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JAC Advance Access originally published online on January 29, 2008
Journal of Antimicrobial Chemotherapy 2008 61(3):679-688; doi:10.1093/jac/dkm503
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Novel strategy for treatment of Japanese encephalitis using arctigenin, a plant lignan

Vivek Swarup{dagger}, Joydeep Ghosh{dagger}, Manoj Kumar Mishra and Anirban Basu*

National Brain Research Centre, Manesar, Gurgaon, Haryana 122050, India

Received 11 September 2007; returned 27 November 2007; revised 15 October 2007; accepted 29 November 2007

* Corresponding author. Tel: +91-124-2338921 ext. 225; Fax: +91-124-2338910/28; E-mail: anirban{at}nbrc.res.in

Objectives: To evaluate therapeutic efficacy of arctigenin in an experimental model of Japanese encephalitis (JE).

Methods: Four- to 5-week-old BALB/c mice of either sex were infected intravenously with lethal dose of 3 x 105 pfu of Japanese encephalitis virus (JEV). By the 9th day post-infection, all untreated animals succumbed to the infection. Arctigenin was dissolved in DMSO at a concentration of 0.5 mg/mL and stored at 4°C. After one day following virus inoculation, animals were given arctigenin intraperitoneally, twice daily (10 mg/kg of body weight) for next 7 days.

Results: Treatment with arctigenin provided complete protection against experimental JE. Arctigenin’s neuroprotective effect was associated with marked decreases in: (i) viral load; (ii) active caspase-3 activity; (iii) reactive oxygen species and reactive nitrogen species; (iv) microgliosis and proinflammatory cytokines; (v) levels of stress-associated signalling molecules; and (vi) neuronal death. Furthermore, treatment with arctigenin also improves the behavioural outcome following JE.

Conclusions: In conclusion, our findings provide a novel mechanistic insight into the actions of arctigenin in JE. Results from our in vivo and in vitro experiments clearly indicate that arctigenin reduced (i) viral load and viral replication within the brain, (ii) neuronal death and (iii) secondary inflammation and oxidative stress resulting from microglial activation, thereby suggesting its potential for treating JE. The antiviral, neuroprotective, anti-inflammatory and antioxidative effects of arctigenin successfully reduced the severity of disease induced by JEV.

Keywords: caspase-3 , microglia , apoptosis , cytokine , reactive oxygen species

{dagger} These authors contributed equally to this work.


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