Amphotericin B potentiates the activation of inducible nitric oxide synthase and causes nitric oxide-dependent mitochondrial dysfunction in cytokine-treated rodent astrocytes

✍ Scribed by Vladimir Trajkovic; Milos Markovic; Tatjana Samardzic; Djordje J. Miljkovic; Dusan Popadic; Marija Mostarica Stojkovic

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 183 KB
• Volume: 35
• Category: Article
• ISSN: 0894-1491
• DOI: 10.1002/glia.1083

✦ Synopsis

Abstract

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‐γ (IFN‐γ)‐stimulated rat and mouse astrocytes, as well as in IFN‐γ + tumor necrosis factor‐α (TNF‐α)‐activated rat astrocytoma cell line C6. Treatment of rat astrocytes with AMB markedly potentiated IFN‐γ‐triggered expression of mRNA for iNOS, but not for its transcription factor IRF‐1. The activation of transcription factor NF‐κB was apparently required for AMB‐induced iNOS mRNA expression, as the latter was abolished by NF‐κB 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‐γ + 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‐γ‐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. GLIA 35:180–188, 2001. © 2001 Wiley‐Liss, Inc.