Experimental diabetes mellitus type 1 increases hippocampal content of kynurenic acid in rats

Chmiel-Perzyñska, Iwona; Perzyński, Adam; Urbańska, Ewa M.

doi:10.1016/j.pharep.2014.07.014

Cited by 15 publications

(13 citation statements)

References 45 publications

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“…Increased hypothalamic KYNA content was reported in STZ-induced diabetes [31]. It is noteworthy that KYNA, but not other kynurenines, selectively activates GPR35 receptor on the surface of immune cells and inhibits synthesis of IDO-inducing proinflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Elevated anthranilic acid plasma concentrations in type 1 but not type 2 diabetes mellitus

Oxenkrug¹,

Hart²,

Summergrad³

2015

Integr Mol Med

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Experimental data suggested involvement of tryptophan (Trp) – kynurenine (Kyn) pathway (TKP) in mechanisms of autoimmune, type 1 (T1D), and metabolic, type 2 (T2D), diabetes. However, clinical evaluations of TKP metabolites were limited to T2D. We assessed Trp, Kyn and TKP metabolites: anthranilic (AA), kynurenic (KYNA) and xanthurenic (XA) acids, in plasma samples of fifteen T1D, thirty T2D patients and twenty eight non-diabetic subjects by HPLC-mass spectrometry. Trp concentrations were higher in T1D than in T2D and controls while Kyn concentrations were not changed suggesting down-regulation of indoleamine-2,3-dioxygenase (IDO), a rate-limiting enzyme of TKP, in T1D. AA concentrations were 2.3-fold higher in T1D than in T2D and in controls. KYNA and XA concentrations were higher in T1D than in controls, and in previously reported T2D. AA elevation might be a specific feature of T1D. TKP shift towards AA formation in T1D may result from riboflavin deficiency, that increases AA in rats and baboons, and is highly associated with T1D but not T2D. AA augments autoimmune-induced apoptosis of pancreatic cells (PC) by increasing formation of antibodies to PC auto-antigen. Marked increase of AA was reported in rheumatoid arthritis, another autoimmune disorder. Trp, an essential amino acid for humans, is synthesized from AA by diabetogenic intestinal microbiome. AA down-regulates IDO by inhibition of Trp entry into cells. Resulting elevation of Trp attenuates Trp depletion-induced protection of PC against autoimmunity. Further studies of TKP might offer new tools for prevention and treatment of T1D and other autoimmune disorders.

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Section: Discussionmentioning

confidence: 99%

Elevated anthranilic acid plasma concentrations in type 1 but not type 2 diabetes mellitus

Oxenkrug¹,

Hart²,

Summergrad³

2015

Integr Mol Med

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“…Chronic exposure to a high-fat and low-protein/carbohydrate ketogenic diet shows a several-fold increase in KYNA concentrations in the rat striatum and hippocampus [47]. Experimental diabetes mellitus type 1 enhances KAT II activity and increases KYNA levels in the rat cortex and hippocampus [48]. Thioacetamide-induced acute liver failure enhances peripheral kynurenine production, and thus increases brain KYNA levels [49].…”

Section: Kynurenic Acid Synthesismentioning

confidence: 99%

Possibility of Amino Acid Treatment to Prevent the Psychiatric Disorders via Modulation of the Production of Tryptophan Metabolite Kynurenic Acid

Fukuwatari

2020

Nutrients

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Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan catabolism, acts as an antagonist for both the α7 nicotinic acetylcholine receptor and glycine coagonist sites of the N-methyl-d-aspartic acid receptor at endogenous brain concentrations. Elevation of brain kynurenic acid levels reduces the release of neurotransmitters such as dopamine and glutamate, and kynurenic acid is considered to be involved in psychiatric disorders such as schizophrenia and depression. Thus, the control of kynurenine pathway, especially kynurenic acid production, in the brain is an important target for the improvement of brain function or the effective treatment of brain disorders. Astrocytes uptake kynurenine, the immediate precursor of kynurenic acid, via large neutral amino acid transporters, and metabolize kynurenine to kynurenic acid by kynurenine aminotransferases. The former transport both branched-chain and aromatic amino acids, and the latter have substrate specificity for amino acids and their metabolites. Recent studies have suggested the possibility that amino acids may suppress kynurenic acid production via the blockade of kynurenine transport or via kynurenic acid synthesis reactions. This approach may be useful in the treatment and prevention of neurological and psychiatric diseases associated with elevated kynurenic acid levels.

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“…Certainly, there are numerous other techniques describing Trp and its metabolite measurement, including liquid chromatographic methods with UV and fluorescence detection as well as gas chromatography and liquid chromatography coupled to mass spectrometry (Badawy & Morgan, 2010;Eckstein, Ammerman, Reveles, & Ackermann, 2008;Meinitzer et al, 2014;Notarangelo, Wu, Macherone, Graham, & Schwarcz, 2012). However, our method could simultaneously monitor six closely related components spanning KP and 5-HT pathways of Trp ( Figure 1a) from brain tissue, serum, and CSF, which was also successfully used in characterizing the dynamics of these metabolic pathways in a streptozotocin (STZ)-induced DE rat model (Chmiel-Perzynska, Perzynski, & Urbanska, 2014;Kanth, Lavanya, & Srinivas, 2009). Given the biological significance of Trp metabolic routes in cognitive disorders of neurodegenerative disease, the developed method will be expected to contribute to identifying these compounds as the potential biomarkers in clinical diagnosis of DE and also to present a better understanding of its pathogenesis.…”

mentioning

confidence: 99%

Quantitative profiling of neurotransmitter abnormalities in brain, cerebrospinal fluid, and serum of experimental diabetic encephalopathy male rat

Han

Min

Wang

et al. 2017

J of Neuroscience Research

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Diabetic encephalopathy (DE), one of the most prevalent chronic complications of diabetes mellitus, is short of effective prevention and formidable therapeutic strategies. The aim of the present study is to reveal the imbalance of tryptophan (Trp) and its metabolites in streptozotocin (STZ)-induced experimental DE rats to underscore their critical values in clinical diagnosis of the disease.For this purpose, we first developed an accurate and appropriate simultaneous method for measuring Trp and its metabolites using liquid chromatography-tandem mass spectrometry, which was in accordance with the requirements of biological sample analysis. Secondly, a single STZ intraperitoneal injection was administered to male Sprague-Dawley rats, and their cognitive function was detected by Morris water maze tests. Cerebrospinal fluid (CSF), serum, and brain tissue were then collected for the determination of Trp and its metabolites. Compared with age-matched control rats, the levels of neuroprotective serotonin decreased significantly in the samples of cortices, hippocampi, striatum, CSF, and serums in the STZ-induced DE rats, while the levels of neurotoxic 3-hydroxykynurenine increased significantly. Moreover, analogous changes of both compounds were found in the central nervous system and peripheral blood of the STZ-induced DE rats. In conclusion, we established a quantitative method for the simultaneous detection of Trp and its metabolites, and we also present a critical elucidation of the nervous system dysfunction in DE.

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Experimental diabetes mellitus type 1 increases hippocampal content of kynurenic acid in rats

Abstract: A novel factor potentially implicated in diabetic hippocampal dysfunction has been identified. Observed increase of KYNA level may stem from the activation of endogenous neuroprotection, however, it may also have negative impact on cognition.

Cited by 15 publications

References 45 publications

Elevated anthranilic acid plasma concentrations in type 1 but not type 2 diabetes mellitus

Elevated anthranilic acid plasma concentrations in type 1 but not type 2 diabetes mellitus

Possibility of Amino Acid Treatment to Prevent the Psychiatric Disorders via Modulation of the Production of Tryptophan Metabolite Kynurenic Acid

Quantitative profiling of neurotransmitter abnormalities in brain, cerebrospinal fluid, and serum of experimental diabetic encephalopathy male rat

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