Modulation of the inflammatory response in experimental bacterial meningitis

Sammanfattning: In bacterial meningitis, tissue damage in the central nervous system (CNS) is inflicted by the host's inflammatory response to invading pathogens, rather than by the bacteria itself. Adjuvant treatment with anti-inflammatory drugs in experimental bacterial meningitis has demonstrated beneficial effects on CNS pathology. Of all the anti-inflammatory agents tested experimentally, only corticosteroids (dexamethasone) have attained clinical application. However, the efficacy of this use of dexamethasone in patients has been limited. In the search for better adjunctive treatment in bacterial meningitis, two anti-inflammatory substances, namely fucoidin and CNI- 1493, have been evaluated in the present study. Fucoidin, a carbohydrate, block leukocyte rolling by binding to selectin receptors, thereby preventing leukocyte adhesion to vessel endothelium and migration to the site of tissue inflammation. In a rabbit model, meningitis was induced by intracisternal injection of Streptococcus pneumoniae. Intravenous fucoidin treatment resulted in an almost complete inhibition of leukocyte accumulation in the subarachnoid space (SAS). Fucoidin also reduced cerebrospinal fluid (CSF) concentrations of the pro- inflammatory cytokines tumor necrosis factor alpha (TNF[alpha]) and interleukin- 1 (IL- 1), in the early phase of meningitis. Moreover, fucoidin efficiently prevented the CSF inflammatory burst induced by ampicillin in the same model of experimental meningitis (Papers I-III). CNI- 1493, a tetravalent guanylhydrazone, inhibits macrophage activation, primarily by attenuating TNF[alpha] production. CNI- 1493 was tested in a meningitis model in infant rats infected with Haemophilus influezae type b (Hib), injected intraperitoneally (i.p.). The group of animals pre-treated with CNI- 1493 i.p. had a 75 percent survival. In contrast, the untreated control group all died within 3 days. CNI- 1493 therapy significantly reduced the number of infiltrating granulocytes in the brain and the number of cells producing TNF[alpha] and IL- 1ß in the spleen (Paper IV). Conclusion: This study has demonstrated, for the first time in an in vivo disease model, that blocking of leukocyte rolling with a carbohydrate attenuate inflammation. Furthermore, its shown for the first time, that treatment with fucoidin and CNI-1493 have the capacity to markedly attenuate CNS inflammation evoked by bacteria. These findings illustrate novel, therapeutic approaches to the treatment of bacterial meningitis.