L18 Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

Abstract

BackgroundThe kynurenine pathway (KP), the major catabolic route of tryptophan (TRP) metabolism, has been closely linked to the pathogenesis of several brain disorders. This pathway produces several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA). A shift towards the synthesis of neurotoxic 3-HK and QUIN relative to neuroprotective KYNA has been found in Huntington’s disease (HD) patients and models. In a Drosophila model of HD, genetic inhibition of two pivotal KP enzymes – kynurenine 3-monooxygenase (KMO) and tryptophan 2,3-dioxygenase (TDO) – normalises KP imbalances and rescues neurodegeneration. Genetic down-regulation of TDO has also been found to improve phenotypes in worm models of neurodegeneration, including a polyglutamine model.AimsOur goal was to characterise the neuroprotection conferred by TDO inhibition in HD.Methods/techniquesWe employed Drosophila melanogaster expressing a mutant HTT exon 1 fragment (HTT93Q) for elucidating phenotypic and metabolitic effects arising from genetic and pharmacological manipulation of the KP.Results/outcomeAs TDO inhibition results in increased levels of TRP, we explored the neuroprotective potential of TRP in HD flies, which was previously found to improve phenotypes in a worm model of Parkinson’s disease. Animals fed with TRP showed a dose-dependent reduction of neurodegeneration and increased levels of KYNA relative to 3-HK. Similarly, TDO-/- HD flies displayed a decreased 3-HK/KYNA ratio. When KYNA synthesis was pharmacologically blocked in TDO-/- HD flies, a dramatic reversal of the neuroprotection conferred by TDO mutation was observed. Moreover, restoration of physiological 3-HK levels in TDO-/- HD flies was not sufficient for inducing neurodegeneration, suggesting that increased KYNA levels is central to the protection arising from TDO inhibition in this model. Interestingly, QUIN feeding enhanced neurodegeneration in HD flies, and abolished the protective effects of KMO inhibition. In addition, a transgenic Drosophila line encoding human kynurenine aminotransferase (hKAT) – the enzyme which synthesises KYNA - reduced neurodegeneration in HD flies, further supporting that increased KYNA levels is neuroprotective in HD flies. Finally, we found that treatment with the TDO inhibitor 680C91 was protective in HD flies.ConclusionsThis study supports the concept that the targeted manipulation of TDO and KMO may constitute a viable therapeutic strategy in HD.

Targeting regulation of tryptophan metabolism for colorectal cancer therapy: a systematic review

“…It is an important functional amino acid with a variety of nutritional and physiological functions. 1 It is indicated that many diseases are associated with TRP metabolism disorders, such Huntington's disease, 3 and gastrointestinal diseases 4 to name a few, also, miscarriage. 2 In recent years, a large number of studies have shown that tumor growth is closely related to TRP metabolism.…”