Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration
نویسندگان
چکیده
Metabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases.
منابع مشابه
Treating the Periphery to Ameliorate Neurodegenerative Diseases
Abnormalities in the kynurenine pathway are associated with neurodegenerative disorders. Zwilling et al. (2011) show that inhibition of kynurenine 3-monooxygenase in the body's periphery leads to an increase in kyneuric acid, a neuroprotective compound, in the brain. This intervention ameliorates neurodegeneration in mouse models of Alzheimer's disease and Huntington's disease.
متن کاملThe Kynurenine Pathway Modulates Neurodegeneration in a Drosophila Model of Huntington's Disease
Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been implicated in the pathophysiology of neurodegenerative disorders, including Huntington's disease (HD) [1]. A central hallmark of HD is neurodegeneration caused by a polyglutamine expansion in the huntingtin (htt) protein [2]. Here we exploit a transgenic Drosophila melanogaster model of HD to interrogate ...
متن کاملTryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites.
Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO i...
متن کاملInhibition of kynureninase ( L kynurenine hydrolase , EC 3 . 7 . 1 . 3 )
(1981). Inhibition of kynureninase (Lkynurenine hydrolase, EC 3.7.1.3) by oestrone sulphate: an alternative explanation for abnormal results of tryptophan load tests in women receiving oestrogenic steroids.
متن کاملKynurenine Pathway Activation in Human African Trypanosomiasis
Background The kynurenine pathway of tryptophan oxidation is associated with central nervous system (CNS) inflammatory pathways. Inhibition of this pathway ameliorates CNS inflammation in rodent models of the late (meningoencephalitic) stage of human African trypanosomiasis (HAT). In this study, we evaluate whether the kynurenine pathway is activated in clinical HAT and associated with CNS infl...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Cell
دوره 145 شماره
صفحات -
تاریخ انتشار 2011