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Journal of Virology, June 2007, p. 6248-6253, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.00323-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Therapy with Minocycline Aggravates Experimental Rabies in Mice{triangledown}

Alan C. Jackson,1,2,3* Courtney A. Scott,2,3 James Owen,2 Simon C. Weli,1,2 and John P. Rossiter3,4

Department of Medicine (Neurology),1 Department of Microbiology and Immunology,2 Centre for Neuroscience Studies,3 Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada4

Received 13 February 2007/ Accepted 28 March 2007

Minocycline is a tetracycline derivative with antiapoptotic and anti-inflammatory properties, and the drug has been shown to have beneficial effects in a variety of models of neurological disorders. The potentially neuroprotective role of minocycline was assessed in experimental in vitro and in vivo models of rabies virus infection. In this study, 5 nM minocycline did not improve the viability of embryonic mouse cortical and hippocampal neurons infected in vitro with the attenuated SAD-D29 strain of rabies virus, based on assessments using trypan blue exclusion. Two-day-old ICR mice were inoculated in the right hind limb thigh muscle with SAD-D29, and they received daily subcutaneous injections of either 50 mg/kg minocycline or vehicle (phosphate-buffered saline). Infected minocycline-treated mice experienced an earlier onset of neurologic signs and greater mortality (83% versus 50%) than those receiving vehicle (log rank test, P = 0.002 and P = 0.003, respectively). Immunohistochemical analysis of rabies virus antigen distribution was performed at early time points and in moribund mice. There were greater numbers of infected neurons in the regional brain areas of minocycline-treated mice than in vehicle-treated mice, which was significant in the CA1 region of the hippocampus. There was less apoptosis (P = 0.01) and caspase 3 immunostaining (P = 0.0008) in the midbrains of mice treated with minocycline than in mice treated with vehicle, consistent with a neuroprotective role of neuronal apoptosis that may have had a mild effect of inhibiting viral spread. Reduced infiltration of CD3+ T cells was observed in the pons/medulla of moribund mice that received minocycline therapy (P = 0.008), suggesting that the anti-inflammatory actions of minocycline may intensify the neurologic disease. These findings indicate that minocycline has important detrimental effects in the therapy of experimental rabies. Empirical therapy with minocycline should therefore be approached with caution in cases of human rabies and possibly other viral encephalitides until more experimental data become available.

* Corresponding author. Mailing address: Kingston General Hospital, Connell 725, 76 Stuart Street, Kingston, ON, Canada K7L 2V7. Phone: (613) 548-1316. Fax: (613) 548-1317. E-mail: jacksona{at}post.queensu.ca

{triangledown} Published ahead of print on 4 April 2007.

Journal of Virology, June 2007, p. 6248-6253, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.00323-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Scott, C. A., Rossiter, J. P., Andrew, R. D., Jackson, A. C. (2008). Structural Abnormalities in Neurons Are Sufficient To Explain the Clinical Disease and Fatal Outcome of Experimental Rabies in Yellow Fluorescent Protein-Expressing Transgenic Mice. J. Virol. 82: 513-521 [Abstract] [Full Text]  


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