Minocycline inhibits West Nile virus replication and apoptosis in human neuronal cells.
OBJECTIVE
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.
Michaelis
Martin
M
Institut für Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universität, Paul-Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
Kleinschmidt
Malte Christian
MC
Doerr
Hans Wilhelm
HW
Cinatl
Jindrich
J
D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000821:virology*; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D014779:Virus Replication / Q000187:drug effects*; D014902:West Nile virus / Q000187:drug effects* / Q000502:physiology
D000998:Antiviral Agents; C525168:L-JNKI-1; D010455:Peptides; D048670:MAP Kinase Kinase 4; D008911:Minocycline