Inducible nitric oxide synthase (iNOS) IS upregulated in experimental meningitis, but NOS inhibition is detrimental

S. L. Leib, Y. S. Kim, S. M. Black, M. G. Täuber

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Nitric oxide (NO) has been shown to mediate selected pathophysiologic changes in models of bacterial meningitis (M). Using a model of neonatal M, we examined whether M leads to upregulation of the inducible nitric oxide synthase (iNOS), the NOS isoform most commonly identified as causing tissue injury, and whether inhibition of NOS reduces neuronal injury. In brains of infant rats infected intracisternally with 104 cfu of group B streptococcus, enzyme activity of iNOS (pmol/min/mg protein) was markedly increased 18h after infection (infected: 1.36 ±0.77 (n=7); controls: 0.19 ±0.06 (n=4); p=0.006). Western blots of brain tissue confirmed the increase of iNOS. We then examined the effect of aminoguanidine (AG), a relatively selective inhibitor of iNOS, on the extent of neuronal injury in the same model. Rats were treated with AG, 130 mg/kg q8h s.c. (n=19), or saline (n=20), beginning at the time of infection, and all animals received 100 mg/kg of ceftriaxone s.c. after 18h. A neuronal injury score (range 0-8) was assessed by histopathology after 24h. Animals treated with AG had significantly more neuronal injury than controls (median [range] of score: 1.4 [0-7] vs. 0 [0-4]; p<0.05). In both groups, the predominant injury pattern was compatible with ischemic injury. Thus, M led to dramatic upregulation of iNOS, but treatment with AG proved to be detrimental for the neuropathologic outcome. This suggests that some of the NO produced during M is beneficial, possibly in the cerebral vasculature. Importantly, our results point out that inhibition of NOS as adjunctive therapy of M must be approached with great caution.

Original languageEnglish (US)
Pages (from-to)111A
JournalJournal of Investigative Medicine
Volume44
Issue number1
StatePublished - Jan 1 1996

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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