Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis
- Meli, Damian N. Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, P.O. Box 61, CH-3010 Bern, Switzerland
- Coimbra, Roney S. Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, P.O. Box 61, CH-3010 Bern, Switzerland
- Erhart, Dominik G. Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, P.O. Box 61, CH-3010 Bern, Switzerland
- Loquet, Gerard Department of Medicine, Unit of Physiology, University of Fribourg, Fribourg, Switzerland
- Bellac, Caroline L. Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, P.O. Box 61, CH-3010 Bern, Switzerland
- Täuber, Martin G. Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, P.O. Box 61, CH-3010 Bern, Switzerland
- Neumann, Ulf Novartis Institute for Biomedical Research, Basel, Switzerland
- Leib, Stephen L. Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, P.O. Box 61, CH-3010 Bern, Switzerland
Published in:
- Infection and Immunity. - American Society for Microbiology. - 2006, vol. 74, no. 7, p. 3890-3896
English
ABSTRACT
Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 μM in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1128/iai.01949-05
- ISSN 0019-9567
- Persistent URL
- https://sonar.ch/global/documents/186788
Statistics
Document views: 15
File downloads:
- fulltext.pdf: 0