Activation of the kynurenine pathway (KP) of tryptophan metabolism results from chronic inflammation and is known to exacerbate progression of neurodegenerative disease. To gain insights into the links between inflammation, the KP and multiple sclerosis (MS) pathogenesis, we investigated the KP metabolomics profile of MS patients. Most significantly, we found aberrant levels of two key KP metabolites, kynurenic acid (KA) and quinolinic acid (QA). The balance between these metabolites is important as it determines overall excitotoxic activity at the N-methyl-D-Aspartate (NMDA) receptor. We also identified that serum KP metabolic signatures in patients can discriminate clinical MS subtypes with high sensitivity and specificity. A C5.0 Decision Tree classification model discriminated the clinical subtypes of MS with a sensitivity of 91%. After validation in another independent cohort, sensitivity was maintained at 85%. Collectively, our studies suggest that abnormalities in the KP may be associated with the switch from early-mild stage MS to debilitating progressive forms of MS and that analysis of KP metabolites in MS patient serum may have application as MS disease biomarkers."
Showing posts with label Kynurenine. Show all posts
Showing posts with label Kynurenine. Show all posts
Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression.
Depression is a debilitating condition with a profound impact on quality
of life for millions of people worldwide. Physical exercise is used as a
treatment strategy for many patients, but the mechanisms that underlie
its beneficial effects remain unknown. Here, we describe a mechanism by
which skeletal muscle PGC-1α1 (PPARGC1A)induced by exercise training changes
kynurenine metabolism and protects from stress-induced depression.
Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle
expression of kynurenine aminotransferases, thus enhancing the
conversion of kynurenine into kynurenic acid, a metabolite unable to
cross the blood-brain barrier. Reducing plasma kynurenine protects the
brain from stress-induced changes associated with depression and renders
skeletal muscle-specific PGC-1α1 transgenic mice resistant to
depression induced by chronic mild stress or direct kynurenine
administration. This study opens therapeutic avenues for the treatment
of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle,
without the need to cross the blood-brain barrier.
of life for millions of people worldwide. Physical exercise is used as a
treatment strategy for many patients, but the mechanisms that underlie
its beneficial effects remain unknown. Here, we describe a mechanism by
which skeletal muscle PGC-1α1 (PPARGC1A)induced by exercise training changes
kynurenine metabolism and protects from stress-induced depression.
Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle
expression of kynurenine aminotransferases, thus enhancing the
conversion of kynurenine into kynurenic acid, a metabolite unable to
cross the blood-brain barrier. Reducing plasma kynurenine protects the
brain from stress-induced changes associated with depression and renders
skeletal muscle-specific PGC-1α1 transgenic mice resistant to
depression induced by chronic mild stress or direct kynurenine
administration. This study opens therapeutic avenues for the treatment
of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle,
without the need to cross the blood-brain barrier.
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