scholarly journals A Potential Interface between the Kynurenine Pathway and Autonomic Imbalance in Schizophrenia

2021 ◽  
Vol 22 (18) ◽  
pp. 10016
Author(s):  
Alexandra Büki ◽  
Gabriella Kekesi ◽  
Gyongyi Horvath ◽  
László Vécsei
Keyword(s):  
Kynurenic Acid ◽  
Medication Compliance ◽  
Kynurenine Pathway ◽  
Potential Interaction ◽  
Autonomic Functions ◽  
Altered Level ◽  
Autonomic Imbalance ◽  
Autonomic Disturbances ◽  
Few Data ◽  
Almost All

Schizophrenia is a neuropsychiatric disorder characterized by various symptoms including autonomic imbalance. These disturbances involve almost all autonomic functions and might contribute to poor medication compliance, worsened quality of life and increased mortality. Therefore, it has a great importance to find a potential therapeutic solution to improve the autonomic disturbances. The altered level of kynurenines (e.g., kynurenic acid), as tryptophan metabolites, is almost the most consistently found biochemical abnormality in schizophrenia. Kynurenic acid influences different types of receptors, most of them involved in the pathophysiology of schizophrenia. Only few data suggest that kynurenines might have effects on multiple autonomic functions. Publications so far have discussed the implication of kynurenines and the alteration of the autonomic nervous system in schizophrenia independently from each other. Thus, the coupling between them has not yet been addressed in schizophrenia, although their direct common points, potential interfaces indicate the consideration of their interaction. The present review gathers autonomic disturbances, the impaired kynurenine pathway in schizophrenia, and the effects of kynurenine pathway on autonomic functions. In the last part of the review, the potential interaction between the two systems in schizophrenia, and the possible therapeutic options are discussed.

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.

The in vitro effect of kynurenic acid on the rainbow trout (Oncorhynchus mykiss) leukocyte and splenocyte activity

2014 ◽  
Vol 17 (3) ◽  
pp. 453-458 ◽  
Author(s):  
J. Małaczewska ◽  
A. K. Siwicki ◽  
R. Wójcik ◽  
W. a. Turski ◽  
E. Kaczorek
Keyword(s):  
Rainbow Trout ◽  
Immune Cells ◽  
Kynurenic Acid ◽  
Kynurenine Pathway ◽  
Phagocytic Cells ◽  
Mitogenic Response ◽  
Tryptophan Degradation ◽  
Selective Ligand ◽  
Vitro Effect

Abstract Kynurenic acid (KYNA), an endogenous neuroprotectant formed along the kynurenine pathway of tryptophan degradation, is a selective ligand of the GPR35 receptor, which can be found on the surface of various populations of human immune cells. In infections and inflammations, KYNA produces an anti-inflammatory effect through this receptor, by depressing the synthesis of reactive oxygen species and pro-inflammatory cytokines. However, it is still unrecognized whether receptors for kynurenic acid are also localized on immune cells of poikilothermic animals, or whether KYNA is able to affect these cells. The objective of this study has been to determine the effect of different concentrations of kynurenic acid (12.5 μM to 10 mM) on the viability and mitogenic response of lymphocytes and on the activity of phagocytic cells isolated from blood and the spleen of rainbow trout. The results imply low toxicity of kynurenic acid towards fish immune cells, and the proliferative effect observed at the two lowest concentrations of KYNA (12.5 μM and 25 μM) seems indicative of endogenous kynurenic acid being capable of activating fish lymphocytes. Non-toxic, micromole concentrations of KYNA, however, had no influence on the mitogenic response of lymphocytes nor on the activity of phagocytes in rainbow trout under in vitro conditions. There is some likelihood that such an effect could be observed at lower, nanomole concentrations of KYNA.

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.

Discontinuation of Medication Overuse in Headache Patients: Recovery of Therapeutic Responsiveness

Cephalalgia ◽  
2006 ◽  
Vol 26 (10) ◽  
pp. 1192-1198 ◽  
Author(s):  
P Zeeberg ◽  
J Olesen ◽  
R Jensen
Keyword(s):  
Drug Withdrawal ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Headache Frequency ◽  
Female Ratio ◽  
Headache Centre ◽  
Before And After ◽  
Male Female Ratio ◽  
Few Data ◽  
Almost All

It is generally accepted that ongoing medication overuse nullifies the effect of prophylactic treatment, although few data support this contention. We set out to describe the treatment outcome in patients withdrawn from medication overuse and relate any improvement to a renewed effect of prophylaxis. For patients with probable medication-overuse headache (pMOH), treated and dismissed from the Danish Headache Centre in 2002 and 2003, we assed, from prospective headache diaries, the headache frequency before and after withdrawal of offending drugs and compared these frequencies with the headache frequency at dismissal. Among 1326 patients, 337 had pMOH. Eligible were 175, mean age 49 years, male/female ratio 1: 2.7. Overall, there was a 46% decrease in headache frequency from the first visit to dismissal ( P < 0.0001). Patients with no improvement 2 months after complete drug withdrawal ( N = 88) subsequently responded to pharmacological and/or non-pharmacological prophylaxis with a 26% decrease in headache frequency as measured from the end of withdrawal to dismissal ( P < 0.0001). At dismissal, 47% were on prophylaxis. Former non-responders to medical prophylaxis had a 49% decrease in headache frequency from first visit to dismissal ( P < 0.0001), whereas those who had never received prophylaxis had a 56% reduction ( P < 0.0001). This difference was not statistically significant ( P = 0.22). Almost all MOH patients benefit from drug withdrawal, either just from the withdrawal or by transformation from therapeutic non-responsiveness to responsiveness. According to the International Classification of Headache Disorders, 2nd edn, the MOH diagnosis requires improvement after drug withdrawal. Our data suggest that these diagnostic criteria are too strict.

scholarly journals Kynurenines with Neuroactive and Redox Properties: Relevance to Aging and Brain Diseases

2014 ◽  
Vol 2014 ◽  
pp. 1-22 ◽  
Author(s):  
Jazmin Reyes Ocampo ◽  
Rafael Lugo Huitrón ◽  
Dinora González-Esquivel ◽  
Perla Ugalde-Muñiz ◽  
Anabel Jiménez-Anguiano ◽  
...  
Keyword(s):  
Aging Process ◽  
Kynurenine Pathway ◽  
Experimental Models ◽  
Redox Properties ◽  
Brain Diseases ◽  
Oxygen Species ◽  
Neurodegenerative Process ◽  
Feedback Cycle ◽  
Tryptophan Degradation ◽  
Almost All

The kynurenine pathway (KP) is the main route of tryptophan degradation whose final product is NAD+. The metabolism of tryptophan can be altered in ageing and with neurodegenerative process, leading to decreased biosynthesis of nicotinamide. This fact is very relevant considering that tryptophan is the major source of body stores of the nicotinamide-containing NAD+coenzymes, which is involved in almost all the bioenergetic and biosynthetic metabolism. Recently, it has been proposed that endogenous tryptophan and its metabolites can interact and/or produce reactive oxygen species in tissues and cells. This subject is of great importance due to the fact that oxidative stress, alterations in KP metabolites, energetic deficit, cell death, and inflammatory events may converge each other to enter into a feedback cycle where each one depends on the other to exert synergistic actions among them. It is worth mentioning that all these factors have been described in aging and in neurodegenerative processes; however, has so far no one established any direct link between alterations in KP and these factors. In this review, we describe each kynurenine remarking their redox properties, their effects in experimental models, their alterations in the aging process.

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

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1403 ◽  
Author(s):  
Tsutomu Fukuwatari
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Psychiatric Disorders ◽  
Acid Production ◽  
Kynurenic Acid ◽  
Acid Synthesis ◽  
Kynurenine Pathway ◽  
Amino Acid Transporters ◽  
Large Neutral Amino Acid ◽  
Α7 Nicotinic Acetylcholine Receptor

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.

scholarly journals Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

2020 ◽  
Vol 21 (5) ◽  
pp. 1795 ◽  
Author(s):  
Rooban B. Nahomi ◽  
Mi-Hyun Nam ◽  
Johanna Rankenberg ◽  
Stefan Rakete ◽  
Julie A. Houck ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Kynurenic Acid ◽  
Ganglion Cells ◽  
Ischemia Reperfusion ◽  
Fasting Blood Glucose ◽  
Kynurenine Pathway ◽  
Retinal Ganglion ◽  
Diabetic Mice ◽  
Wild Type ◽  
Ganglion Cell Death

Background: Glaucoma is an optic neuropathy and involves the progressive degeneration of retinal ganglion cells (RGCs), which leads to blindness in patients. We investigated the role of the neuroprotective kynurenic acid (KYNA) in RGC death against retinal ischemia/reperfusion (I/R) injury. Methods: We injected KYNA intravenously or intravitreally to mice. We generated a knockout mouse strain of kynurenine 3-monooxygenase (KMO), an enzyme in the kynurenine pathway that produces neurotoxic 3-hydroxykynurenine. To test the effect of mild hyperglycemia on RGC protection, we used streptozotocin (STZ) induced diabetic mice. Retinal I/R injury was induced by increasing intraocular pressure for 60 min followed by reperfusion and RGC numbers were counted in the retinal flat mounts. Results: Intravenous or intravitreal administration of KYNA protected RGCs against I/R injury. The I/R injury caused a greater loss of RGCs in wild type than in KMO knockout mice. KMO knockout mice had mildly higher levels of fasting blood glucose than wild type mice. Diabetic mice showed significantly lower loss of RGCs when compared with non-diabetic mice subjected to I/R injury. Conclusion: Together, our study suggests that the absence of KMO protects RGCs against I/R injury, through mechanisms that likely involve higher levels of KYNA and glucose.

Interaction between Warfarin and Trazodone

2000 ◽  
Vol 34 (6) ◽  
pp. 734-736 ◽  
Author(s):  
Nancy L Small ◽  
Kathy A Giamonna
Keyword(s):  
Chart Review ◽  
Retrospective Chart Review ◽  
International Normalized Ratio ◽  
Potential Interaction ◽  
Case Summary ◽  
Subsequent Decrease ◽  
Clinically Significant ◽  
Few Data ◽  
Time To Onset ◽  
Potentially Clinically Significant

BACKGROUND: It is well known that there are many drug interactions involving warfarin. However, few data have been supplied to guide clinicians concerning the interaction between trazodone and warfarin. CASE SUMMARY: Three clinically significant cases of suspected trazodone and warfarin interactions were identified in a retrospective chart review based on changes in the prothrombin time (PT) and international normalized ratio (INR) that were not explained by other factors. In each of the cases, the INR changed by ≥1.0 after the initiation or discontinuation of trazodone. In the patients who started trazodone, a subsequent decrease in the PT and INR resulted; conversely, the PT and INR increased in the patient who stopped trazodone therapy. Although none of the patients experienced adverse effects due to the marked changes in PT and INR, the warfarin dosages had to be adjusted accordingly on initiation and discontinuation of trazodone. DISCUSSION: These cases show that there is a potentially clinically significant interaction between trazodone and warfarin. The time to onset of the interaction is variable; the mechanism behind it is not known, but it may involve substrate or protein-binding competition. CONCLUSIONS: The use of trazodone on an as-needed basis for sleep is strongly discouraged in patients who are receiving warfarin, due to the difficulty of achieving a therapeutic PT and INR. Until more is known, patients and clinicians should be educated about this potential interaction and monitor for changes in the anticoagulant effects when trazodone is initiated or stopped.

scholarly journals Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

2016 ◽  
Vol 113 (19) ◽  
pp. 5435-5440 ◽  
Author(s):  
Carlo Breda ◽  
Korrapati V. Sathyasaikumar ◽  
Shama Sograte Idrissi ◽  
Francesca M. Notarangelo ◽  
Jasper G. Estranero ◽  
...  
Keyword(s):  
Quinolinic Acid ◽  
Neurodegenerative Disorders ◽  
Kynurenic Acid ◽  
Therapeutic Potential ◽  
Fruit Fly ◽  
Kynurenine Pathway ◽  
Locomotor Performance ◽  
Potential Treatment ◽  
Regulatory Enzymes ◽  
Therapeutic Benefits

Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway—kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP—the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington’s disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer’s and Parkinson’s disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits.

scholarly journals Beyond Susceptible and Resistant, Part III: Treatment of Infections due to Gram-Negative Organisms Producing Carbapenemases

2016 ◽  
Vol 21 (2) ◽  
pp. 110-119 ◽  
Author(s):  
Navaneeth Narayanan ◽  
Linda Johnson ◽  
Conan MacDougall
Keyword(s):  
Antimicrobial Agents ◽  
Treatment Options ◽  
Resistance Mechanisms ◽  
Beta Lactam ◽  
Treatment Regimens ◽  
Healthcare Settings ◽  
Gram Negative Organisms ◽  
Few Data ◽  
Almost All

Carbapenemases are enzymes that are capable of inactivating all or almost all beta-lactam antimicrobial agents. These enzymes are frequently coexpressed with other resistance mechanisms to non–beta-lactams, leading to extremely drug-resistant pathogens. Once a curiosity, these enzymes have spread into organisms that are among the most common causes of infection, such as Klebsiella pneumoniae and Escherichia coli. Identification of these organisms has proved challenging for clinical microbiology laboratories, leading to revisions in susceptibility standards for carbapenems. Although currently a rare cause of infection in children, these carbapenem-resistant Enterobacteriaceae (CRE) are becoming endemic in a variety of healthcare settings. Management of infections due to CRE is complicated by a lack of effective treatment options and clinical data on their effectiveness. Treatment of CRE infections in children is particularly challenging because therapeutic options for CRE lack adequate data on dosing and safety in children. Use of unconventional combination treatment regimens, including agents to which the organism is resistant in vitro, may provide some benefit in the treatment of severe CRE infection. Fortunately, several agents with the potential for treatment of CRE infections have been recently approved or are in late clinical development, although few data will be available in the short term to inform use in children.

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