Journal Mobile Options
Table of Contents
Vol. 80, No. 1, 2001
Issue release date: July 2001
Biol Neonate 2001;80:53–59

7-Nitroindazole, but Not Aminoguanidine, Attenuates the Acute Inflammatory Responses and Brain Injury during the Early Phase of Escherichia coli Meningitis in the Newborn Piglet

Park W.S. · Chang Y.S. · Lee M.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


We evaluated the anti-inflammatory and neuroprotective effects of the selective neuronal nitric oxide synthase inhibitor 7-nitroindazole and aminoguanidine, which predominantly inhibits inducible nitric oxide synthase, during the early phase of experimental bacterial meningitis in the newborn piglet. Meningitis was induced by intracisternal injection of 108 colony-forming units of Escherichia coli in 100 µl of saline. 7-Nitroindazole significantly attenuated the meningitis-induced acute inflammatory responses such as increased intracranial pressure, decreased cerebrospinal fluid (CSF) glucose concentration, and CSF leukocytosis at 2 h. However, meningitis-induced CSF leukocytosis at 4 h and increased CSF lactate and tumor necrosis factor alpha levels were not significantly attenuated. Reduced cerebral cortical cell membrane Na+,K+-ATPase activity and increased lipid peroxidation products, indicative of meningitis-induced brain cell membrane dysfunction, were also significantly improved with 7-nitroindazole treatment. In contrast, although aminoguanidine significantly attenuated the increase in the CSF tumor necrosis factor alpha level, it failed to attenuate the acute inflammation and the ensuing brain injury in bacterial meningitis. In summary, 7-nitroindazole, but not aminoguanidine, significantly attenuated the acute inflammatory responses and brain injury during the early phase of neonatal bacterial meningitis.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Anderson SG, Giulbert GL: Neonatal gram negative meningitis: A 10-year review, with reference to outcome and relapse of infection. J Paediatr Child Health 1990;26:212–216.
  2. De Louvois J: Acute bacterial meningitis in the newborn. J Antimicrob Chemother 1994;34(suppl A):61–73.
  3. Quagliarello V, Scheld WM: Bacterial meningitis: Pathogenesis, pathophysiology, and progress. N Engl J Med 1992;327:864–872.
  4. Sáez-Llorens X, Ramilo O, Mustafa MM, Mertsola J, McCracken GH Jr: Molecular pathophysiology of bacterial meningitis: Current concepts and therapeutic implications. J Pediatr 1990;116:671–684.
  5. Tunkel AR, Wispelwey B, Scheld WM: Bacterial meningitis: Recent advances in pathophysiology and treatment. Ann Intern Med 1990;112:610–623.
  6. Buster BL, Weintrob AC, Townsend GC, Scheld WM: Potential role of nitric oxide in the pathophysiology of experimental bacterial meningitis in rats. Infect Immun 1995;63:3835–3839.
  7. Kim YS, Täuber MG: Neurotoxicity of glia activated by gram-positive bacterial products depends on nitric oxide production. Infect Immun 1996;64:3148–3153.
  8. Koedel U, Bernatowicz A, Paul R, Frei K, Fontana A, Pfister HW: Experimental pneumococcal meningitis: Cerebrovascular alterations, brain edema, and meningeal inflammation are linked to the production of nitric oxide. Ann Neurol 1995;37:312–323.
  9. Boje KMK: Inhibition of nitric oxide synthase attenuates blood-brain barrier disruption during experimental meningitis. Brain Res 1996;720:75–83.

    External Resources

  10. Haberl RL, Anneser F, Ködel U, Pfister HW: Is nitric oxide involved as a mediator of cerebrovascular changes in the early phase of experimental pneumococcal meningitis? Neurol Res 1994;16;108–112.
  11. Leib SL, Kim YS, Black SM, Ferriero DM, Täuber MG: Detrimental effect of nitric oxide inhibition in experimental bacterial meningitis. Ann Neurol 1996;39:555–556.
  12. Leib SL, Kim YS, Black SM, Tureen JH, Täuber MG: Inducible nitric oxide synthase and the effect of aminoguanidine in experimental neonatal meningitis. J Infect Dis 1998;177:692–700.
  13. Dalkara T, Yoshida K, Irikura K, Moskowitz MA: Dual role of nitric oxide in focal cerebral ischemia. Neuropharmacology 1994;33:1447–1452.
  14. Higuchi Y, Hattori H, Kume T, Tsuji M, Akaike A, Furusho K: Increase in nitric oxide in the hypoxic-ischemic neonatal rat brain and suppression by 7-nitroindazole and aminoguanidine. Eur J Pharmacol 1998;342:47–49.
  15. Gidday JM, Shah AR, Maceren RG, Wang Q, Pelligrino DA, Holtzman DM, Park TS: Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. J Cereb Blood Flow Metab 1999;19:331–340.
  16. Yao SK, Ober JC, Krishnaswami A, Ferguson JJ, Anderson V, Golino P, Buja LM, Willerson JT: Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries. Circulation 1992;86:1302–1309.
  17. Kubes P, Suzuki M, Granger D: Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991;88:4651–4655.
  18. Kurose I, Kubes P, Wolf R, Anderson DC, Paulson J, Miyasaka M, Granger DN: Inhibition of nitric oxide production. Mechanisms of vascular albumin leakage. Circ Res 1993;73:164–171.
  19. Moncada S, Higgs A: The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002–2012.
  20. Nathan CF, Hibbs JB Jr: Role of nitric oxide in macrophage antimicrobial activity. Curr Opin Immunol 1991;3:65–70.
  21. Vladutiu AO: Role of nitric oxide in autoimmunity. Clin Immunol Immunopathol 1995;76:1–11.
  22. MacKenzie GM, Rose S, Bland-Ward PA, Moore PK, Jenner P, Mardsnen CD: Time course of inhibition of brain nitric oxide synthase by 7-nitroindazole. Neuroreport 1994;5:1993–1996.

    External Resources

  23. Scott JA, McCormack DG: Selective in vivo inhibition of inducible nitric oxide synthase in a rat model of sepsis. J Appl Physiol 1999;86:1739–1744.

    External Resources

  24. Park WS, Chang YS, Lee M: Effect of induced hyperglycemia on brain cell membrane function and energy metabolism during the early phase of experimental meningitis in newborn piglets. Brain Res 1998;798:195–203.
  25. Park WS, Chang YS, Ko SY, Kang MJ, Han JM, Lee M: Efficacy of anti-tumor necrosis factor-alpha antibody as an adjunctive therapy in experimental Escherichia coli meningitis in the newborn piglet. Biol Neonate 1999;75:377–387.
  26. Park WS, Chang YS, Lee M: Effect of α-phenyl-N-tert-butylnitrone on brain cell membrane function and energy metabolism in experimental Escherichia coli meningitis in the newborn piglet. J Neurochem 2000;74:763–769.
  27. Weiser JN, Gotschlich EC: Outer membrane protein A (Omp A) contributes to serum resistance and pathogenicity of Escherichia coli. Infect Immun 1991;59:2252–2258.

    External Resources

  28. Chang YS, Park WS, Lee M, Kim KS, Shin SM, Choi JH: Effect of hyperglycemia on brain cell membrane function and energy metabolism during hypoxia-ischemia in newborn piglets. Brain Res 1998;798:271–280.
  29. Szabó C, Mitchell JA, Thiemermann C, Vane JR: Nitric oxide-mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock. Br J Pharmacol 1993;108:786–792.
  30. Wong ML, Rettori V, Al-Shekhlee A, Bongiorno PB, Canteros G, McCann SM, Gold PW, Licinio J: Inducible nitric oxide synthase gene expression in the brain during systemic inflammation. Nature Med 1996;2:581–584.
  31. Paul R, Koedel U, Pfister HW: 7-Nitroindazole inhibits pial arteriolar vasodilation in a rat model of pneumococcal meningitis. J Cereb Blood Flow Metab 1997;17:985–991.

    External Resources

  32. Radi R, Beckman JS, Bush KM, Freeman BA: Peroxynitrite-induced membrane lipid peroxidation: The cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys 1991;288:481–487.
  33. Mattson MP: Modification of ion homeostasis by lipid peroxidation: Roles in neuronal degeneration and adaptive plasticity. Trends Neurosci 1998;21:53–57.
  34. Sun AY: The effect of lipoxidation on synaptosomal (Na+ + K+)-ATPase isolated from the cerebral cortex of squirrel monkey. Biochim Biophys Acta 1972;266:350–360.

    External Resources

  35. Lees GJ: Inhibition of sodium-potassium-ATPase: A potentially ubiquitous mechanism contributing to central nervous system neuropathology. Brain Res Brain Res Rev 1991;16:283–300.
  36. Szabó C, Zingarelli B, Salzman AL: Role of poly-ADP ribosyltransferase activation in the vascular contractile and energetic failure elicited by exogenous and endogenous nitric oxide and peroxynitrite. Circ Res 1996;78:1051–1063.
  37. Kennedy MC, Antholine WE, Beinert H: An EPR investigation of the products of the reaction of cytosolic and mitochondrial aconitases with nitric oxide. J Biol Chem 1997;272:20340–20347.
  38. Moore PK, Wallace P, Gaffen Z, Hart SL, Babbedge RC: Characterization of the novel nitric oxide synthase inhibitor 7-nitroindazole and related indazoles: Antinociceptive and cardiovascular effects. Br J Pharmacol 1993;110:219–224.
  39. Mustafa MM, Ramilo O, Olsen KD, Franklin PS, Hansen EJ, Bertler B, McCracken GH Jr: Tumor necrosis factor α in mediating experimental Haemophilus influenzae type b meningitis. J Clin Invest 1989;84:1253–1259.
  40. Van Furth AM, Seijmonsbergen EM, Groeneveld PH, van Furth R, Langermans JA: Levels of nitric oxide correlate with high levels of tumor necrosis factor alpha in cerebrospinal fluid samples from children with bacterial meningitis. Clin Infect Dis 1996;22:876–878.
  41. Koedel U, Pfister HW: Protective effect of the antioxidant N-acetyl-L-cysteine in pneumococcal meningitis in the rat. Neurosci Lett 1997;225:33–36.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50