DOCSLIB.ORG

The Causative Role and Therapeutic Potential of the Kynurenine Pathway in Neurodegenerative Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Causative Role and Therapeutic Potential of the Kynurenine Pathway in Neurodegenerative Disease J Mol Med (2013) 91:705–713 DOI 10.1007/s00109-013-1046-9 REVIEW The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease Marta Amaral & Tiago F. Outeiro & Nigel S. Scrutton & Flaviano Giorgini Received: 14 January 2013 /Revised: 11 April 2013 /Accepted: 17 April 2013 /Published online: 1 May 2013 # Springer-Verlag Berlin Heidelberg 2013 Abstract Metabolites of the kynurenine pathway (KP), inhibitors which may ultimately expedite clinical applica- which arise from the degradation of tryptophan, have been tion of these compounds. studied in detail for over a century and garnered the interest of the neuroscience community in the late 1970s and early Keywords Kynurenine 3-monooxygenase . 1980s with work uncovering the neuromodulatory potential Kynurenine pathway . Neurodegenerative disease of this pathway. Much research in the following decades has found that perturbations in the levels of KP metabolites likely contribute to the pathogenesis of several neurodegen- The kynurenine pathway erative diseases. More recently, it has become apparent that targeting KP enzymes, in particular kynurenine 3- The kynurenine pathway (KP) degrades >95 % of tryptophan in monooxygenase (KMO), may hold substantial therapeutic mammals by a series of enzymatic reactions that ultimately leads potential for these disorders. Here we provide an overview to the formation of the cofactor nicotinamide adenosine dinu- of the KP, the neuroactive properties of KP metabolites and cleotide (NAD+). The metabolites formed during this cascade their role in neurodegeneration. We also discuss KMO as a include a subset which are neuroactive or have the capacity to therapeutic target for these disorders, and our recent resolu- generate free radicals. The initial step in the KP is the oxidative tion of the crystallographic structure of KMO, which will cleavage of the indole-ring present in L-tryptophan yielding N- permit the development of new and improved KMO formylkynurenine, which in the brain is catalyzed by either indoleamine-2,3-dioxygenase-1 (IDO1), indoleamine-2,3- dioxygenase-2 (IDO-2), or tryptophan 2,3-dioxygenase M. Amaral : F. Giorgini (*) (TDO2), followed by the synthesis of the first stable intermedi- Department of Genetics, University of Leicester, ate L-kynurenine (L-KYN) [1, 2](Fig.1). Subsequently, L- Leicester LE1 7RH, UK KYN is metabolized via three different routes. In the first, L- e-mail: [email protected] KYN is deaminated to form the neuroactive metabolite M. Amaral : N. S. Scrutton kynurenic acid (KYNA) by the kynurenine aminotransferase Manchester Institute of Biotechnology, (KAT) family of enzymes, four of which can catalyze this The University of Manchester, 131 Princess Street, reaction in mammalian brains [3]. In the second route, the same Manchester M1 7DN, UK substrate is degraded to anthranilic acid by kynureninase. And in M. Amaral : T. F. Outeiro the third route, L-KYN is hydroxylated by kynurenine 3- Cell and Molecular Neuroscience Unit, monooxygenase (KMO) into the free radical generator 3- Instituto de Medicina Molecular, Lisboa, Portugal hydroxykynurenine (3-HK). 3-HK is metabolized further into a second free radical generator, 3-hydroxyanthranilic acid (3- M. Amaral : T. F. Outeiro Instituto de Fisiologia, Faculdade de Medicina da Universidade de HANA), by kynureninase and then oxidized into 2-amino-3- Lisboa, Lisboa, Portugal carboxymuconic 6-semialdehyde by 3-hydroxyanthranilate 3,4- dioxygenase. This intermediate then undergoes non-enzymatic T. F. Outeiro cyclization yielding the excitotoxic metabolite quinolinic acid Department of Neurodegeneration and Restorative Research, University Medical Center Goettingen, Waldweg 33, (QUIN), which is subsequently transaminated to generate nico- 37073 Goettingen, Germany tinic acid, and ultimately the final KP product NAD+ [4]. 706 J Mol Med (2013) 91:705–713 Fig. 1 Schematic overview of the kynurenine pathway, the major route of tryptophan degradation in higher eukaryotes. Enzymes are indicated in italics. The neurotoxic metabolites QUIN and 3-HK are highlighted in red and the neuroprotective metabolite KYNA in green The role of kynurenine metabolites in health and disease modulate T cells by suppressing their proliferation and in- ducing apoptosis, thereby mediating immune tolerance [7]. The physiological role of the KP was initially thought to be Of particular importance in the latter process is IDO, which limited to the formation of the coenzyme NAD+, which is has been found to promote immune tolerance to foreign involved in several biological processes such as redox re- antigens in cases of over-activation of the immune system, actions essential for mitochondrial function and energy me- preventing tissue damage [8, 9]. However, this immune tabolism [5]. Subsequent studies have established that the suppression can also result in the inability of the immune metabolites produced by this biosynthetic pathway—known system to prevent tumor growth and survival. Indeed, IDO as kynurenines—play a variety of roles in the peripheral has been shown to be overexpressed in tumors [10, 11]. immune system and the central nervous system. Recent studies have also found a correlation between IDO Kynurenines are involved in peripheral immunomodulation activity and aryl hydrocarbon receptor (AHR) activation by which inhibits growth of intracellular pathogens, the main- the endogenous ligand L-KYN, which appears to be impor- tenance of maternal immune tolerance which prevents em- tant in promoting generation of regulator T cells and there- bryo rejection, and immune surveillance [6]. KP metabolites fore suppressing self-reactive cells and immune responses J Mol Med (2013) 91:705–713 707 [12, 13]. IDO inhibitors have been shown to significantly structures of KATs from different organisms [29–31]. The promote tumoral immune rejection and increase the efficien- level of KYNA is reduced in several neurodegenerative dis- cy of chemotherapeutic agents [14, 15]. Complementary eases such as Huntington’s disease (HD) and Alzheimer’s recent work also suggests that TDO activity in tumor cells disease (AD) [32], which likely plays an important role in constitutively generates L-KYN, which in turn serves as a modulating neurotoxicity. Two additional KP metabolites ligand for the AHR, thereby suppressing antitumor immune have been implicated in neurodegeneration: 3-HK and 3- responses and promoting tumor cell survival [16]. HANA. These tryptophan metabolites are neurotoxic because In addition, KP metabolites play important roles in they induce the formation of free radicals and elevate the the central nervous system in both normal physiology oxidative stress level causing neuronal death [33, 34]. 3-HK and disease states. These metabolites were first linked and 3-HANA also stimulate the formation of chemokines by with neurological conditions in 1978 when the stimulant inducing target receptors in astrocytes, thereby potentiating and convulsive effects of kynurenines in the murine brain inflammation [35, 36]. The concentration of these KP brain were described, with a particularly strong effect metabolites are in the range of nanomolar levels in mamma- of QUIN observed in motor excitement [17]. Subse- lian brains but they have been found to be significantly in- quently, it was found that QUIN selectively activates creased in pathological conditions such as HD [37], N-methyl-D-aspartate (NMDA) receptors, which can lead Parkinson’s disease (PD) [38], and human immunodeficiency to excitotoxicity, and that intrastriatal injections of this virus (HIV)-1-associated dementia [39]. Neuronal cell culture metabolite lead to axon-sparing neuronal lesions proxi- studies also provide strong evidence that 3-HK and 3-HANA mal to the site of injection [18, 19]. QUIN has been potentiate cell death with apoptotic features, with cortical and shown to stimulate lipid peroxidation, production of striatal neurons being the most vulnerable to KP metabolites reactive oxygen species, and mitochondrial dysfunction toxicity [33]. Furthermore, 3-HK potentiates QUIN-induced [20, 21]. Studies performed in organotypic cultures of excitotoxicity such that intrastriatal coinjection of both me- rat corticostriatal system indicate that concentrations of tabolites results in substantial neuronal loss, whereas the same QUIN even just slightly higher than physiological con- doses applied individually do not cause neurodegeneration centrations can cause neurodegeneration after a few [40]. Finally, recent work has shown that two additional KP weeks of exposure [22]. Spinal neurons have been metabolites—xanthurenic acid and cinnabarinic acid—are found to be especially sensitive to QUIN variations neuroactive by modulating activity of metabotropic glutamate causing cell death with just nanomolar concentrations receptors, and thus may also play a role in neurodegenerative of this metabolite [23]. processes [41, 42]. At high micromolar concentrations, KYNA is a non- selective NMDA receptor antagonist and can also block ex- citatory neurotransmission of other ionotropic amino acid re- Perturbation of KP metabolites in neurodegeneration ceptors such as kainate and AMPA receptors [4, 24]. KYNA has also been shown to be a ligand for GPR35, an orphan G Alterations in levels of KP metabolites have been implicated protein-coupled receptor [25]. In addition, KYNA is a non- in the pathophysiology of several neurological conditions competitive antagonist of α7-nicotinic acetylcholine receptors such as HD, AD, PD, AIDS-dementia
Load more

Recommended publications
  • Microbiota Alterations in Alzheimer's Disease: Involvement of The
    Neurotoxicity Research (2019) 36:424–436 https://doi.org/10.1007/s12640-019-00057-3 REVIEW ARTICLE Microbiota Alterations in Alzheimer’s Disease: Involvement of the Kynurenine Pathway and Inflammation Michelle L. Garcez1 & Kelly R. Jacobs1 & Gilles J. Guillemin1 Received: 13 December 2018 /Revised: 30 April 2019 /Accepted: 2 May 2019 /Published online: 14 May 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Alzheimer’s disease (AD) is a neurodegenerative disease considered the major cause of dementia in the elderly. The main pathophysiological features of the disease are neuronal loss (mainly cholinergic neurons), glutamatergic excitotoxicity, extracel- lular accumulation of amyloid beta, and intracellular neurofibrillary tangles. However, other pathophysiological features of the disease have emerged including neuroinflammation and dysregulation of the kynurenine pathway (KP). The intestinal microbiota is a large and diverse collection of microorganisms that play a crucial role in regulating host health. Recently, studies have highlighted that changes in intestinal microbiota contribute to brain dysfunction in various neurological diseases including AD. Studies suggest that microbiota compositions are altered in AD patients and animal models and that these changes may increase intestinal permeability and induce inflammation. Considering that microbiota can modulate the kynurenine pathway and in turn neuroinflammation, the gut microbiome may be a valuable target for the development of new disease-modifying therapies. The present review aims to link the interactions between AD, microbiota, and the KP. Keywords Alzheimer’sdisease . Microbiota . Probiotics . Inflammation . Kynurenine pathway Alzheimer’sDisease However, in sporadic late-onset AD (LOAD), which accounts for over 90% of AD cases, apolipoprotein E (APOE) gene poly- Alzheimer’s disease (AD) is a chronic neurodegenerative dis- morphisms are the only known genetic risk factor consistently ease that causes progressive loss of brain functions resulting in identified (Yu et al.
    [Show full text]
  • Kynurenine Metabolism and Inflammation-Induced Depressed Mood: a Human Experimental Study
    UCLA UCLA Previously Published Works Title Kynurenine metabolism and inflammation-induced depressed mood: A human experimental study. Permalink https://escholarship.org/uc/item/9s30n2hp Authors Kruse, Jennifer L Cho, Joshua Hyong-Jin Olmstead, Richard et al. Publication Date 2019-11-01 DOI 10.1016/j.psyneuen.2019.104371 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Psychoneuroendocrinology 109 (2019) 104371 Contents lists available at ScienceDirect Psychoneuroendocrinology journal homepage: www.elsevier.com/locate/psyneuen Kynurenine metabolism and inflammation-induced depressed mood: A human experimental study T ⁎ Jennifer L. Krusea,b,1, Joshua Hyong-Jin Choa,b, ,1, Richard Olmsteada,b, Lin Hwangb,c, Kym Faullb,c, Naomi I. Eisenbergera,d, Michael R. Irwina,b a Cousins Center for Psychoneuroimmunology, University of California Los Angeles, United States b Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, United States c Pasarow Mass Spectrometry Laboratory, University of California Los Angeles, United States d Department of Psychology, University of California Los Angeles, United States ARTICLE INFO ABSTRACT Keywords: Inflammation has an important physiological influence on mood and behavior. Kynurenine metabolism is hy- Kynurenine metabolism pothesized to be a pathway linking inflammation and depressed mood, in part through the impact of kynurenine Inflammation metabolites on glutamate neurotransmission in the central nervous system. This study evaluated whether the Depression circulating concentrations of kynurenine and related compounds change acutely in response to an inflammatory Sex differences challenge (endotoxin administration) in a human model of inflammation-induced depressed mood, and whether Experimental design such metabolite changes relate to mood change.
    [Show full text]
  • Dysregulation of Kynurenine Metabolism Is Related to Proinflammatory Cytokines, Attention, and Prefrontal Cortex Volume in Schizophrenia
    Molecular Psychiatry https://doi.org/10.1038/s41380-019-0401-9 ARTICLE Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia 1,2,3 4 1,2,5 2,5 6,7,8 Jochen Kindler ● Chai K. Lim ● Cynthia Shannon Weickert ● Danny Boerrigter ● Cherrie Galletly ● 6,8 4 9 1,2 1,10 Dennis Liu ● Kelly R. Jacobs ● Ryan Balzan ● Jason Bruggemann ● Maryanne O’Donnell ● 1,2,5 4 1,2,5 Rhoshel Lenroot ● Gilles J. Guillemin ● Thomas W. Weickert Received: 5 October 2017 / Revised: 22 February 2019 / Accepted: 5 March 2019 © The Author(s) 2019. This article is published with open access Abstract The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated 1234567890();,: 1234567890();,: with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup.
    [Show full text]
  • Resistant Depressed Patients
    Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment- resistant depressed patients The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Schwieler, Lilly, Martin Samuelsson, Mark A. Frye, Maria Bhat, Ina Schuppe-Koistinen, Oscar Jungholm, Anette G. Johansson, Mikael Landén, Carl M. Sellgren, and Sophie Erhardt. 2016. “Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment-resistant depressed patients.” Journal of Neuroinflammation 13 (1): 51. doi:10.1186/ s12974-016-0517-7. http://dx.doi.org/10.1186/s12974-016-0517-7. Published Version doi:10.1186/s12974-016-0517-7 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:26318660 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Schwieler et al. Journal of Neuroinflammation (2016) 13:51 DOI 10.1186/s12974-016-0517-7 RESEARCH Open Access Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment-resistant depressed patients Lilly Schwieler1*, Martin Samuelsson1,2, Mark A. Frye3, Maria Bhat4,5, Ina Schuppe-Koistinen1,6, Oscar Jungholm1, Anette G. Johansson5, Mikael Landén7,8, Carl M. Sellgren1,9,10 and Sophie Erhardt1 Abstract Background: Neuroinflammation is increasingly recognized as contributing to the pathogenesis of depression. Key inflammatory markers as well as kynurenic acid (KYNA) and quinolinic acid (QUIN), both tryptophan metabolites, have been associated with depressive symptoms and suicidality.
    [Show full text]
  • Alterations in Serum Kynurenine Pathway Metabolites In
    www.nature.com/scientificreports OPEN Alterations in serum kynurenine pathway metabolites in individuals with high neocortical amyloid-β Received: 21 February 2018 Accepted: 24 April 2018 load: A pilot study Published: xx xx xxxx Pratishtha Chatterjee1,2, Kathryn Goozee 1,2,3,4,5,7, Chai K. Lim1, Ian James8, Kaikai Shen9, Kelly R. Jacobs1, Hamid R. Sohrabi1,2,5,6, Tejal Shah1,2,6, Prita R. Asih3,10, Preeti Dave1,4, Candice ManYan4, Kevin Taddei2,6, David B. Lovejoy1, Roger Chung1, Gilles J. Guillemin 1 & Ralph N. Martins1,2,3,5,6,7 The kynurenine pathway (KP) is dysregulated in neuroinfammatory diseases including Alzheimer’s disease (AD), however has not been investigated in preclinical AD characterized by high neocortical amyloid-β load (NAL), prior to cognitive impairment. Serum KP metabolites were measured in the cognitively normal KARVIAH cohort. Participants, aged 65–90 y, were categorised into NAL+ (n = 35) and NAL− (n = 65) using a standard uptake value ratio cut-of = 1.35. Employing linear models adjusting for age and APOEε4, higher kynurenine and anthranilic acid (AA) in NAL+ versus NAL− participants were observed in females (kynurenine, p = 0.004; AA, p = 0.001) but not males (NALxGender, p = 0.001, 0.038, respectively). To evaluate the predictive potential of kynurenine or/and AA for NAL+ in females, logistic regressions with NAL+/− as outcome were carried out. After age and APOEε4 adjustment, kynurenine and AA were individually and jointly signifcant predictors (p = 0.007, 0.005, 0.0004, respectively). Areas under the receiver operating characteristic curves were 0.794 using age and APOEε4 as predictors, and 0.844, 0.866 and 0.871 when kynurenine, AA and both were added.
    [Show full text]
  • Caffeine Protects Against Stress-Induced Murine Depression
    www.nature.com/scientificreports OPEN Cafeine protects against stress‑induced murine depression through activation of PPARγC1α‑mediated restoration of the kynurenine pathway in the skeletal muscle Chongye Fang1,2,8, Shuhei Hayashi2,5,8, Xiaocui Du1,8, Xianbin Cai3,4, Bin Deng6, Hongmei Zheng6, Satoshi Ishido5, Hiroko Tsutsui2,5* & Jun Sheng1,7* Exercise prevents depression through peroxisome proliferator‑activated receptor‑gamma coactivator 1α (PGC‑1α)‑mediated activation of a particular branch of the kynurenine pathway. From kynurenine (KYN), two independent metabolic pathways produce neurofunctionally diferent metabolites, mainly in somatic organs: neurotoxic intermediate metabolites via main pathway and neuroprotective end product, kynurenic acid (KYNA) via the branch. Elevated levels of KYN have been found in patients with depression. Herein, we investigated whether and how cafeine prevents depression, focusing on the kynurenine pathway. Mice exposed to chronic mild stress (CMS) exhibited depressive‑like behaviours with an increase and decrease in plasma levels of pro‑neurotoxic KYN and neuroprotective KYNA, respectively. However, cafeine rescued CMS‑exposed mice from depressive‑like behaviours and restored the plasma levels of KYN and KYNA. Concomitantly, cafeine induced a key enzyme converting KYN into KYNA, namely kynurenine aminotransferase‑1 (KAT1), in murine skeletal muscle. Upon cafeine stimulation murine myotubes exhibited KAT1 induction and its upstream PGC‑1α sustainment. Furthermore, a proteasome inhibitor, but not translational inhibitor, impeded cafeine sustainment of PGC‑1α, suggesting that cafeine induced KAT1 by inhibiting proteasomal degradation of PGC‑1α. Thus, cafeine protection against CMS‑induced depression may be associated with sustainment of PGC‑1α levels and the resultant KAT1 induction in skeletal muscle, and thereby consumption of pro‑neurotoxic KYN.
    [Show full text]
  • Kynurenine Pathway Metabolites in Cerebrospinal Fluid and Blood As Potential Biomarkers in Huntington’S Disease
    medRxiv preprint doi: https://doi.org/10.1101/2020.08.06.20169524; this version posted August 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington’s disease Filipe B Rodrigues1†, Lauren M Byrne1†, Alexander J Lowe1, Rosanna Tortelli1, Mariette Heins2, Gunnar Flik2, Eileanoir B Johnson1, Enrico De Vita3,4, Rachael I Scahill1, Flaviano Giorgini5 and Edward J Wild1* 1 UCL Huntington’s Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK 2 Charles River Laboratories, Groningen, the Netherlands 3 Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, UK 4 Department of Biomedical Engineering, School of Biomedical Engineering and Imaging Sciences, King's College London, UK 5 Department of Genetics and Genome Biology, University of Leicester, Leicester, UK † These authors contributed equally as first authors of this study * Dr Edward J Wild, [email protected], UCL Huntington’s Disease Centre, University College London, 10-12 Russell Square, London WC1B 5EH Running title: Kynurenine pathway in Huntington’s disease NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.1 medRxiv preprint doi: https://doi.org/10.1101/2020.08.06.20169524; this version posted August 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Review Article HIV-Associated Neurotoxicity: the Interplay of Host and Viral Proteins
    Hindawi Mediators of Inflammation Volume 2021, Article ID 1267041, 11 pages https://doi.org/10.1155/2021/1267041 Review Article HIV-Associated Neurotoxicity: The Interplay of Host and Viral Proteins Sushama Jadhav 1,2 and Vijay Nema 1 1Division of Molecular Biology, National AIDS Research Institute (ICMR-NARI), 73, G Block, MIDC, Bhosari, Post Box No. 1895, Pune, 411026 Maharashtra, India 2Symbiosis International University (SIU), Lavale, Mulshi, Pune, 412115 Maharashtra, India Correspondence should be addressed to Vijay Nema; [email protected] Received 15 April 2021; Revised 12 July 2021; Accepted 9 August 2021; Published 25 August 2021 Academic Editor: Nadra Nilsen Copyright © 2021 Sushama Jadhav and Vijay Nema. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. HIV-1 can incite activation of chemokine receptors, inflammatory mediators, and glutamate receptor-mediated excitotoxicity. The mechanisms associated with such immune activation can disrupt neuronal and glial functions. HIV-associated neurocognitive disorder (HAND) is being observed since the beginning of the AIDS epidemic due to a change in the functional integrity of cells from the central nervous system (CNS). Even with the presence of antiretroviral therapy, there is a decline in the functioning of the brain especially movement skills, noticeable swings in mood, and routine performance activities. Under the umbrella of HAND, various symptomatic and asymptomatic conditions are categorized and are on a rise despite the use of newer antiretroviral agents. Due to the use of long-lasting antiretroviral agents, this deadly disease is becoming a manageable chronic condition with the occurrence of asymptomatic neurocognitive impairment (ANI), symptomatic mild neurocognitive disorder, or HIV-associated dementia.
    [Show full text]
  • Behavioral Deficits Are Accompanied by Immunological and Neurochemical Changes in a Mouse Model for Neuropsychiatric Lupus (NP-SLE)
    Int. J. Mol. Sci. 2015, 16, 15150-15171; doi:10.3390/ijms160715150 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Article Behavioral Deficits Are Accompanied by Immunological and Neurochemical Changes in a Mouse Model for Neuropsychiatric Lupus (NP-SLE) Yan Li 1, Amanda R. Eskelund 1,2, Hua Zhou 1, David P. Budac 1, Connie Sánchez 1 and Maria Gulinello 3,* 1 Lundbeck Research USA, Paramus, NJ 07652, USA; E-Mails: [email protected] (Y.L.); [email protected] (H.Z.); [email protected] (D.P.B.); [email protected] (C.S.) 2 Translational Neuropsychiatry Unit, Aarhus University, Risskov DK-8240, Denmark; E-Mail: [email protected] 3 Behavioral Core Facility, Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +718-430-4042; Fax: +718-430-8821. Academic Editor: Chak-Sing Lau Received: 28 April 2015 / Accepted: 24 June 2015 / Published: 3 July 2015 Abstract: Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. Neuropsychiatric symptoms, particularly affective and cognitive indications, may be among the earliest manifestations of SLE. Among the potential pathophysiological mechanisms responsible for NP-SLE are increased peripheral pro-inflammatory cytokines, subsequent induction of indoleamine-2,3-dioxygenase (IDO) and activation of the kynurenine pathway. In the MRL/MpJ-Faslpr (MRL/lpr) murine model of lupus, depression-like behavior and cognitive dysfunction is evident before significant levels of autoantibody titers and nephritis are present.
    [Show full text]
  • Stress-Related Regulation of the Kynurenine Pathway: Relevance to Neuropsychiatric and Degenerative Disorders
    Neuropharmacology xxx (2015) 1e17 Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm Invited review Stress-related regulation of the kynurenine pathway: Relevance to neuropsychiatric and degenerative disorders * Katherine O'Farrell a, Andrew Harkin a, b, a Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland b Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland article info abstract Article history: The kynurenine pathway (KP), which is activated in times of stress and infection has been implicated in Received 15 October 2015 the pathophysiology of neurodegenerative and psychiatric disorders. Activation of this tryptophan Received in revised form metabolising pathway results in the production of neuroactive metabolites which have the potential to 2 December 2015 interfere with normal neuronal functioning which may contribute to altered neuronal transmission and Accepted 8 December 2015 the emergence of symptoms of these brain disorders. This review investigates the involvement of the KP Available online xxx in a range of neurological disorders, examining recent in vitro, in vivo and clinical discoveries highlights evidence to indicate that the KP is a potential therapeutic target in both neurodegenerative and stress- Keywords: fi Stress related neuropsychiatric disorders. Furthermore, this review identi es gaps in our knowledge with re- fi Inflammation gard to this eld which are yet to be examined to lead to a more comprehensive understanding of the Kynurenine pathway role of KP activation in brain health and disease. Neurodegenerative diseases © 2015 Elsevier Ltd. All rights reserved.
    [Show full text]
  • Clinical Relevance of Kynurenine Pathway in HIV/AIDS: an Immune
    AIDS Reviews. 2015;17 Contents available at PubMed www.aidsreviews.com PERMANYER AIDS Rev. 2015;17:96-106 www.permanyer.com Clinical Relevance of Kynurenine Pathway in HIV/AIDS: An Immune Checkpoint at the Crossroads of Metabolism and Inflammation Jean-Pierre Routy1,2,3, Vikram Mehraj1,2, Kishanda Vyboh1,2, Wei Cao1,2, Ido Kema4 and Mohammad-Ali Jenabian5 © Permanyer Publications 2014 1Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada; 2Research Institute, McGill University Health Centre, Montreal, QC, Canada; 3Division of Hematology, McGill University Health Centre, Montreal, QC, Canada; 4Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 5Department of Biological Sciences and Center for Biomedical Research, Université du Québec à Montréal (UQAM), Montreal, QC, Canada Abstract Tryptophan degradation along the kynurenine pathway is associated with a wide variety of pathophysio- logical processes, of which tumor tolerance and immune dysfunction in several chronic viral infections including HIV are well known. The kynurenine pathway is at the crossroads of metabolism and immunity and plays an important role in inflammation while also playing an opposing role in the control of acute and chronic infections. In this review we have summarized findings from recent studies reporting modulation of tryptophan degrading the kynurenine pathway in the context of HIV infection. This immuno-metabolic path- way is modulated by three distinct inducible enzymes: indoleamine 2,3-dioxygenase 1 and 2 and tryptophan 2,3-dioxygenase. Increased expression of these enzymes by antigen-presenting cells leads to local or systemic tryptophan depletion, resulting in a mechanism of defense against certain microorganisms.
    [Show full text]
  • Correlation Between Plasma and CSF Concentrations of Kynurenine Pathway Metabolites in Alzheimer’S Disease and Relationship to Amyloid-Β and Tau
    Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer’s disease and relationship to amyloid-β and tau. Kelly R. Jacobsa, Chai K. Lima, Kaj Blennowb,c, Henrik Zetterbergb,c?, Yb,c?, Pratishtha Chatterjeed,e, Ralph N. Martinsd,e,f,g,h,i, Bruce J. Brewj,k,l, Gilles J. Guillemina* and David B. Lovejoy a* aNeuroinflammation Group, Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia. bDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden. cClinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. Henrik also: UK Dementia Research Institute at University College London, London, United Kingdom Department of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square, London, United Kingdom dDepartment of Biomedical Sciences, Macquarie University, North Ryde, NSW, Australia. eSchool of Medical Health and Sciences, Edith Cowan University, Joondalup, WA, Australia. fKaRa Institute of Neurological Disease, Sydney, Macquarie Park, Australia gSchool of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia hAustralian Alzheimer’s Research Foundation, Nedlands, WA, Australia iThe Cooperative Research Centre for Mental Health, Carlton South, Australia jApplied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent's Centre for Applied Medical ResearchSydney, NSW, Australia. kFaculty of Medicine, St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia. lDepartments of Neurology and Immunology, St. Vincent's Hospital, Sydney, NSW, Australia. *Co-corresponding authors Abstract Chronic kynurenine pathway (KP) activation is implicated in Alzheimer’s disease (AD) pathophysiology and results in quinolinic acid-induced excitotoxic stimulation of the N- methyl-D-aspartate receptor.
    [Show full text]