scholarly journals Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Amira Ben Afia ◽  
Èlia Vila ◽  
Karina S. MacDowell ◽  
Aida Ormazabal ◽  
Juan C. Leza ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
High Performance ◽  
Interaction Analysis ◽  
Kynurenine Pathway ◽  
Psychotic Symptoms ◽  
Post Mortem ◽  
Control Subjects ◽  
Network Interaction ◽  
Hydroxyindoleacetic Acid ◽  
Cortical Circuit

Abstract Background The cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA). Methods This work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by high-performance liquid chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored. Results In the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzyme expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolite content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC. Conclusions Thus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.

scholarly journals Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology

2021 ◽  
Author(s):  
Amira Ben Afia ◽  
Èlia Vila ◽  
Karina S. MacDowell ◽  
Aida Ormazabal ◽  
Juan Carlos Leza ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Interaction Analysis ◽  
Kynurenine Pathway ◽  
Psychotic Symptoms ◽  
Monoamine Metabolites ◽  
Post Mortem ◽  
Control Subjects ◽  
Network Interaction ◽  
Hydroxyindoleacetic Acid ◽  
Cortical Circuit

AbstractBackgroundthe cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA).Methodsthis work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by High Performance Liquid Chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored.Resultsin the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzymes expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolites content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC.Conclusionsthus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.

Decreased levels of kynurenic acid in prefrontal cortex in a genetic animal model of depression

2016 ◽  
Vol 29 (1) ◽  
pp. 54-58 ◽  
Author(s):  
Xi-Cong Liu ◽  
Sophie Erhardt ◽  
Michel Goiny ◽  
Göran Engberg ◽  
Aleksander A. Mathé
Keyword(s):  
Prefrontal Cortex ◽  
Rat Model ◽  
High Performance ◽  
Kynurenic Acid ◽  
Kynurenine Pathway ◽  
Genetic Animal Model ◽  
Animal Model Of Depression ◽  
Tryptophan Metabolites ◽  
Sensitive Line

ObjectiveThere is a growing interest in the role of kynurenine pathway and tryptophan metabolites in the pathophysiology of depression. In the present study, the metabolism of tryptophan along the kynurenine pathway was analysed in a rat model of depression.MethodsKynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK) were measured by high-performance liquid chromatography (HPLC) in prefrontal cortex (PFC) and frontal cortex (FC) in a rat model of depression, the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL) rats. In addition, KYNA was also measured in hippocampus, striatum and cerebellum.ResultsKYNA levels were reduced in the PFC of FSL rats compared with FRL rats, but did not differ with regard to the FC, hippocampus, striatum or cerebellum. 3-HK levels in PFC and FC, representing the activity of the microglial branch of the kynurenine pathway, did not differ between the FSL and FRL strains.ConclusionOur results suggest an imbalanced metabolism of the kynurenine pathway in the PFC of FSL rats.

scholarly journals Early Life Stress and the Fate of Kynurenine Pathway Metabolites

2021 ◽  
Vol 15 ◽  
Author(s):  
Jeremy D. Coplan ◽  
Roza George ◽  
Shariful A. Syed ◽  
Annalam V. Rozenboym ◽  
Jean E. Tang ◽  
...  
Keyword(s):  
Life Stress ◽  
Early Life ◽  
High Performance ◽  
Early Life Stress ◽  
Kynurenine Pathway ◽  
Primate Model ◽  
Social Affiliation ◽  
Control Subjects ◽  
Increased Risk ◽  
Maternal Variable

Early life stress (ELS) precedes alterations to neuro-immune activation, which may mediate an increased risk for stress-related psychiatric disorders, potentially through alterations of central kynurenine pathway (KP) metabolites, the latter being relatively unexplored. We hypothesized that ELS in a non-human primate model would lead to a reduction of neuroprotective and increases of neurotoxic KP metabolites. Twelve adult female bonnet macaques reared under conditions of maternal variable foraging demand (VFD) were compared to 27 age- and weight-matched non-VFD-exposed female controls. Baseline behavioral observations of social affiliation were taken over a 12-week period followed by the first cerebrospinal fluid (CSF) sample. Subjects were then either exposed to a 12-week repeated separation paradigm (RSP) or assigned to a “no-RSP” condition followed by a second CSF. We used high-performance liquid chromatography for kynurenine (KYN), tryptophan, 5-hydroxyindoleacetic acid, kynurenic acid (KYNA), and anthranilic acid (ANTH) as a proxy for quinolinic acid determination. At baseline, social affiliation scores were reduced in VFD-reared versus control subjects. CSF log KYNA and log KYNA/KYN ratio were lower in VFD-reared versus control subjects. CSF log KYNA/KYN was positively correlated with CSF log ANTH in VFD only (r = 0.82). Controlling for log KYNA/KYN, log ANTH was elevated in VFD-reared subjects versus controls. CSF log KYNA/KYN obtained post-RSP was positively correlated with mean social affiliation scores during RSP, specifically in VFD. ELS is associated with a reduced neuroprotective and increased neurotoxic pathway products. That the two contrasting processes are paradoxically correlated following ELS suggests a cross-talk between two opposing KP enzymatic systems.

Standardised ginseng extract G115® potentiates the antidepressant-like properties of fluoxetine in the forced swim test

2021 ◽  
pp. 1-7
Author(s):  
Dylan J. Terstege ◽  
Debra S. MacDonald ◽  
R. Andrew Tasker
Keyword(s):  
Prefrontal Cortex ◽  
Forced Swim Test ◽  
Ginseng Root ◽  
Group Differences ◽  
Post Mortem ◽  
Ginseng Extract ◽  
Significant Group ◽  
Swim Test ◽  
Forced Swim ◽  
Plus Maze

Abstract Objective: Ginsenosides, biologically active components of the root of Panax ginseng, have been reported to have therapeutic benefits in a number of disease states including psychiatric conditions such as major depressive disorder. Our objective was to determine if a standardised commercial ginseng extract, G115®, could reduce the signs of behavioural despair commonly observed in animal models of depression either alone or in combination with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Methods: Male Sprague-Dawley (SD) rats (N = 51) were divided into four groups: vehicle control, G115® ginseng root extract, fluoxetine and fluoxetine plus G115®. Rats were trained to voluntarily consume treatments twice daily for 14 days and were then tested in an open field (OF), elevated plus maze (EPM) and forced swim test (FST). Post-mortem hippocampal and prefrontal cortex tissue was analysed for expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) by western blot. Results: One-way Analysis of Variance revealed no significant group differences in the OF or plus-maze performance on any variable examined. In the FST, fluoxetine significantly reduced immobility time and increased latency to immobility. The effects of fluoxetine were further significantly potentiated by co-administration of G115®. Post-mortem tissue analysis revealed significant group differences in BDNF expression in the left hippocampus and left prefrontal cortex without any accompanying changes in TrkB expression. Conclusions: We conclude that oral G115® significantly potentiates the antidepressant-like effect of fluoxetine in the FST in the absence of potentially confounding effects on locomotion and anxiety.

Endogenously Generated and Visually Guided Saccades after Lesions of the Human Frontal Eye Fields

1994 ◽  
Vol 6 (4) ◽  
pp. 400-411 ◽  
Author(s):  
Avishai Henik ◽  
Robert Rafal ◽  
Dell Rhodes
Keyword(s):  
Prefrontal Cortex ◽  
Visual Display ◽  
Covert Attention ◽  
Visual Signal ◽  
Frontal Eye Fields ◽  
Opposite Pattern ◽  
Control Subjects ◽  
Key Press ◽  
Reflexive Saccades ◽  
Voluntary Saccades

Nine patients with chronic, unilateral lesions of the dorso-lateral prefrontal cortex including the frontal eye fields (FEF) made saccades toward contralesional and ipsilesional fields. The saccades were either voluntarily directed in response to arrows in the center of a visual display, or were reflexively summoned by a peripheral visual signal. Saccade latencies were compared to those made by seven neurologic control patients with chronic, unilateral lesions of dorsolateral prefrontal cortex sparing the FEF, and by 13 normal control subjects. In both the normal and neurologic control subjects, reflexive saccades had shorter Latencies than voluntary saccades. In the FEF lesion patients, voluntary saccades had longer latencies toward the contralesional field than toward the ipsilesional field. The opposite pattern was found for reflexive saccades: latencies of saccades to targets in the contralesional field were shorter than saccades summoned to ipsilesional targets. Reflexive saccades toward the ipsilesional field had abnormally prolonged latencies; they were comparable to the latencies observed for voluntary Saccades. The effect of FEF lesions on saccacles contrasted with those observed in a second experiment requiring a key press response: FEF lesion patients were slower in making key press responses to signals detected in the contralesional field. To assess covert attention and preparatory set the effects of precues providing advance information were measured in both saccade and key press experiments. Neither patient group showed any deficiency in using precues to shift attention or to prepare saccades. The FEF facilitates the generation of voluntary saccatles and also inhibits reflexive saccades to exogenous signals. FEF lesions may disinhibit the ipsilesional midbrain which in turn may inhibit the opposite colliculus to slow reflexive saccades toward the ipsilesional field.

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 Serum profiles of tryptophan-kynurenine pathway metabolites in psoriasis

2021 ◽  
Author(s):  
Mariko Seishima ◽  
Yasuko Yamamoto ◽  
Masashi Sakurai ◽  
Rika Sakai ◽  
Kento Fujii ◽  
...  
Keyword(s):  
High Performance ◽  
Severity Index ◽  
Skin Lesions ◽  
Kynurenine Pathway ◽  
Psoriasis Area Severity Index ◽  
Systemic Inflammatory Disease ◽  
Cytokine Levels ◽  
Uninvolved Skin ◽  
Psoriasis Therapy ◽  
Hydroxyanthranilic Acid

Aim: Chronic inflammation is closely associated with tryptophan (TRP)-kynurenine (KYN) metabolic pathway. However, TRP-KYN pathway has not been fully elucidated in psoriasis, a systemic inflammatory disease with skin lesions and extracutaneous manifestations. Herein, we studied comprehensively serum profiles of TRP-KYN pathway metabolites in psoriatic patients (PSOs) to clarify the involvement of this pathway in the pathophysiology of psoriasis and to evaluate serum biomarkers reflecting systemic inflammation in PSOs. Methods: The concentrations of main TRP metabolites, TRP, KYN, 3-hydroxykynurenine (3HK), kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3HAA), and anthranilic acid (AA), were determined by high-performance liquid chromatography in the sera from 65 PSOs and 35 healthy controls (HCs). The levels of these metabolites and the ratios of metabolites were compared between these subjects. The correlations between these values and the psoriasis area severity index (PASI) scores were analyzed. Skin samples from PSOs and HCs were subjected to immunohistochemical staining for kynureninase. Cytokine concentrations were comprehensively measured in the same samples and the correlations between the cytokine levels and TRP-KYN pathway metabolite levels were examined. Results: Serum TRP, KYN, and KYNA concentrations were lower and the 3HAA concentrations were higher in PSOs than in HCs. The ratios of 3HK/KYN, 3HAA/3HK, and 3HK/AA were higher in PSOs than in HCs. The AA levels and the ratio of AA/KYN were weakly positively correlated, and TRP, KYNA, and 3HK levels and the ratios of KYNA/KYN and 3HAA/AA were weakly negatively correlated with the PASI scores. The AA, KYN, and KYNA levels were positively correlated with the interferon gamma-induced protein 10 (IP-10) concentrations. Kynureninase expression was enhanced in the epidermis, both involved and uninvolved skin. Conclusions: Serum profiles of TRP-KYN pathway metabolites differed between PSOs and HCs. TRP-KYN pathway-associated processes, including kynureninase activation, may be involved in the pathogenesis of psoriasis, and thus serve as targets for psoriasis therapy.

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