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

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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.

Original languageEnglish
Pages (from-to)314-323
Number of pages10
JournalInternational Congress Series
Volume1304
DOIs
Publication statusPublished - 01-11-2007
Externally publishedYes

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Kynurenine
Cell Death
Tryptophan
Quinolinic Acid
Autoimmune Experimental Encephalomyelitis
Pyramidal Cells
Central Nervous System Diseases
Immune System Diseases
Nervous System Diseases
Hippocampus
Ischemia
Enzymes

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

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title = "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.",
author = "Hidetsugu Fujigaki and Kuniaki Saito",
year = "2007",
month = "11",
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T1 - Inhibition of increased indoleamine 2,3-dioxygenase activity exacerbates neuronal cell death in various CNS disorders

AU - Fujigaki, Hidetsugu

AU - Saito, Kuniaki

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N2 - 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.

AB - 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.

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