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 Blocking Astrocytic GABA Restores Synaptic Plasticity in Prefrontal Cortex of Rat Model of Depression

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1705
Author(s):  
Ipsit Srivastava ◽  
Erika Vazquez-Juarez ◽  
Lukas Henning ◽  
Marta Gómez-Galán ◽  
Maria Lindskog
Keyword(s):  
Prefrontal Cortex ◽  
Synaptic Plasticity ◽  
Rat Model ◽  
Synaptic Function ◽  
Mao B ◽  
Gaba Inhibition ◽  
Sensitive Line ◽  
Gaba Synthesis ◽  
Depression Disorder

A decrease in synaptic plasticity and/or a change in excitation/inhibition balance have been suggested as mechanisms underlying major depression disorder. However, given the crucial role of astrocytes in balancing synaptic function, particular attention should be given to the contribution of astrocytes in these mechanisms, especially since previous findings show that astrocytes are affected and exhibit reactive-like features in depression. Moreover, it has been shown that reactive astrocytes increase the synthesis and release of GABA, contributing significantly to tonic GABA inhibition. In this study we found decreased plasticity and increased tonic GABA inhibition in the prelimbic area in acute slices from the medial prefrontal cortex in the Flinders Sensitive Line (FSL) rat model of depression. The tonic inhibition can be reduced by either blocking astrocytic intracellular Ca2+ signaling or by reducing astrocytic GABA through inhibition of the synthesizing enzyme MAO-B with Selegiline. Blocking GABA synthesis also restores the impaired synaptic plasticity in the FSL prefrontal cortex, providing a new antidepressant mechanism of Selegiline.

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.

ROLE OF KYNURENINE PATHWAY METABOLITES IN DEPRESSION-A REVIEW

2020 ◽  
pp. 1-6
Author(s):  
Priyadarshini Soni ◽  
Lubhan Singh ◽  
Prabhat Singh ◽  
Sokindra Kumar
Keyword(s):  
Amino Acid ◽  
Kynurenic Acid ◽  
Kynurenine Pathway ◽  
World Health ◽  
The World ◽  
Important Pathway ◽  
Hydroxyanthranilic Acid ◽  
Health Organization

Today most common psychiatric problem across the world is depression and stress is main source of ailment. According to World health organization, it will be the main cause of morbidity by 2020 in the world. Depression can critically affects the quality of life  as it is characterized by many symptoms like unhappy feeling, lack of interest and pleasure, down energy, inadequacy, regret feeling, slow-down of thoughts or reduction in physical movement, speech can affects, altered appetite or sleep, sad,  and increase the risk of suicide. Human body is inadequate to produce tryptophan which is a crucial amino acid; therefore it must be required from diet. After absorption, L-tryptophan crosses the BBB (Blood brain barrier) by non-specific L-type amino acid transporter and act as precursor to various metabolic pathways in central nervous system (CNS). Kynurenine is an important pathway that is associated with tryptophan (TRP) metabolism, where it develops a lot of metabolites such as 3-hydroxykynurenine (3HK), anthranilic acid (AA), kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3HAA) and quinolinic acid (QUIN) known as kynurenines. It is already reported previously that disturbance in neuroprotective and neurotoxic metabolites leads to many psychiatric disorders. This review summarizes the role of kynurenine pathway metabolites in depression.   

scholarly journals Systematic Review of the Kynurenine Pathway and Psychoneurological Symptoms Among Adult Cancer Survivors

2020 ◽  
Vol 22 (4) ◽  
pp. 472-484
Author(s):  
Hongjin Li ◽  
Tingting Liu ◽  
Lacey W. Heinsberg ◽  
Mark B. Lockwood ◽  
Derek A. Wainwright ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cancer Survivors ◽  
Kynurenic Acid ◽  
Kynurenine Pathway ◽  
Future Research ◽  
Pathway Activation ◽  
Adult Cancer Survivors ◽  
Psychoneurological Symptoms ◽  
Cognitive Disturbance

The co-occurrence of multiple psychoneurological symptoms, including pain, sleep disturbance, fatigue, depression, anxiety, and cognitive disturbance among adult cancer survivors led us to question which common biological mechanisms are shared among these conditions. Variances in tryptophan (Trp) levels and downstream metabolites of the kynurenine (Kyn) metabolic pathway are known to affect immune response and psychoneurological symptoms. The objective of this systematic review was to help us (a) better understand the role of the Kyn pathway in psychoneurological symptoms among adult cancer survivors and (b) identify common significant biomarkers across psychoneurological symptoms as a guide for future research. Some evidence has shown that decreased Trp levels and increased Kyn, Trp/Kyn ratio, and kynurenic acid/Trp ratio in parallel with immune activation are correlated with some psychoneurological symptoms among people undergoing cancer treatment, although discrepancies exist between studies. Kyn pathway activation could also be associated with psychoneurological symptoms among adult cancer survivors, but further research is needed to confirm its exact etiological role with respect to psychoneurological symptoms.

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.

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