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Infection and Immunity, June 2004, p. 3294-3298, Vol. 72, No. 6
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.6.3294-3298.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Tyrosine Kinase Inhibition Reduces Inflammation in the Acute Stage of Experimental Pneumococcal Meningitis

Klemens Angstwurm,1 Uwe-Karsten Hanisch,2 Tarraneh Gassemi,1 Margrethe Bastholm Bille,1 Marco Prinz,2,3 Ulrich Dirnagl,1 Helmut Kettenmann,2 and Joerg R. Weber1*

Department of Neurology, Charité, Humboldt University Berlin, 10098 Berlin,1 Max Delbrück Center for Molecular Medicine, 13092 Berlin,2 Department of Neuropathology, Georg August University, 37075 Göttingen, Germany3

Received 27 October 2003/ Returned for modification 5 January 2004/ Accepted 26 February 2004

Bacterial meningitis is an acute inflammatory disease of the central nervous system with a mortality rate of up to 30%. Excessive stimulation of the host immune system by bacterial surface components contributes to this devastating outcome. In vitro studies have shown that protein tyrosine kinase inhibitors are highly effective in preventing the release of proinflammatory cytokines induced by pneumococcal cell walls in microglia. In a well-established rat model, intracisternal injection of purified pneumococcal cell walls induced meningitis characterized by increases in the regional cerebral blood flow and intracranial pressure, an influx of leukocytes, and high concentrations of tumor necrosis factor alpha (TNF-{alpha}) in the cerebrospinal fluid. Compared with the values at the beginning of the experiment, intraperitoneal injection of tyrphostin AG 126 reduced the increases in regional cerebral blood flow (at 6 h, 127% ± 14% versus 222% ± 51% of the baseline value; P < 0.05) and intracranial pressure (at 6 h, 0.8 ± 2.4 versus 5.4 ± 2.0 mm of Hg; P < 0.05), the influx of leukocytes (at 6 h, 1,336 ± 737 versus 4,350 ± 2,182 leukocytes/µl; P < 0.05), and the TNF-{alpha} concentration (at 6 h, 261 ± 188 versus 873 ± 135 pg/µl; P < 0.05). These results demonstrate that inhibition of AG 126-sensitive tyrosine kinase pathways may provide new approaches for preventing excessive inflammation and reducing the increases in blood flow and intracranial pressure in the acute phase of bacterial meningitis.

* Corresponding author. Mailing address: Department of Neurology, Charité, 10098 Berlin, Germany. Phone: 49 30 450 560104. Fax: 49 30 450 560942. E-mail: joerg.weber{at}charite.de.

Editor: J. N. Weiser

Infection and Immunity, June 2004, p. 3294-3298, Vol. 72, No. 6
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.6.3294-3298.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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