Pentoxifylline modulates meningeal inflammation in experimental bacterial meningitis.
Pentoxifylline has been shown to decrease endotoxin-induced tumor necrosis factor alpha production and reverse the inflammatory actions of interleukin-1 (IL-1) and tumor necrosis factor on leukocyte function. Because of the potential role of this cytokine-leukocyte interaction in the pathogenesis of bacterial meningitis, we investigated the ability of pentoxifylline to modulate meningeal inflammation in the rabbit meningitis model. Pentoxifylline treatment (initially an intravenous injection of 20 mg/kg followed by 6 mg/kg per h) started 20 min before intracisternal injection of 20 ng of Haemophilus influenzae type b lipooligosaccharide (endotoxin) reduced significantly concentrations in cerebrospinal fluid of leukocytes (P less than 0.0001), protein (P less than 0.001), and lactate (P less than 0.001) during the 9-h infusion compared with values in intravenous-saline-treated rabbits. When pentoxifylline was given 1 h after H. influenzae type b endotoxin, the mean peak lactate and leukocyte concentrations in cerebrospinal fluid were significantly lower than those in control animals. Pentoxifylline also significantly decreased lactate and protein concentrations (P less than 0.05) and tended to diminish leukocyte counts (P = 0.08) compared with results in control animals after antibiotic-induced release of endotoxin in animals with H. influenzae meningitis. In this regard, dexamethasone was superior to pentoxifylline and no synergism was observed when the drugs were combined. Additionally, pentoxifylline attenuated meningeal inflammatory changes induced by intracisternal inoculation of 10 ng of rabbit recombinant IL-1 beta compared with results in either dexamethasone- or saline-treated animals. We conclude that pentoxifylline is effective in this animal model in modulating the meningeal inflammatory response following intracisternal inoculation of H. influenzae type b endotoxin or organisms or rabbit recombinant IL-1beta.
Sáez-Llorens
X
X
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235.
Ramilo
O
O
Mustafa
M M
MM
Mertsola
J
J
de Alba
C
C
Hansen
E
E
McCracken
G H
GH
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002556:Cerebrospinal Fluid Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004731:Endotoxins / Q000494:pharmacology; D006193:Haemophilus influenzae; D007375:Interleukin-1 / Q000494:pharmacology; D007773:Lactates / Q000134:cerebrospinal fluid; D008297:Male; D008583:Meningitis, Haemophilus / Q000188:drug therapy*; D010431:Pentoxifylline / Q000627:therapeutic use*; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D013805:Theobromine / Q000031:analogs & derivatives*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D002556:Cerebrospinal Fluid Proteins; D004731:Endotoxins; D007375:Interleukin-1; D007773:Lactates; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D013805:Theobromine; D010431:Pentoxifylline