Kynurenine pathway in Parkinson's disease-An update.
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ABSTRACT:
SUBMITTER: Venkatesan D
PROVIDER: S-EPMC7585940 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
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Kynurenine pathway in Parkinson's disease-An update.
Venkatesan Dhivya D Iyer Mahalaxmi M Narayanasamy Arul A Siva Kamalakannan K Vellingiri Balachandar B
eNeurologicalSci 20200910
Parkinson's disease (PD) is a complex multi-factorial neurodegenerative disorder where various altered metabolic pathways contribute to the progression of the disease. Tryptophan (TRP) is a major precursor in kynurenine pathway (KP) and it has been discussed in various <i>in vitro</i> studies that the metabolites quinolinic acid (QUIN) causes neurotoxicity and kynurenic acid (KYNA) acts as neuroprotectant respectively. More studies are also focused on the effects of other KP metabolites and its ...[more]
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Project description:The kynurenine (Kyn) pathway, which regulates neuroinflammation and N-methyl-d-aspartate receptor activation, is implicated in Parkinson's disease (PD) and Alzheimer's disease (AD). Age-related changes in Kyn metabolism and altered cerebral Kyn uptake along large neutral amino acid transporters, could contribute to these diseases. To gain further insight into the role and prognostic potential of the Kyn pathway in PD and AD, we investigated systemic and cerebral Kyn metabolite production and estimations of their transporter-mediated uptake in the brain. Kyn metabolites and large neutral amino acids were retrospectively measured in serum and cerebrospinal fluid (CSF) of clinically well-characterized PD patients (n = 33), AD patients (n = 33), and age-matched controls (n = 39) using solid-phase extraction-liquid chromatographic-tandem mass spectrometry. Aging was disease independently associated with increased Kyn, kynurenic acid and quinolinic acid in serum and CSF. Concentrations of kynurenic acid were reduced in CSF of PD and AD patients (p = 0.001; p = 0.002) but estimations of Kyn brain uptake did not differ between diseased and controls. Furthermore, serum Kyn and quinolinic acid levels strongly correlated with their respective content in CSF and Kyn in serum negatively correlated with AD disease severity (p = 0.002). Kyn metabolites accumulated with aging in serum and CSF similarly in PD patients, AD patients, and control subjects. In contrast, kynurenic acid was strongly reduced in CSF of PD and AD patients. Differential transporter-mediated Kyn uptake is unlikely to majorly contribute to these cerebral Kyn pathway disturbances. We hypothesize that the combination of age- and disease-specific changes in cerebral Kyn pathway activity could contribute to reduced neurogenesis and increased excitotoxicity in neurodegenerative disease.
| S-EPMC6899862 | biostudies-literature
Project description:Background. There is substantial evidence that the kynurenine pathway (KP) plays a role in the normal physiology of the brain and is involved in the pathology of neurodegenerative disorders such as Huntington's disease and Parkinson's disease (PD). Objective. We set out to investigate the potential roles in PD of single nucleotide polymorphisms (SNPs) from one of the key enzymes of the KP, kynurenine 3-monooxygenase (KMO). Methods. 105 unrelated, clinically definitive PD patients and 131 healthy controls were enrolled to investigate the possible effects of the different alleles of KMO. Fluorescently labeled TaqMan probes were used for allele discrimination. Results. None of the four investigated SNPs proved to be associated with PD or influenced the age at onset of the disease. Conclusions. The genetic link between the KP and PD is still missing. The investigated SNPs presumably do not appear to influence the function of KMO and probably do not contain binding sites for regulatory proteins of relevance in PD. This is the first study to assess the genetic background behind the biochemical alterations of the kynurenine pathway in PD, directing the attention to this previously unexamined field.
| S-EPMC4346699 | biostudies-literature
Project description:BackgroundTryptophan (TRP) is an essential amino acid that must be provided in the diet. The kynurenine pathway (KP) is the main route of TRP catabolism into nicotinamide adenosine dinucleotide (NAD+), and metabolites of this pathway may have protective or degenerative effects on the nervous system. Thus, the KP may be involved in neurodegenerative diseases.ObjectivesThe purpose of this systematic review and meta-analysis is to assess the changes in KP metabolites such as TRP, kynurenine (KYN), kynurenic acid (KYNA), Anthranilic acid (AA), 3-hydroxykynurenine (3-HK), 5-Hydroxyindoleacetic acid (5-HIAA), and 3-Hydroxyanthranilic acid (3-HANA) in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) patients compared to the control group.MethodsWe conducted a literature search using PubMed/Medline, Scopus, Google Scholar, Web of Science, and EMBASE electronic databases to find articles published up to 2022. Studies measuring TRP, KYN, KYNA, AA, 3-HK, 5-HIAA, 3-HANA in AD, PD, or HD patients and controls were identified. Standardized mean differences (SMDs) were used to determine the differences in the levels of the KP metabolites between the two groups.ResultsA total of 30 studies compromising 689 patients and 774 controls were included in our meta-analysis. Our results showed that the blood levels of TRP was significantly lower in the AD (SMD=-0.68, 95% CI=-0.97 to -0.40, p=0.000, I2 = 41.8%, k=8, n=382), PD (SMD=-0.77, 95% CI=-1.24 to -0.30, p=0.001, I2 = 74.9%, k=4, n=352), and HD (SMD=-0.90, 95% CI=-1.71 to -0.10, p=0.028, I2 = 91.0%, k=5, n=369) patients compared to the controls. Moreover, the CSF levels of 3-HK in AD patients (p=0.020) and the blood levels of KYN in HD patients (p=0.020) were lower compared with controls.ConclusionOverall, the findings of this meta-analysis support the hypothesis that the alterations in the KP may be involved in the pathogenesis of AD, PD, and HD. However, additional research is needed to show whether other KP metabolites also vary in AD, PD, and HD patients. So, the metabolites of KP can be used for better diagnosing these diseases.
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Project description:The current mainstay treatment of Parkinson's disease (PD) consists of dopamine replacement therapy which, in addition to causing several side effects, does not delay disease progression. The field of gene therapy offers a potential means to improve current therapy. The present review gives an update of the present status of gene therapy for PD. Both non-disease and disease modifying transgenes have been tested for PD gene therapy in animal and human studies. Non-disease modifying treatments targeting dopamine or GABA synthesis have been successful and promising at improving PD symptomatology in randomized clinical studies, but substantial testing remains before these can be implemented in the standard clinical treatment repertoire. As for disease modifying targets that theoretically offer the possibility of slowing the progression of disease, several neurotrophic factors show encouraging results in preclinical models (e.g., neurturin, GDNF, BDNF, CDNF, VEGF-A). However, so far, clinical trials have only tested neurturin, and, unfortunately, no trial has been able to meet its primary endpoint. Future clinical trials with neurotrophic factors clearly deserve to be conducted, considering the still enticing goal of actually slowing the disease process of PD. As alternative types of gene therapy, opto- and chemogenetics might also find future use in PD treatment and novel genome-editing technology could also potentially be applied as individualized gene therapy for genetic types of PD.
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Project description:Deep brain stimulation (DBS) is considered a safe and well tolerated surgical procedure to alleviate Parkinson's disease (PD) and other movement disorders symptoms along with some psychiatric conditions. Over the last few decades DBS has been shown to provide remarkable therapeutic effect on carefully selected patients. Although its precise mechanism of action is still unknown, DBS improves motor functions and therefore quality of life. To date, two main targets have emerged in PD patients: the globus pallidus pars interna and the subthalamic nucleus. Two other targets, the ventralis intermedius and zona incerta have also been selectively used, especially in tremor-dominant PD patients. The main indications for PD DBS have traditionally been motor fluctuations, debilitating medication induced dyskinesias, unpredictable "off time" state, and medication refractory tremor. Medication refractory tremor and intolerable dyskinesia are potential palliative indications. Besides aforementioned targets, the brainstem pedunculopontine nucleus (PPN) is under investigation for the treatment of ON-state freezing of gait and postural instability. In this article, we will review the most recent literature on DBS therapy for PD, including cutting-edge advances and data supporting the role of DBS in advanced neural-network modulation.
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Project description:Under normal physiological conditions, the kynurenine pathway (KP) plays a critical role in generating cellular energy and catabolizing tryptophan. Under inflammatory conditions, however, there is an upregulation of the KP enzymes, particularly kynurenine 3-monooxygenase (KMO). KMO has garnered much attention due to its production of toxic metabolites that have been implicated in many diseases and disorders. With many of these illnesses having an inadequate or modest treatment, there exists a need to develop KMO inhibitors that reduce the production of these toxic metabolites. Though prior efforts to find an appropriate KMO inhibitor were unpromising, the development of a KMO crystal structure has provided the opportunity for a rational structure-based design in the development of inhibitors. Therefore, the purpose of this review is to describe the kynurenine pathway, the kynurenine 3-monooxygenase enzyme, and KMO inhibitors and their potential candidacy for clinical use.
| S-EPMC8747024 | biostudies-literature
Project description:Progressive degeneration of neurons and aggravation of dopaminergic neurons in the substantia nigra pars compacta results in the loss of dopamine in the brain of Parkinson's disease (PD) patients. Numerous therapies, exhibiting transient efficacy have been developed; however, they are mostly accompanied by side effects and limited reliability, therefore instigating the need to develop novel optimistic treatment targets. Significant therapeutic targets have been identified, namely: chaperones, protein Abelson, glucocerebrosidase-1, calcium, neuromelanin, ubiquitin-proteasome system, neuroinflammation, mitochondrial dysfunction, and the kynurenine pathway (KP). The role of KP and its metabolites and enzymes in PD, namely quinolinic acid (QUIN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranillic acid (3-HAA), kunurenine-3-monooxygenase (KMO), etc. has been reported. The neurotoxic QUIN, N-methyl-D-aspartate (NMDA) receptor agonist, and neuroprotective KYNA-which antagonizes QUIN actions-primarily justify the Janus-faced role of KP in PD. Moreover, KP has been reported to play a biomarker role in PD detection. Therefore, the authors detail the neurotoxic, neuroprotective, and immunomodulatory neuroactive components, alongside the upstream and downstream metabolic pathways of KP, forming a basis for a therapeutic paradigm of the disease while recognizing KP as a potential biomarker in PD, thus facilitating the development of a suitable target in PD management.
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Project description:BackgroundThe kynurenine pathway (KP) is the major catabolic pathway for tryptophan degradation. The KP plays an important role as the sole de novo nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in normal human physiology and functions as a counter-regulatory mechanism to mitigate immune responses during inflammation. Although the KP has been implicated in a variety of disorders including Huntington's disease, seizures, cardiovascular disease, and osteoporosis, its role in renal diseases is seldom discussed.SummaryThis review summarizes the roles of the KP and its metabolites in acute kidney injury (AKI) and chronic kidney disease (CKD) based on current literature evidence. Metabolomics studies demonstrated that the KP metabolites were significantly altered in patients and animal models with AKI or CKD. The diagnostic and prognostic values of the KP metabolites in AKI and CKD were highlighted in cross-sectional and longitudinal human observational studies. The biological impact of the KP on the pathophysiology of AKI and CKD has been studied in experimental models of different etiologies. In particular, the activation of the KP was found to confer protection in animal models of glomerulonephritis, and its immunomodulatory mechanism may involve the regulation of T cell subsets such as Th17 and regulatory T cells. Manipulation of the KP to increase NAD+ production or diversion toward specific KP metabolites was also found to be beneficial in animal models of AKI. Key Messages: KP metabolites are reported to be dysregulated in human observational and animal experimental studies of AKI and CKD. In AKI, the magnitude and direction of changes in the KP depend on the etiology of the damage. In CKD, KP metabolites are altered with the onset and progression of CKD all the way to advanced stages of the disease, including uremia and its related vascular complications. The activation of the KP and diversion to specific sub-branches are currently being explored as therapeutic strategies in these diseases, especially with regards to the immunomodulatory effects of certain KP metabolites. Further elucidation of the KP may hold promise for the development of biomarkers and targeted therapies for these kidney diseases.
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Project description:BackgroundIt is known that inflammatory responses play an important role in the pathophysiology of COVID-19.AimsIn this study, we aimed to examine the role of kynurenine (KYN) metabolism on the severity of COVID-19 disease AQ5.Materials & methodsSeventy COVID-19 patients of varying severity and 30 controls were included in the study. In addition to the classical laboratory parameters, KYN, tryptophan (TRP), kynurenic acid (KYNA), 3 hydroxykynurenine (3OHKYN), quinolinic acid (QA), and picolinic acid (PA) were measured with mass spectrometry.ResultsTRP, KYN, KYN:TRP ratio, KYNA, 3OHKYN, PA, and QA results were found to be significantly different in COVID-19 patients (p < 0.001 for all). The KYN:TRP ratio and PA of severe COVID-19 patients was statistically higher than that of mild-moderate COVID-19 patients (p < 0.001 for all). When results were examined, statistically significant correlations with KYN:TRP ratio, IL-6, ferritin, and procalcitonin were only found in COVID-19 patients. ROC analysis indicated that highest AUC values were obtained by KYN:TRP ratio and PA (0.751 vs 0.742). In determining the severity of COVID-19 disease, the odd ratios (and confidence intervals) of KYN:TRP ratio and PA levels that were adjusted according to age, gender, and comorbidity were determined to be 1.44 (1.1-1.87, p = 0.008) and 1.06 (1.02-1.11, p = 0.006), respectively.Discussion & conclusionAccording to the results of this study, KYN metabolites play a role in the pathophysiology of COVID-19, especially KYN:TRP ratio and PA could be markers for identification of severe COVID-19 cases.
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Project description:Management of Parkinson's disease (PD) is complicated due to its progressive nature, the individual patient heterogeneity, and the wide range of signs, symptoms, and daily activities that are increasingly affected over its course. The last 10-15 years have seen great progress in the identification, evaluation, and management of PD, particularly in the advanced stages. Highly specialized information can be found in the scientific literature, but updates do not always reach general neurologists in a practical and useful way, potentially creating gaps in knowledge of PD between them and neurologists subspecialized in movement disorders, resulting in several unmet patient needs. However, general neurologists remain instrumental in diagnosis and routine management of PD. This review provides updated practical information to identify problems and resolve common issues, particularly when the advanced stage is suspected. Some tips are provided for efficient communication with the members of a healthcare team specialized in movement disorders, in order to find support at any stage of the disease in a given patient, and especially for a well-timed decision on referral.
| S-EPMC7136815 | biostudies-literature