PLoS ONE (Jan 2023)

Indoleamine 2, 3-dioxygenase is responsible for low stress tolerance after intracerebral hemorrhage.

  • Masatoshi Ohnishi,
  • Marina Akagi,
  • Mako Kotsuki,
  • Seishi Yonemura,
  • Hikari Aokawa,
  • Maki Yamashita-Ibara,
  • Osamu Yokofujita,
  • Shoji Maehara,
  • Toshiyuki Hata,
  • Atsuko Inoue

DOI
https://doi.org/10.1371/journal.pone.0273037
Journal volume & issue
Vol. 18, no. 2
p. e0273037

Abstract

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In the chronic phase after intracerebral hemorrhage (ICH), the aftereffect-associated lowering of motivation burdens many patients; however, the pathogenic mechanism is unclear. Here, we revealed for the first time that indoleamine 2, 3-dioxygenase (IDO) expression and enzyme activity are increased in the collagenase-induced murine ICH model. IDO is a rate-limiting enzyme situated at the beginning of the kynurenine pathway and converts tryptophan, a source of serotonin (5-hydroxytryptamine; 5-HT), to kynurenine. In this study, we showed that IDO is localized in 5-HTergic neurons. After ICH, the synaptosomal 5-HT level decreased, but this effect was neutralized by subcutaneous injections of 1-methyl tryptophan (MT), a specific IDO inhibitor. These results suggest that ICH-induced IDO weakens the activity of 5-HTergic neurons. Accordingly, we next investigated whether the IDO increase contributes to the depression-like behaviors of ICH mice. The immobility times of tail suspension and forced swimming tests were significantly prolonged after ICH but shortened by the administration of 1-MT. In conclusion, the increased IDO after ICH was found to decrease 5-HT levels and subsequently reduce stress tolerance. These findings indicate that IDO is a novel therapeutic target for the ICH aftereffect-associated lowering of motivation.