ivy extract and its compounds, particularly hedrasaponin F, significantly reduced the cytopathic effect in PR8-infected A549 cells in the presence of oseltamivir. Compared with oseltamivir treatment alone, coadministration of the fraction of ivy extract that contained the highest proportion of hedrasaponin F with oseltamivir decreased pulmonary inflammation in PR8-infected mice. Inflammatory cytokines and chemokines, including tumor necrosis factor-alpha and chemokine (C-C motif) ligand 2, were reduced by treatment with oseltamivir and the fraction of ivy extract. Analysis of inflammatory cell infiltration in the bronchial alveolar of PR8-infected mice revealed that CD11b+Ly6G+ and CD11b+Ly6Cint cells were recruited after virus infection; coadministration of the ivy extract fraction with oseltamivir reduced infiltration of these inflammatory cells. In a model of suboptimal oseltamivir treatment, coadministration of ivy extract fraction that includes hedrasaponin F increased protection against PR8 infection that could be explained by its antiviral and anti-inflammatory activities.

No MeSH data available.


Related in: MedlinePlus