Abstract

Metabolomics analysis implies noninvolvement of the kynurenine pathway neurotoxins in the interferon-gamma- induced neurotoxicity of adult human astrocytes

Author(s): Sadayuki Hashioka, Hideyuki Suzuki, Daisuke Nakajima, Tsuyoshi Miyaoka, Rei Wake, Maiko Hayashida, Jun Horiguchi, Andis Klegeris

Emerging evidence indicates that the kynurenine pathway (KP) contributes to neurodegenerative diseases associated with glial activation. Interferon (IFN)-γ is a potent activator of indole-2,3-dioxygenase, the first and rate-limiting enzyme of the KP. Our previous studies have shown that adult human astrocytes become neurotoxic when activated by IFN-γ. We now used high performance liquid chromatographymass spectrometry in both the positive- and negative- ionization mode of electrospray interface, to examine whether the IFN-γ-activated adult human astrocytes secrete neurotoxic KP metabolites, such as quinolinic acid (QUIN), 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA). Kynurenine was detected in cell culture supernatants of IFN-γ-stimulated astrocytes, but not in supernatants of unstimulated astrocytes. On the other hand, QUIN, 3-HK and 3-HAA were not detected in samples from either IFN-γ- stimulated or unstimulated cells. These results indicate that the KP may not be involved in the IFN-γ-induced neurotoxicity of adult human astrocytes. Therefore, neurotoxins other than KP metabolites could be responsible for the IFN-γ-induced astrocyte neurotoxicity.