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JAC Advance Access originally published online on September 14, 2007
Journal of Antimicrobial Chemotherapy 2007 60(5):981-986; doi:10.1093/jac/dkm307
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© The Author 2007. 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

Minocycline inhibits West Nile virus replication and apoptosis in human neuronal cells

Martin Michaelis, Malte Christian Kleinschmidt, Hans Wilhelm Doerr and Jindrich Cinatl, Jr*

Institut für Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universität, Paul-Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany

Received 20 June 2007; returned 17 July 2007; revised 24 July 2007; accepted 25 July 2007

* Corresponding author. Tel: +49-69-6301-6409; Fax: +49-69-6301-4302; E-mail: cinatl{at}em.uni-frankfurt.de

Objectives: West Nile virus (WNV) infection causes severe meningitis and encephalitis in a subset of patients. WNV-induced apoptosis has been suggested to contribute to WNV pathogenesis. Tetracyclines exert antiviral effects against HIV and inhibit apoptosis in different models of neuronal disease. Here, the effects of the tetracyclines minocycline, demeclocycline and chlortetracycline were observed on WNV replication and WNV-induced apoptosis in different human CNS-derived cell types (primary human brain neurons, primary human retinal pigment epithelial cells and T98G human glioma cell line).

Methods: WNV replication was studied by cytopathic effects and virus yield reduction assay. Cell viability was examined by MTT assay. Apoptosis was investigated by immunostaining for activated caspase 3 and cleaved poly(ADP-ribose) polymerase. Expression and phosphorylation of cellular proteins were examined by western blot.

Results: Minocycline exerted the strongest anti-WNV activity. Non-toxic minocycline concentrations that can be achieved in human tissues significantly reduced WNV titres in all cell types tested. Minocycline inhibited WNV-induced apoptosis and suppressed virus-induced activation of c-Jun N-terminal kinase (JNK) and its target c-jun. The JNK inhibitor L-JNKi exerted similar effects to minocycline.

Conclusions: These data suggest that minocycline-induced inhibition of JNK activation contributes to minocycline-induced inhibition of WNV replication and WNV-induced apoptosis. Minocycline is a clinically available, inexpensive and generally very well-tolerated drug. It could be readily evaluated for the treatment of humans with serious WNV infection.

Keywords: antiviral therapy , brain , central nervous system , antibiotic , encephalitis


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