Vascular expression, activity and function of indoleamine 2,3-dioxygenase-1 following cerebral ischaemia-reperfusion in mice Academic Article uri icon

abstract

  • Indoleamine 2,3-dioxygenases-1 (Ido1) and -2 initiate the kynurenine pathway of tryptophan metabolism. In addition to the established immune regulatory effects of Ido1 and the ability of nitric oxide to regulate Ido1 activity, it is now also known that Ido1-mediated metabolism of tryptophan to kynurenine can modulate vascular tone. Ido activity is reportedly elevated in stroke patients and correlates with increased risk of death. Thus, the present goals were to test whether, following cerebral ischaemia, Ido activity and cerebrovascular Ido1 expression are altered and whether expression of Ido1 contributes to stroke outcome. Transient cerebral ischaemia was induced in wild-type and Ido1 gene-deficient (Ido1 (-/-)) mice. Mice were pre-treated with vehicle, the Ido1 inhibitor, 1-methyl-D-tryptophan (1-MT; 50 mg/kg i.p.) or the inducible nitric oxide synthase (Nos2) inhibitor, aminoguanidine (AG, 100 mg/kg i.p.). At 24 h, neurological function, brain infarct size and swelling were assessed. In addition, Ido activity was estimated by plasma kynurenine and tryptophan, and Ido1 expression was examined in cerebral arterioles. Cerebral ischaemia-reperfusion in wild-type mice increased Ido activity and its expression in cerebral arterioles. Ido1 (-/-) and 1-MT-treated wild-type mice had lower Ido activity but similar post-stroke neurological function and similar total brain infarct volume and swelling, relative to control mice. Inhibition of Nos2 with AG also did not affect Ido activity or outcome following stroke. This study provides molecular and pharmacological evidence that the expression and the activity of Ido1 increase following stroke. However, such Ido1 expression does not appear to affect overall outcome following acute ischaemic stroke, and furthermore, a regulatory role of Nos2-derived nitric oxide on Ido activity following cerebral ischaemia-reperfusion appears unlikely.

publication date

  • 2011