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

Abstract

ABSTRACT 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-α) 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-α 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.