meningitis is an acute inflammatory disease of the central nervous system

meningitis is an acute inflammatory disease of the central nervous system with a mortality rate of up to 30%. even in the context of effective antibiotics is the poor outcome of the disease which has a mortality rate of up to 34% and results in permanent sequelae in up to 50% of the survivors (9). Two major mechanisms that cause damage in AG-1024 (Tyrphostin) the central nervous system have been proposed: (i) direct toxic effects of pneumococci (5) and (ii) excessive stimulation of the host immune system by the bacterial surface (2 28 An important stimulus is the multilayered network of peptidoglycan that makes up the pneumococcal cell wall (PCW) (27). Purified PCW induces AG-1024 (Tyrphostin) meningeal inflammation which is comparable to the acute inflammation caused by living bacteria including the clinical hallmarks of the disease such as an influx of leukocytes and increases in the intracranial pressure (ICP) and regional cerebral blood flow (rCBF) (2 28 31 The immunostimulatory effect of cell wall components is clinically important (34) because antibiotic lysis of bacteria induces the release of these components (11). Moreover the concentration of the cell wall components in the cerebrospinal fluid (CSF) correlates significantly with the outcome of the disease (23). It has been shown that heat-killed pneumococci soluble peptidoglycan and PCW induce signaling through Toll-like receptor 2 (33 35 The downstream signaling involves activation of mitogen-activated protein kinases (MAPK) erk 1/2 (p44/42MAPK) and p38 which has been demonstrated Mouse monoclonal to CHK1 in astrocytes (25) microglia (14) and primary cerebral microvascular endothelial cells (33). Inhibition of the MAPK pathway in vitro reduces the production of tumor necrosis factor alpha (TNF-α) and nitric oxide induced by PCW (25). Specific inhibition of a protein tyrosine kinase that also controls MAPK erk 1/2 by tyrphostin AG 126 attenuates the release of proinflammatory cytokines in mouse microglial cells and decreases the number of invading leukocytes in the CSF (14). AG 126 is a selective protein tyrosine kinase inhibitor that interferes with substrate binding rather than with ATP binding by the corresponding kinase. Tyrosine kinase inhibitors block experimental autoimmune encephalomyelitis by reducing lymphocyte entry into the central nervous system (7 8 In a sepsis model AG 126 protects mice against endotoxin toxicity probably by blocking TNF-α and nitric oxide production (18). In a well-established rat model of meningitis (19 31 we induced meningeal inflammation with PCW a stimulus that obviates any interference by bacterial metabolism and mimics the inflammatory burst caused by bacterial lysis. We tested the effect of AG 126 a protein tyrosine kinase inhibitor on the detrimental hallmarks of early meningitis including leukocyte influx TNF-α production an increase in the blood flow and an increase AG-1024 (Tyrphostin) in the ICP. MATERIALS AND METHODS Animal model. We used a well-characterized model of the acute phase of bacterial meningitis (19 31 In brief male Wistar rats (280 to 330 g) were anesthetized with thiopental AG-1024 (Tyrphostin) (Trapanal; Byk Gulden Konstanz Germany) by AG-1024 (Tyrphostin) injecting 100 mg/kg intraperitoneally followed by 15 mg/kg if required for the whole experiment and they were mechanically ventilated (AP-10; K. Efferberger Pfaffing Germany). The terminal expiratory partial CO2 pressure (pCO2) the arterial blood pressure (determined with a femoral catheter) the ICP (determined with a catheter in the cisterna magna and Statham P10 EZ pressure transducers [Spectramed Oxnard Calif.]) and the rCBF (determined by laser-Doppler flowmetry parietally through thinned bone with a PeriFlux 4001 Master [Perimed J?rf?lla Sweden]) were measured continuously. After a..