Kynurenic acid in brain function and dysfunction

2020 ◽  
pp. 323-332
Author(s):  
Robert Schwarcz ◽  
Sophie Erhardt
Keyword(s):  
Kynurenic Acid ◽  
Kynurenine Pathway ◽  
Psychotic Symptoms ◽  
Gabaergic Neurotransmission ◽  
Novel Approach ◽  
Healthy Control ◽  
Amino Acid Tryptophan ◽  
Persons With Schizophrenia ◽  
And Function ◽  
The Brain

The essential amino acid tryptophan is degraded primarily by the kynurenine pathway, a cascade of enzymatic steps leading to the generation of several neuroactive compounds. Of those, kynurenic acid (KYNA), an antagonist at N-methyl-D-aspartate (NMDA) and alpha7-nicotinic receptors, has gained much attention in schizophrenia research. The concentrations of both KYNA and its precursor, kynurenine, have been repeatedly found significantly elevated both in the postmortem cerebral cortex and in the cerebrospinal fluid of schizophrenia persons as compared to healthy control subjects. Studies in experimental animals have demonstrated that KYNA tightly controls dopaminergic, cholinergic, glutamatergic, and GABAergic neurotransmission, and elevated brain levels appear related to psychotic symptoms and cognitive impairments. The kyurenine pathway is highly inducible by immune activation, and studies have shown that the pro-inflammatory cytokines interleukin (IL)-1β‎ and IL-6 are elevated in schizophrenia and stimulate the production of KYNA. Another mechanism that may account for the abnormally high central kynurenine and KYNA levels seen in schizophrenia might be the observed reduced expression and activity of the enzyme kynurenine 3-monooxygenase (KMO), shunting the synthesis of kynurenine toward KYNA. In line with these studies and concepts, preclinical results suggest that inhibition of kynurenine aminotransferase (KAT) II, by reducing the synthesis and function of KYNA in the brain, offers a novel approach to ameliorate psychosis and to improve cognitive performance in persons with schizophrenia.

scholarly journals Clinical relevance of depressed kynurenine pathway in episodic migraine patients: potential prognostic markers in the peripheral plasma during the interictal period

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Bernadett Tuka ◽  
Aliz Nyári ◽  
Edina Katalin Cseh ◽  
Tamás Körtési ◽  
Dániel Veréb ◽  
...  
Keyword(s):  
Anthranilic Acid ◽  
Clinical Relevance ◽  
Kynurenic Acid ◽  
Picolinic Acid ◽  
Plasma Concentrations ◽  
Episodic Migraine ◽  
Kynurenine Pathway ◽  
Xanthurenic Acid ◽  
Control Subjects ◽  
Healthy Control

Abstract Background Altered glutamatergic neurotransmission and neuropeptide levels play a central role in migraine pathomechanism. Previously, we confirmed that kynurenic acid, an endogenous glutamatergic antagonist, was able to decrease the expression of pituitary adenylate cyclase-activating polypeptide 1–38, a neuropeptide with known migraine-inducing properties. Hence, our aim was to reveal the role of the peripheral kynurenine pathway (KP) in episodic migraineurs. We focused on the complete tryptophan (Trp) catabolism, which comprises the serotonin and melatonin routes in addition to kynurenine metabolites. We investigated the relationship between metabolic alterations and clinical characteristics of migraine patients. Methods Female migraine patients aged between 25 and 50 years (n = 50) and healthy control subjects (n = 34) participated in this study. Blood samples were collected from the cubital veins of subjects (during both the interictal/ictal periods in migraineurs, n = 47/12, respectively). 12 metabolites of Trp pathway were determined by neurochemical measurements (UHPLC-MS/MS). Results Plasma concentrations of the most Trp metabolites were remarkably decreased in the interictal period of migraineurs compared to healthy control subjects, especially in the migraine without aura (MWoA) subgroup: Trp (p < 0.025), L-kynurenine (p < 0.001), kynurenic acid (p < 0.016), anthranilic acid (p < 0.007), picolinic acid (p < 0.03), 5-hydroxy-indoleaceticacid (p < 0.025) and melatonin (p < 0.023). Several metabolites showed a tendency to elevate during the ictal phase, but this was significant only in the cases of anthranilic acid, 5-hydroxy-indoleaceticacid and melatonin in MWoA patients. In the same subgroup, higher interictal kynurenic acid levels were identified in patients whose headache was severe and not related to their menstruation cycle. Negative linear correlation was detected between the interictal levels of xanthurenic acid/melatonin and attack frequency. Positive associations were found between the ictal 3-hydroxykynurenine levels and the beginning of attacks, just as between ictal picolinic acid levels and last attack before ictal sampling. Conclusions Our results suggest that there is a widespread metabolic imbalance in migraineurs, which manifests in a completely depressed peripheral Trp catabolism during the interictal period. It might act as trigger for the migraine attack, contributing to glutamate excess induced neurotoxicity and generalised hyperexcitability. This data can draw attention to the clinical relevance of KP in migraine.

scholarly journals Changes in the immune system in depression and dementia: causal or coincidental effects?

2006 ◽  
Vol 8 (2) ◽  
pp. 163-174 ◽  
Keyword(s):  
Neurotrophic Factors ◽  
Kynurenic Acid ◽  
Neuronal Damage ◽  
Later Life ◽  
Epidemiological Studies ◽  
Kynurenine Pathway ◽  
Pathological Changes ◽  
Induced Apoptosis ◽  
Inflammatory Changes ◽  
The Brain

Epidemiological studies show that there is a correlation between chronic depression and the likelihood of dementia in later life. There is evidence that inflammatory changes in the brain are pathological features of both depression and dementia. This suggests that an increase in inflammation-induced apoptosis, together with a reduction in the synthesis of neurotrophic factors caused by a rise in brain glucocorticoids, may play a role in the pathology of these disorders. A reduction in the neuroprotective components of the kynurenine pathway such as kynurenic acid, and an increase in the neurodegenerative components, 3-hydroxykynurenine and quinolinic acid, contribute to the pathological changes. Such changes are postulated to cause neuronal damage, and thereby predispose chronically depressed patients to dementia.

scholarly journals Effects of Sleep Deprivation on the Tryptophan Metabolism

2020 ◽  
Vol 13 ◽  
pp. 117864692097090
Author(s):  
Abid Bhat ◽  
Ananda Staats Pires ◽  
Vanessa Tan ◽  
Saravana Babu Chidambaram ◽  
Gilles J Guillemin
Keyword(s):  
Sleep Deprivation ◽  
Kynurenic Acid ◽  
Second Messengers ◽  
Sleep Time ◽  
Kynurenine Pathway ◽  
Tryptophan Metabolism ◽  
Cellular Functions ◽  
Intracellular Second Messengers ◽  
The Impact ◽  
The Brain

Sleep has a regulatory role in maintaining metabolic homeostasis and cellular functions. Inadequate sleep time and sleep disorders have become more prevalent in the modern lifestyle. Fragmentation of sleep pattern alters critical intracellular second messengers and neurotransmitters which have key functions in brain development and behavioral functions. Tryptophan metabolism has also been found to get altered in SD and it is linked to various neurodegenerative diseases. The kynurenine pathway is a major regulator of the immune response. Adequate sleep alleviates neuroinflammation and facilitates the cellular clearance of metabolic toxins produced within the brain, while sleep deprivation activates the enzymatic degradation of tryptophan via the kynurenine pathway, which results in an increased accumulation of neurotoxic metabolites. SD causes increased production and accumulation of kynurenic acid in various regions of the brain. Higher levels of kynurenic acid have been found to trigger apoptosis, leads to cognitive decline, and inhibit neurogenesis. This review aims to link the impact of sleep deprivation on tryptophan metabolism and associated complication in the brain.

scholarly journals The future of human cerebral cartography: a novel approach

2015 ◽  
Vol 370 (1668) ◽  
pp. 20140171 ◽  
Author(s):  
Richard Frackowiak ◽  
Henry Markram
Keyword(s):  
Scale Model ◽  
Quarter Century ◽  
Multi Scale ◽  
Novel Approach ◽  
Brain Structure And Function ◽  
Recent Developments ◽  
Spatio Temporal ◽  
And Function ◽  
The Brain ◽  
Different Levels

Cerebral cartography can be understood in a limited, static, neuroanatomical sense. Temporal information from electrical recordings contributes information on regional interactions adding a functional dimension. Selective tagging and imaging of molecules adds biochemical contributions. Cartographic detail can also be correlated with normal or abnormal psychological or behavioural data. Modern cerebral cartography is assimilating all these elements. Cartographers continue to collect ever more precise data in the hope that general principles of organization will emerge. However, even detailed cartographic data cannot generate knowledge without a multi-scale framework making it possible to relate individual observations and discoveries. We propose that, in the next quarter century, advances in cartography will result in progressively more accurate drafts of a data-led, multi-scale model of human brain structure and function. These blueprints will result from analysis of large volumes of neuroscientific and clinical data, by a process of reconstruction, modelling and simulation. This strategy will capitalize on remarkable recent developments in informatics and computer science and on the existence of much existing, addressable data and prior, though fragmented, knowledge. The models will instantiate principles that govern how the brain is organized at different levels and how different spatio-temporal scales relate to each other in an organ-centred context.

Role of Tryptophan-kynurenine Pathway in Depression: Psychopathological Aspect

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1
Author(s):  
A.-M. Myint
Keyword(s):  
Kynurenic Acid ◽  
Excitatory Amino Acid ◽  
Kynurenine Pathway ◽  
Response To Treatment ◽  
Excitatory Amino Acid Receptors ◽  
Amino Acid Receptors ◽  
Tryptophan Catabolism ◽  
Ifn Γ ◽  
The Brain

It was reported that cytokines such as IFN-γ reduce the synthesis of 5-HT by stimulating the activity of indoleamine 2,3 dioxygenase (IDO) enzyme which degrades tryptophan to kynurenine. Kynurenine is further metabolized to kynurenic acid (KYNA), 3-hydroxykynurenine (3OHK) and quinolinic acid (QA) by kynurenine aminotransferase (KAT), kynurenine 3-monooxygenase (KMO) and kynureninase. Both KMO and kynureninase are also shown to be activated by IFNγ. The 3OHK is neurotoxic apoptotic while QA is the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist. Conversely KYNA is an antagonist of all three ionotropic excitatory amino acid receptors and considered neuroprotective. In the brain, tryptophan catabolism occurs in the astrocytes and. The astrocytes are shown to produce mainly KYNA whereas microglia and macrophages produced mainly 3OHK and QA. The astrocytes have been demonstrated to metabolise the QA produced by the neighbouring microglia.Tryptophan breakdown has been found to be increased but KYNA, the neuroprotective metabolite is decreased in both blood and cerebrospinal fluid of the patients with major depression compared to healthy controls. Moreover, the ratio between KYNA and 3OHK showed significant correlation with response to treatment. These findings lead to the hypothesis an imbalance neuroprotection-neurodegener-ation in terms of kynurenine metabolites and their immunological and biochemical interactions in the brain might further induce the apoptosis of the neuroprotective astrocytes and the vulnerability to stress is thereby enhanced.

scholarly journals Autoimmune Concept Of Schizophrenia: HIistorical Roots and Current Facets

2020 ◽  
Author(s):  
Margarita Mayorova ◽  
Boris Butoma ◽  
Leonid Churilov ◽  
Boris Gilburd ◽  
Natalia Petrova ◽  
...  
Keyword(s):  
Autoimmune Encephalitis ◽  
Kynurenine Pathway ◽  
Psychotic Symptoms ◽  
Favorable Prognosis ◽  
Cytokines And Chemokines ◽  
Food Antigens ◽  
Autoimmune Processes ◽  
Autoimmune Pathogenesis ◽  
The Brain

The review analyzes a possible role of autoimmune processes in the pathogenesis of schizophrenia and evolution of concepts on this issue from its origin to present. Risks of autoimmune processes causing schizophrenia are associated with several factors: an impaired functioning of dopaminergic and glutamatergic systems in the brain, kynurenine pathway disorder with overproduction of quinolinic, anthranilic and kynurenic acids (possibly altering both neurons and T-regulators), increased intestinal permeability, as well as food antigens&rsquo; effects, stress and infections with various pathogens at different stages of ontogenesis. An increase in the levels of proinflammatory cytokines and chemokines as well as a decrease in the levels of anti-inflammatory ones also may contribute to schizophrenia risks. Schizophrenia often occurs in those patients having various autoimmune diseases and their first-degree relatives. Cases of schizophrenia resulted from autoimmune pathogenesis (including autoimmune encephalitis caused by autoantibodies against various neuronal antigens) are characterized by quite severe cognitive and psychotic symptoms and less favorable prognosis. This severe course may result from the chronic immune damage of the neuronal receptors such as NMDA, GABA, and others and depend on hyperprolactinemia, induced by antipsychotics, but aggravating autoimmune processes [with 2 tables, 4 figures, bibliography: 99 references].

Ultrastructure of developing visual cortical synapses in the cat superior colliculus

1991 ◽  
Vol 49 ◽  
pp. 156-157
Author(s):  
Caroline A. Miller ◽  
Laura L. Bruce
Keyword(s):  
Superior Colliculus ◽  
Phosphate Buffer ◽  
Receptive Fields ◽  
Visual Cortical Area ◽  
Cortical Synapses ◽  
Visual Cortical ◽  
And Function ◽  
Phosphate Buffered Saline ◽  
The Brain ◽  
Cat Superior Colliculus

The first visual cortical axons arrive in the cat superior colliculus by the time of birth. Adultlike receptive fields develop slowly over several weeks following birth. The developing cortical axons go through a sequence of changes before acquiring their adultlike morphology and function. To determine how these axons interact with neurons in the colliculus, cortico-collicular axons were labeled with biocytin (an anterograde neuronal tracer) and studied with electron microscopy.Deeply anesthetized animals received 200-500 nl injections of biocytin (Sigma; 5% in phosphate buffer) in the lateral suprasylvian visual cortical area. After a 24 hr survival time, the animals were deeply anesthetized and perfused with 0.9% phosphate buffered saline followed by fixation with a solution of 1.25% glutaraldehyde and 1.0% paraformaldehyde in 0.1M phosphate buffer. The brain was sectioned transversely on a vibratome at 50 μm. The tissue was processed immediately to visualize the biocytin.

scholarly journals Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid

2021 ◽  
Vol 22 (1) ◽  
pp. 403
Author(s):  
Fanni Tóth ◽  
Edina Katalin Cseh ◽  
László Vécsei
Keyword(s):  
Neurodegenerative Diseases ◽  
Lipoic Acid ◽  
Kynurenic Acid ◽  
Biological Activities ◽  
Neuroprotective Effect ◽  
Structural Diversity ◽  
Kynurenine Pathway ◽  
Glutamate Excitotoxicity ◽  
Neuroprotective Agents ◽  
Starting Point

The incidence of neurodegenerative diseases has increased greatly worldwide due to the rise in life expectancy. In spite of notable development in the understanding of these disorders, there has been limited success in the development of neuroprotective agents that can slow the progression of the disease and prevent neuronal death. Some natural products and molecules are very promising neuroprotective agents because of their structural diversity and wide variety of biological activities. In addition to their neuroprotective effect, they are known for their antioxidant, anti-inflammatory and antiapoptotic effects and often serve as a starting point for drug discovery. In this review, the following natural molecules are discussed: firstly, kynurenic acid, the main neuroprotective agent formed via the kynurenine pathway of tryptophan metabolism, as it is known mainly for its role in glutamate excitotoxicity, secondly, the dietary supplement pantethine, that is many sided, well tolerated and safe, and the third molecule, α-lipoic acid is a universal antioxidant. As a conclusion, because of their beneficial properties, these molecules are potential candidates for neuroprotective therapies suitable in managing neurodegenerative diseases.

scholarly journals Right Heart Structure, Geometry and Function Assessed by Echocardiography in 6-Year-Old Children Born Extremely Preterm—A Population-Based Cohort Study

2020 ◽  
Vol 10 (1) ◽  
pp. 122
Author(s):  
Lilly-Ann Mohlkert ◽  
Jenny Hallberg ◽  
Olof Broberg ◽  
Gunnar Sjöberg ◽  
Annika Rydberg ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Ductus Arteriosus ◽  
Population Based ◽  
Right Heart ◽  
Functional Changes ◽  
Cardiac Phenotype ◽  
Extremely Preterm ◽  
Healthy Control ◽  
The Right ◽  
And Function

Preterm birth has been associated with altered cardiac phenotype in adults. Our aim was to test the hypothesis that children surviving extremely preterm birth have important structural or functional changes of the right heart or pulmonary circulation. We also examined relations between birth size, gestational age, neonatal diagnoses of bronchopulmonary dysplasia (BPD) and patent ductus arteriosus (PDA) with cardiac outcomes. We assessed a population-based cohort of children born in Sweden before 27 weeks of gestation with echocardiography at 6.5 years of age (n = 176). Each preterm child was matched to a healthy control child born at term. Children born preterm had significantly smaller right atria, right ventricles with smaller widths, higher relative wall thickness and higher estimated pulmonary vascular resistance (PVR) than controls. In preterm children, PVR and right ventricular myocardial performance index (RVmpi’) were significantly higher in those with a PDA as neonates than in those without PDA, but no such associations were found with BPD. In conclusion, children born extremely preterm exhibit higher estimated PVR, altered right heart structure and function compared with children born at term.

The Good Sower: A Novel Approach to Teaching Sunday School

2021 ◽  
pp. 073989132199312
Author(s):  
Lisa Marie Anderson-Umana
Keyword(s):  
Daily Life ◽  
Sunday School ◽  
School Students ◽  
The Bible ◽  
Novel Approach ◽  
Approach To Teaching ◽  
The Brain

The problems related to Sunday school students not making the connection between Scripture and daily life and a superficial teaching of the Bible compelled the author to create a novel approach to teaching Sunday school called the “Good Sower.” The imagery of a “Good Sower” is used to teach volunteers how to teach the Bible. Based on solid research regarding how the brain learns, it serves as an overlay in conjunction with published curriculum.

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