Inhibition of increased indoleamine 2,3-dioxygenase activity exacerbates neuronal cell death in various CNS disorders

Abstract

Increased levels of several tryptophan metabolites have been demonstrated in various neurological disorders and were postulated to be secondary to induction of indoleamine 2,3-dioxygenase (IDO) and other enzymes of the l-tryptophan-kynurenine pathway. Previous reports have proposed that l-tryptophan metabolites (e.g., kynurenine, 3-hydroxykynurenine, quinolinic acid) may be involved in mediating neuronal damage in certain CNS disorders. On the other hand, recent studies have suggested that marked increases in IDO could suppress immune response by locally depleting l-tryptophan and/or accumulation of kynurenine pathway metabolites in various immune-related diseases. In fact, accumulation of kynurenine pathway metabolites in experimental autoimmune encephalomyelitis has been considered to relate to the onset of symptoms; however, recent studies demonstrated that inhibition of IDO by 1-methyl-tryptophan significantly exacerbated disease scores. Furthermore, our study demonstrates that inhibition of IDO significantly exacerbated the loss of pyramidal neurons in the hippocampus following transient ischemia. In this review, the role of IDO and kynurenine pathway metabolites in the pathogenesis of various CNS diseases, especially both beneficial and deleterious effects, were discussed.