Amphotericin B Potentiates the Activation of Inducible Nitric Oxide Synthase and Causes Nitric OxideDependent Mitochondrial Dysfunction in Cytokine-Treated Rodent Astrocytes
2001
Authors:
Trajković, VladimirMarković, Miloš
Samardzić, Tatjana
Miljković, Đorđe
Popadić, Dušan
Mostarica Stojković, Marija
Document Type:
Article (Published version)
,
© 2001 Wiley‐Liss, Inc.
Metadata
Show full item recordAbstract:
Because the neurotoxic effects of the antifungal drug amphotericin B
(AMB) closely resemble those ascribed to the highly reactive gaseous free radical nitric
oxide (NO), we investigated the effect of AMB on NO production in rodent astrocytes.
AMB caused a dose-dependent increase of NO generation in interferon-g (IFN-g)-stimulated rat and mouse astrocytes, as well as in IFN-g 1 tumor necrosis factor-a (TNFa)-activated rat astrocytoma cell line C6. Treatment of rat astrocytes with AMB markedly potentiated IFN-g-triggered expression of mRNA for iNOS, but not for its
transcription factor IRF-1. The activation of transcription factor NF-kB was apparently
required for AMB-induced iNOS mRNA expression, as the latter was abolished by
NF-kB inhibitors: pyrrolidine dithiocarbamate and MG132. AMB-mediated enhancement of astrocyte NO production was partly dependent on endogenous IL-1, as shown by
partial inhibition of AMB effect with IL-1 receptor antagonist. IFN-g 1 AMB treatment
led to reduction of astrocyte mitochondrial respiration (measured by MTT assay) that
has been completely reverted by selective iNOS inhibitor aminoguanidine. AMB toxicity
toward IFN-g-stimulated astrocytes was dependent on both AMB and NO action, since
AMB and NO-releasing substance SNP synergized in inducing astrocyte mitochondrial
dysfunction. These results suggest that the enhancement of cytokine-induced iNOS
activation in astrocytes and the subsequent release of high amounts of NO might be at
least partly responsible for AMB neurotoxicity.
Keywords:
amphotericin B; astrocyte; nitric oxide; neurotoxicity; IFN-gSource:
Glia, 2001, 35, 3, 180-188Funding / projects:
- Ministry of Science and Technology, Republic of Serbia, Yugoslavia
DOI: 10.1002/glia.1083
ISSN: 0894-1491
PubMed: 11494409