Published online before print August 23, 2007

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(American Journal of Pathology. 2007;171:1199-1214.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070231

Minocycline Modulates Neuroinflammation Independently of Its Antimicrobial Activity in Staphylococcus aureus-Induced Brain Abscess

Tammy Kielian^*, Nilufer Esen^*, Shuliang Liu^*, Nirmal K. Phulwani^*, Mohsin M. Syed^*, Napoleon Phillips^*, Koren Nishina, Ambrose L. Cheung, Joseph D. Schwartzman and Jorg J. Ruhe

From the Departments of Neurobiology and Developmental Sciences^* and Infectious Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and the Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire

Minocycline exerts beneficial immune modulatory effects in several noninfectious neurodegenerative disease models; however, its potential to influence the host immune response during central nervous system bacterial infections, such as brain abscess, has not yet been investigated. Using a minocycline-resistant strain of Staphylococcus aureus to dissect the antibiotic’s bacteriostatic versus immune modulatory effects in a mouse experimental brain abscess model, we found that minocycline significantly reduced mortality rates within the first 24 hours following bacterial exposure. This protection was associated with a transient decrease in the expression of several proinflammatory mediators, including interleukin-1ß and CCL2 (MCP-1). Minocycline was also capable of protecting the brain parenchyma from necrotic damage as evident by significantly smaller abscesses in minocycline-treated mice. In addition, minocycline exerted anti-inflammatory effects when administered as late as 3 days following S. aureus infection, which correlated with a significant decrease in brain abscess size. Finally, minocycline was capable of partially attenuating S. aureus-dependent microglial and astrocyte activation. Therefore, minocycline may afford additional therapeutic benefits extending beyond its antimicrobial activity for the treatment of central nervous system infectious diseases typified by a pathogenic inflammatory component through its ability to balance beneficial versus detrimental inflammation.

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