Tryptophan availability for kynurenine pathway metabolism across the life span: Control mechanisms and focus on aging, exercise, diet and nutritional supplements

Badawy, Abdulla A.-B.

doi:10.1016/j.neuropharm.2015.11.015

Cited by 185 publications

(171 citation statements)

References 146 publications

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“…Although we excluded participants identified by diagnostic interview as having current substance abuse disorders, we did not routinely perform drug screens before the study, leaving open the possibility that recent illicit drug use could have altered laboratory or imaging results for some participants. Another limitation of this study was that only total tryptophan was measured, and that kynurenine was the only tryptophan metabolite measured; the KYN/TRP ratio may be only a crude index of IDO/TDO activity (Badawy, 2015). Furthermore, ∼ 5 to 10% of tryptophan is metabolized to serotonin , a pathway that is not examined in the current study.…”

Section: Discussionmentioning

confidence: 92%

“…Levels of tryptophan can be affected by food intake, exercise, stress, gut microbiota, and some medications (Badawy, 2015). We attempted to limit the impact of some of these factors by collecting blood samples in individuals who had been fasting overnight and who were instructed to avoid strenuous exercise the day before blood collection, although we did not precisely regulate intake, stress, or activity levels.…”

Section: Discussionmentioning

confidence: 99%

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Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Chiappelli

Postolache

Kochunov

et al. 2016

Neuropsychopharmacol

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Schizophrenia is associated with abnormalities in the structure and functioning of white matter, but the underlying neuropathology is unclear. We hypothesized that increased tryptophan degradation in the kynurenine pathway could be associated with white matter microstructure and biochemistry, potentially contributing to white matter abnormalities in schizophrenia. To test this, fasting plasma samples were obtained from 37 schizophrenia patients and 38 healthy controls and levels of total tryptophan and its metabolite kynurenine were assessed. The ratio of kynurenine to tryptophan was used as an index of tryptophan catabolic activity in this pathway. White matter structure and function were assessed by diffusion tensor imaging (DTI) and 1 H magnetic resonance spectroscopy (MRS). Tryptophan levels were significantly lower (po0.001), and kynurenine/tryptophan ratios were correspondingly higher (p = 0.018) in patients compared with controls. In patients, lower plasma tryptophan levels corresponded to lower structural integrity (DTI fractional anisotropy) (r = 0.347, p = 0.038). In both patients and controls, the kynurenine/tryptophan ratio was inversely correlated with frontal white matter glutamate level (r = − 0.391 and − 0.350 respectively, p = 0.024 and 0.036). These results provide initial evidence implicating abnormal tryptophan/ kynurenine pathway activity in changes to white matter integrity and white matter glutamate in schizophrenia.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Chiappelli

Postolache

Kochunov

et al. 2016

Neuropsychopharmacol

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“…As the precursor molecule to serotonin (5-HT), kynurenine and downstream metabolites of the kynurenine pathway (Badawy, 2015a;Palego et al, 2016), changes in the supply and availability of the essential amino acid tryptophan has many implications for ENS and CNS functioning and thus brain-gut axis signalling. Around 95% of the body's 5-HT is located within the GI tract, primarily synthesised by enterochromaffin cells, and 5% in the CNS (Camilleri, 2002;Gershon and Tack, 2007;Mayer et al, 2001).…”

Section: Tryptophan Metabolism Serotonin and The Kynurenine Pathwaymentioning

confidence: 99%

“…The majority of preclinical studies to date have focused on total circulating tryptophan levels with less attention given to the dynamics of tryptophan flux down the kynurenine pathway, including the assessment of free tryptophan levels (Badawy, 2015a). Nevertheless, it is clear that total tryptophan concentrations inform the equilibrium with free tryptophan and many consider total tryptophan to be important for brain tryptophan uptake (Fernstrom and Fernstrom, 2006).…”

Section: Preclinical Evidence Supporting a Role For The Gut Microbiotmentioning

confidence: 99%

Kynurenine pathway metabolism and the microbiota-gut-brain axis

et al. 2017

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“…The initial and rate-limiting step of the KP is the conversion of tryptophan to the central metabolite L-kynurenine and is mediated by 3 enzymes: indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), and tryptophan 2,3-dioxygenase 2 (TDO2) (2). Kynurenine can be transformed to downstream KP metabolites including quinolinic acid, an excitotoxic glutamate receptor agonist (2,3). KP metabolites are implicated in the pathophysiology underlying neurodegenerative diseases such as Parkinson, Alzheimer, and Huntington disease (3,4).…”

mentioning

confidence: 99%

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-¹⁸F-Fluoroethyl)-l-Tryptophan and α-¹¹C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

et al. 2016

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Abnormal tryptophan metabolism via the kynurenine pathway is involved in the pathophysiology of a variety of human diseases including cancers. a-11 C-methyl-L-tryptophan ( 11 C-AMT) PET imaging demonstrated increased tryptophan uptake and trapping in epileptic foci and brain tumors, but the short half-life of 11 C limits its widespread clinical application. Recent in vitro studies suggested that the novel radiotracer 1-(2-18 F-fluoroethyl)-L-tryptophan ( 18 F-FETrp) may be useful to assess tryptophan metabolism via the kynurenine pathway. In this study, we tested in vivo organ and tumor uptake and kinetics of 18 F-FETrp in patient-derived xenograft mouse models and compared them with 11 C-AMT uptake. Methods: Xenograft mouse models of glioblastoma and metastatic brain tumors (from lung and breast cancer) were developed by subcutaneous implantation of patient tumor fragments. Dynamic PET scans with 18 F-FETrp and 11 C-AMT were obtained for mice bearing human brain tumors 1-7 d apart. The biodistribution and tumoral SUVs for both tracers were compared. Results: 18 F-FETrp showed prominent uptake in the pancreas and no bone uptake, whereas 11 C-AMT showed higher uptake in the kidneys. Both tracers showed uptake in the xenograft tumors, with a plateau of approximately 30 min after injection; however, 18 F-FETrp showed higher tumoral SUV than 11 C-AMT in all 3 tumor types tested. The radiation dosimetry for 18 F-FETrp determined from the mouse data compared favorably with the clinical 18 F-FDG PET tracer. Conclusion: 18 F-FETrp tumoral uptake, biodistribution, and radiation dosimetry data provide strong preclinical evidence that this new radiotracer warrants further studies that may lead to a broadly applicable molecular imaging tool to examine abnormal tryptophan metabolism in human tumors.

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Tryptophan availability for kynurenine pathway metabolism across the life span: Control mechanisms and focus on aging, exercise, diet and nutritional supplements

Cited by 185 publications

References 146 publications

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Kynurenine pathway metabolism and the microbiota-gut-brain axis

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-¹⁸F-Fluoroethyl)-l-Tryptophan and α-¹¹C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

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Tryptophan availability for kynurenine pathway metabolism across the life span: Control mechanisms and focus on aging, exercise, diet and nutritional supplements

Cited by 185 publications

References 146 publications

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Kynurenine pathway metabolism and the microbiota-gut-brain axis

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-18F-Fluoroethyl)-l-Tryptophan and α-11C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

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Assessment of Tryptophan Uptake and Kinetics Using 1-(2-¹⁸F-Fluoroethyl)-l-Tryptophan and α-¹¹C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts