DOCSLIB.ORG

Magnetic Resonance Imaging of Neuroinflammation in Chronic Pain

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Magnetic Resonance Imaging of Neuroinflammation in Chronic Pain Research Paper Magnetic resonance imaging of neuroinflammation in chronic pain: a role for astrogliosis? Changjin Junga,b, Eric Ichescoc, Eva-Maria Rataia,d, Ramon Gilberto Gonzaleza,d, Tricia Burdoe, Marco L. Loggiaa,d, Richard E. Harrisc, Vitaly Napadowa,d,f,* Abstract Noninvasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton magnetic resonance spectroscopy (1H-MRS) metabolites have been linked with glial activity (ie, choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting functional magnetic resonance imaging connectivity and 1H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (aIns) (P 5 0.03), with greater choline levels linked with worse pain interference (r 5 0.41, P 5 0.01). In addition, reduced resting functional connectivity between aIns and putamen wasassociatedwithbothpaininterference(wholebrainanalysis,pcorrected , 0.01) and elevated aIns choline (r 520.37, P 5 0.03). In fact, aIns/putamen connectivity statistically mediated the link between aIns choline and pain interference (P , 0.01), highlighting the pathway by which neuroinflammation can impact clinical pain dysfunction. To further elucidate the molecular substrates of the effects observed, we investigated how putative neuroinflammatory 1H-MRS metabolites are linked with ex vivo tissue inflammatory markers in a nonhuman primate model of neuroinflammation. Results demonstrated that cortical choline levels were correlated with glial fibrillary acidic protein, a known marker for astrogliosis (Spearman r 5 0.49, P 5 0.03). Choline, aputativeneuroinflammatory1H-MRS-assessed metabolite elevated in fibromyalgia and associated with pain interference, may be linked with astrogliosis in these patients. Keywords: Chronic pain, Pain interference, Fibromyalgia, Neuroinflammation, Astrogliosis 1. Introduction with neuroinflammation,13 choline and myo-inositol, are Prior studies have suggested that magnetic resonance altered in chronic pain patients suffering from fibromyalgia (FM). Brain neuroinflammation has been noted in animal imaging (MRI) methods such as proton magnetic resonance 29 spectroscopy (1H-MRS)3,13 may be promising for noninvasive models of chronic pain, and FM is a chronic centralized evaluation of neuroinflammation. Our aim was to explicitly pain disorder that has recently been shown to display evaluate whether 1H-MRS metabolites previously associated a neuroinflammatory component assessed with more invasive positron emission tomography (PET).2 We further sought to evaluate possible mechanisms by which levels of the above- Sponsorships or competing interests that may be relevant to content are disclosed 1 at the end of this article. mentioned H-MRS metabolites are linked with neuroinflam- mation and contribute to chronic pain pathology. R.E. Harris and V. Napadow contributed equally to this work. Several neuroimaging studies have suggested that neuro- a Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States, b Clinical inflammation, mediated by activation of microglia or astrocytes, is Research Division, Korean Institute of Oriental Medicine, Daejeon, South Korea, pronounced in chronic pain patients. For instance, PET imaging c Department of Anesthesiology, Chronic Pain and Fatigue Research Center, using the glia-linked radioligand [11C] PBR28 demonstrated d University of Michigan, Ann Arbor, MI, United States, Department of Radiology, increased binding for chronic low back pain patients and Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 2,4,31 2 United States, e Department of Neuroscience, Temple University, Philadelphia, FM, with elevated levels linked with fatigue. In contrast to 1 PA, United States, f Department of Anesthesiology, Pain Management Center, PET, H-MRS is a noninvasive neuroimaging technique that has Brigham and Women’s Hospital, Harvard Medical School, Chestnut Hill, MA, suggested neuroinflammation by quantifying levels of metabolites United States such as choline, which shows greater concentration in glial cells *Corresponding author. Address: Center for Integrative Pain Neuroimaging, Martinos than neurons, and has been linked with glial cell membrane Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 13 1 #2301 149 Thirteenth St, Charlestown, MA 02129, United States. Tel.: 11-617-724-3402; turnover. Myo-inositol, another H-MRS metabolite, plays a role fax: 11-617-726-7422. E-mail address: [email protected] (V. Napadow). in regulating glial cell volume and may also be a marker for 13 Supplemental digital content is available for this article. Direct URL citations appear neuroinflammation. Myo-inositol is believed to be an essential in the printed text and are provided in the HTML and PDF versions of this article on requirement for cell growth, an osmolyte, and a storage source of the journal’s Web site (www.painjournalonline.com). glucose.50 Furthermore, this metabolite is thought to serve as PAIN 00 (2020) 1–10 marker of neuroinflammation/gliosis10,46; however, its role as © 2020 International Association for the Study of Pain a glial marker has also been questioned.44 Choline and/or myo- http://dx.doi.org/10.1097/j.pain.0000000000001815 inositol are elevated in the anterior cingulate cortex in spinal cord Month 2020· Volume 00· Number 00 www.painjournalonline.com 1 Copyright © 2020 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. 2 C. Jung et al.·00 (2020) 1–10 PAIN® injury patients with neuropathic pain57 and rheumatoid arthritis usage of all subjects has been included in Supplementary Table 1 patients.18 Choline has also been found to be elevated in the (available at http://links.lww.com/PAIN/A952). anterior cingulate cortex in chronic pelvic pain patients and We enrolled 43 (N 5 43) female FM patients and 16 (N 5 16) associated with higher levels of negative affect.24 However, the health controls (HCs). All subjects were right-handed and there precise role that choline and myo-inositol play in neuroinflamma- was no statistically significant age difference between FM and HC tion and how they are linked with other markers and maladaptive groups (FM: 41.07 6 11.64 years old, HC: 44.94 6 16.29 years brain changes in FM are unknown. old, mean 6 SD; P 5 0.31, 2-sample Student t-test). Twelve In this study, analyses focused on whether purported 1H-MRS patients reported using pregabalin or gabapentin for treatment, markers of neuroinflammation (ie, choline and myo-inositol) are which was controlled for in analyses due to our prior publications linked with functional brain connectivity and clinical variables for demonstrating significant neuroimaging changes within the insula FM. Our prior neuroimaging studies with chronic pain patients after pregabalin treatment.25 demonstrated that anterior insula (aIns) cortex connectivity was increased to the default mode network37 and, specifically, aIns to 2.2. Image acquisition and preprocessing medial prefrontal cortex connectivity was associated with 1H-MRS Glx metabolite concentration and clinical pain intensity in pelvic 2.2.1. Proton magnetic resonance spectroscopy pain patients.7 In a separate study, FM patients’ response to 1H-MRS acquisition was conducted on a 3.0T scanner Philips pharmacotherapy was associated with reduced 1H-MRS Glx Ingenia 3.0T (Philips Healthcare, Best, the Netherlands) using metabolite concentration and insula connectivity to default mode a 15-channel receive head coil. Anatomical T1-weighted images network brain regions.25 Given prior evidence of physiological (Axial 3D-MP-RAGE, repetition time (TR)/echo time (TE) 5 8.2/3.7 disruption in the insula cortex, we assessed 1H-MRS-derived ms, matrix 5 240 3 240, number slices 5 154) were acquired to metabolite levels in both anterior and posterior insula (pIns), and guide region of interest (ROI) definition for 1H-MRS. PRESS single functional connectivity between insula and the rest of the brain. An voxel spectra (TR/TE 5 2000/35 ms) were acquired from a 2 3 2 exploratory analysis evaluated the fractional amplitude of low- 3 3-cm sized voxel covering the right aIns region. A second voxel frequency fluctuations (fALFF) of the resting functional MRI (fMRI) was acquired in the right pIns region. Values for different signal, which has also been associated with neuroinflammation in metabolites were computed from the raw spectra data based chronic pain.6,26 Finally, to better understand the mechanisms on a linear combination of individual spectra using the LCModel supporting altered choline or myo-inositol in neuroinflammation, software42 (Version 6.3; Stephen Provencher, Inc, Oakville, ON, we directly linked levels of these metabolites with tissue pathology Canada). Because our study focused on potential neuroinflam- markers for astrogliosis and microglia activation in a nonhuman mation, analyses evaluated choline and myo-inositol concentra- primate model of widespread viral neuroinflammation.48 tion. For the sake of transparency,
Load more

Recommended publications
  • Neuroinflammation White Paper
    NEUROINFLAMMATION Our understanding of the molecular pathogenesis of neuroinflammation is growing steadily. Progress in different areas of basic research, new animal models, and the generation of specific antibody markers to target essential proteins help to find and improve the treatment of patients with neuroimmunological diseases. In this white paper, we discuss the role of microglia, oligodendrocytes, and astrocytes in the neuroinflammatory processes highlighting the relevant antibody markers with a particular focus on multiple sclerosis. Neuroinflammation broadly defines the collective peripheral blood cells, mainly T-and B-cells, into reactive immune response in the brain and the brain parenchyma 1,2,3. spinal cord in response to injury and disease. Inflammation in the central nervous system Neuroinflammatory processes are the key (CNS) is commonly associated with various causative factors behind brain and spinal cord degrees of tissue damage, such as loss of myelin injury. This is true not only for acute brain and neurons. trauma and hypoxic-ischemic brain damage following stroke, but also for chronic infection The neuroinflammatory process is complex and and neurodegenerative diseases, such as involves disruption of the blood-brain barrier Alzheimer’s disease, amyotrophic lateral (BBB), peripheral leukocyte infiltration, edema, sclerosis (ALS), Lewy body dementia, and and gliosis. The inflammatory response is leukoencephalopathies like multiple sclerosis characterized by a host of cellular and molecular (MS). In addition, local peritumoral inflammation aberrations within the brain. plays a role in the clinical progression and malignancy of glioblastomas, the most aggressive Neuroinflammation arises within the CNS primary brain tumors. through phenotypic changes of different non- neuronal cell types in the brain, such as microglia, Recent studies have revealed unexpected oligodendrocytes, and astrocytes, causing the insights by providing hints of a protective role of release of different cytokines and chemokines, inflammation.
    [Show full text]
  • Neuroinflammation and Functional Connectivity in Alzheimer's Disease: Interactive Influences on Cognitive Performance
    Research Articles: Neurobiology of Disease Neuroinflammation and functional connectivity in Alzheimer's disease: interactive influences on cognitive performance https://doi.org/10.1523/JNEUROSCI.2574-18.2019 Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.2574-18.2019 Received: 5 October 2018 Revised: 25 March 2019 Accepted: 11 April 2019 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2019 Passamonti et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Neuroinflammation and functional connectivity in Alzheimer’s disease: 2 interactive influences on cognitive performance 3 4 L. Passamonti1*, K.A. Tsvetanov1*, P.S. Jones1, W.R. Bevan-Jones2, R. Arnold2, R.J. Borchert1, 5 E. Mak2, L. Su2, J.T. O’Brien2#, J.B. Rowe1,3# 6 7 Joint *first and #last authorship 8 9 10 Authors’ addresses 11 1Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK 12 2Department of Psychiatry, University of Cambridge, Cambridge, UK 13 3Cognition and Brain Sciences Unit, Medical Research Council, Cambridge,
    [Show full text]
  • Investigating the Role of Vascular Activation in Alzheimerâ•Žs Disease-Related Neuroinflammation
    University of Rhode Island DigitalCommons@URI Open Access Dissertations 2020 INVESTIGATING THE ROLE OF VASCULAR ACTIVATION IN ALZHEIMER’S DISEASE-RELATED NEUROINFLAMMATION Jaclyn M. Iannucci University of Rhode Island, [email protected] Follow this and additional works at: https://digitalcommons.uri.edu/oa_diss Recommended Citation Iannucci, Jaclyn M., "INVESTIGATING THE ROLE OF VASCULAR ACTIVATION IN ALZHEIMER’S DISEASE- RELATED NEUROINFLAMMATION" (2020). Open Access Dissertations. Paper 1186. https://digitalcommons.uri.edu/oa_diss/1186 This Dissertation is brought to you for free and open access by DigitalCommons@URI. It has been accepted for inclusion in Open Access Dissertations by an authorized administrator of DigitalCommons@URI. For more information, please contact [email protected]. INVESTIGATING THE ROLE OF VASCULAR ACTIVATION IN ALZHEIMER’S DISEASE-RELATED NEUROINFLAMMATION BY JACLYN M. IANNUCCI A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN INTERDISCIPLINARY NEUROSCIENCE PROGRAM UNIVERSITY OF RHODE ISLAND 2020 DOCTOR OF PHILOSOPHY DISSERTATION OF JACLYN M. IANNUCCI APPROVED: Dissertation Committee: Major Professor Paula Grammas Robert Nelson David Rowley Brenton DeBoef DEAN OF THE GRADUATE SCHOOL UNIVERSITY OF RHODE ISLAND 2020 ABSTRACT Alzheimer’s disease (AD) is the most common form of dementia, affecting 5.8 million people in the United States alone. Currently, there are no disease-modifying treatments for AD, and the cause of the disease is unclear. With the increasing number of cases and the lack of treatment options, AD is a growing public health crisis. As such, there is a push for investigation of novel pathological mediators to inform new therapeutic approaches.
    [Show full text]
  • Can We Treat Neuroinflammation in Alzheimer's Disease?
    International Journal of Molecular Sciences Review Can We Treat Neuroinflammation in Alzheimer’s Disease? Sandra Sánchez-Sarasúa y, Iván Fernández-Pérez y, Verónica Espinosa-Fernández , Ana María Sánchez-Pérez * and Juan Carlos Ledesma * Neurobiotechnology Group, Department of Medicine, Health Science Faculty, Universitat Jaume I, 12071 Castellón, Spain; [email protected] (S.S.-S.); [email protected] (I.F.-P.); [email protected] (V.E.-F.) * Correspondence: [email protected] (A.M.S.-P.); [email protected] (J.C.L.) These authors contributed equally to this work. y Received: 3 November 2020; Accepted: 16 November 2020; Published: 19 November 2020 Abstract: Alzheimer’s disease (AD), considered the most common type of dementia, is characterized by a progressive loss of memory, visuospatial, language and complex cognitive abilities. In addition, patients often show comorbid depression and aggressiveness. Aging is the major factor contributing to AD; however, the initial cause that triggers the disease is yet unknown. Scientific evidence demonstrates that AD, especially the late onset of AD, is not the result of a single event, but rather it appears because of a combination of risk elements with the lack of protective ones. A major risk factor underlying the disease is neuroinflammation, which can be activated by different situations, including chronic pathogenic infections, prolonged stress and metabolic syndrome. Consequently, many therapeutic strategies against AD have been designed to reduce neuro-inflammation, with very promising results improving cognitive function in preclinical models of the disease. The literature is massive; thus, in this review we will revise the translational evidence of these early strategies focusing in anti-diabetic and anti-inflammatory molecules and discuss their therapeutic application in humans.
    [Show full text]
  • Emerging Role of Extracellular Vesicles in the Pathophysiology of Multiple Sclerosis
    International Journal of Molecular Sciences Review Emerging Role of Extracellular Vesicles in the Pathophysiology of Multiple Sclerosis 1, 1, 1,2, 1 Ettore Dolcetti y, Antonio Bruno y , Livia Guadalupi y, Francesca Romana Rizzo , Alessandra Musella 2,3, Antonietta Gentile 2, Francesca De Vito 4, Silvia Caioli 4, Silvia Bullitta 1,2, Diego Fresegna 2, Valentina Vanni 1,2, Sara Balletta 1, Krizia Sanna 1, Fabio Buttari 4, Mario Stampanoni Bassi 4 , Diego Centonze 1,4,* and Georgia Mandolesi 2,3 1 Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; [email protected] (E.D.); [email protected] (A.B.); [email protected] (L.G.); [email protected] (F.R.R.); [email protected] (S.B.); [email protected] (V.V.); [email protected] (S.B.); [email protected] (K.S.) 2 Synaptic Immunopathology Lab, IRCCS San Raffaele Pisana, 00163 Rome, Italy; [email protected] (A.M.); [email protected] (A.G.); [email protected] (D.F.); [email protected] (G.M.) 3 Department of Human Sciences and Quality of Life Promotion, University of Rome San Raffaele, 00163 Rome, Italy 4 Unit of Neurology, IRCCS Neuromed, Pozzilli (Is), 86077 Pozzilli, Italy; [email protected] (F.D.V.); [email protected] (S.C.); [email protected] (F.B.); [email protected] (M.S.B.) * Correspondence: [email protected]; Tel.:+39-06 7259-6010; Fax: +39-06-7259-6006 Co-first authors. y Received: 30 August 2020; Accepted: 1 October 2020; Published: 4 October 2020 Abstract: Extracellular vesicles (EVs) represent a new reality for many physiological and pathological functions as an alternative mode of intercellular communication.
    [Show full text]
  • Markers of Microglia in Post-Mortem Brain Samples from Patients with Alzheimer’S Disease: a Systematic Review
    OPEN Molecular Psychiatry (2018) 23, 177–198 www.nature.com/mp REVIEW Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review KE Hopperton1, D Mohammad1,2, MO Trépanier1, V Giuliano1 and RP Bazinet1 Neuroinflammation is proposed as one of the mechanisms by which Alzheimer’s disease pathology, including amyloid-β plaques, leads to neuronal death and dysfunction. Increases in the expression of markers of microglia, the main neuroinmmune cell, are widely reported in brains from patients with Alzheimer’s disease, but the literature has not yet been systematically reviewed to determine whether this is a consistent pathological feature. A systematic search was conducted in Medline, Embase and PsychINFO for articles published up to 23 February 2017. Papers were included if they quantitatively compared microglia markers in post- mortem brain samples from patients with Alzheimer’s disease and aged controls without neurological disease. A total of 113 relevant articles were identified. Consistent increases in markers related to activation, such as major histocompatibility complex II (36/43 studies) and cluster of differentiation 68 (17/21 studies), were identified relative to nonneurological aged controls, whereas other common markers that stain both resting and activated microglia, such as ionized calcium-binding adaptor molecule 1 (10/20 studies) and cluster of differentiation 11b (2/5 studies), were not consistently elevated. Studies of ionized calcium-binding adaptor molecule 1 that used cell counts almost uniformly identified no difference relative to control, indicating that increases in activation occurred without an expansion of the total number of microglia. White matter and cerebellum appeared to be more resistant to these increases than other brain regions.
    [Show full text]
  • Impact of Microbiota on Central Nervous System and Neurological Diseases: the Gut- Brain Axis Qianquan Ma1,2, Changsheng Xing1, Wenyong Long2, Helen Y
    Ma et al. Journal of Neuroinflammation (2019) 16:53 https://doi.org/10.1186/s12974-019-1434-3 REVIEW Open Access Impact of microbiota on central nervous system and neurological diseases: the gut- brain axis Qianquan Ma1,2, Changsheng Xing1, Wenyong Long2, Helen Y. Wang1, Qing Liu2* and Rong-Fu Wang1,3,4* Abstract Development of central nervous system (CNS) is regulated by both intrinsic and peripheral signals. Previous studies have suggested that environmental factors affect neurological activities under both physiological and pathological conditions. Although there is anatomical separation, emerging evidence has indicated the existence of bidirectional interaction between gut microbiota, i.e., (diverse microorganisms colonizing human intestine), and brain. The cross-talk between gut microbiota and brain may have crucial impact during basic neurogenerative processes, in neurodegenerative disorders and tumors of CNS. In this review, we discuss the biological interplay between gut-brain axis, and further explore how this communication may be dysregulated in neurological diseases. Further, we highlight new insights in modification of gut microbiota composition, which may emerge as a promising therapeutic approach to treat CNS disorders. Keywords: Gut microbiota, Central nervous system, Immune signaling, Neurological disorder, Glioma, Gut-brain axis Introduction The maturation and development of human central Abundant and diverse microbial communities coexist in nervous system (CNS) is regulated by both intrinsic and humans and mice. Majority of these microorganisms extrinsic factors. Studies mostly from germ-free (GF) including bacteria, archaea, fungi, and viruses reside in animals or animals treated with broad-spectrum anti- human gastrointestinal tract, and are collectively biotics show that specific microbiota can impact CNS referred as gut “microbiota” [1].
    [Show full text]
  • Glia As a Link Between Neuroinflammation and Neuropathic Pain
    http://dx.doi.org/10.4110/in.2012.12.2.41 REVIEW ARTICLE pISSN 1598-2629 eISSN 2092-6685 Glia as a Link between Neuroinflammation and Neuropathic Pain Mithilesh Kumar Jha, Sangmin Jeon and Kyoungho Suk* Department of Pharmacology, Brain Science & Engineering Institute, Kyungpook National University School of Medicine, Daegu 700-422, Korea Contemporary studies illustrate that peripheral injuries acti- clude astrocytes and oligodendrocytes (2). Glial cells that vate glial components of the peripheral and central cellular were, up to several years ago, considered the ٘forgotten brain circuitry. The subsequent release of glial stressors or activat- cells,ٙ or neglected stepchildren of neuroscience, now act as ing signals contributes to neuropathic pain and neuroinflam- orchestrators in the tetrapartite synapse, and control of their mation. Recent studies document the importance of glia in activation state is crucial to the integrity of CNS function. the development and persistence of neuropathic pain and Recent technical advances and increased interest in elucidat- neuroinflammation as a connecting link, thereby focusing at- ing the role of non-neuronal cells of the CNS in both the tention on the glial pathology as the general underlying fac- physiological and pathophysiologial processes have cata- tor in essentially all age-related neurodegenerative diseases. There is wide agreement that excessive glial activation is a pulted these cells into the forefront of neuroscience research. key process in nervous system disorders involving the re- Glial cells do not conduct nerve impulses, and they provide lease of strong pro-inflammatory cytokines, which can trig- structural support for the brain, assisting in nervous system ger worsening of multiple disease states.
    [Show full text]
  • Neuroinflammation and Neurodegeneration
    nutrients Editorial Neuroinflammation and Neurodegeneration: The Promising Protective Role of the Citrus Flavanone Hesperetin Egeria Scoditti National Research Council (CNR) Institute of Clinical Physiology (IFC), 73100 Lecce, Italy; [email protected]; Tel.: +39-0832298860 Received: 22 July 2020; Accepted: 31 July 2020; Published: 5 August 2020 Over the past 20 years, there has been a remarkable increase in the scientific interest in polyphenols, bioactive compounds naturally present in plant foods and beverages, due to the recognition of their biological actions, their great abundance in the human diet, and their plausible role in the prevention of various chronic degenerative diseases, such as cancer, cardiovascular and neurodegenerative diseases [1]. Great advancements have been made in understanding the health effects of polyphenols in several pathophysiological settings, their mechanism(s) of action, as well as their bioavailability and metabolism, opening up new opportunities for the food and nutraceutical industry. Over 500 different molecules with a polyphenol structure (i.e., several hydroxyl groups on aromatic rings) with different properties and bioavailabilities have been identified in edible plants, where they are synthetized as secondary metabolites for defense against biotic and abiotic stress. They are divided into five main groups according to structure: phenolic acids, flavonoids, stilbenes, lignans and others. The flavonoid class is further divided into six subclasses, including flavonols, flavones, isoflavones, flavanones, anthocyanidins, and flavanols [2]. Flavonoids are among the most consumed polyphenols: in the European cohort of the PREDIMED (PREvencion con DIeta MEDiterranea) study aimed at assessing the effect of the Mediterranean diet, rich in polyphenols, on the primary prevention of cardiovascular disease, the mean total polyphenol intake was 820 323 mg daily, of which 443 218 mg daily was provided by flavonoids [3], mainly ± ± from fruits, vegetables, alcoholic and non-alcoholic beverages, and cereals.
    [Show full text]
  • Neuroinflammation and the Kynurenine Pathway in CNS
    cells Review Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications Mustafa N. Mithaiwala 1,2 , Danielle Santana-Coelho 1,2, Grace A. Porter 1,2 and Jason C. O’Connor 1,2,3,* 1 Integrated Biomedical Sciences Program, Graduate School of Biomedical Sciences, UT Health San Antonio, San Antonio, TX 78229, USA; [email protected] (M.N.M.); [email protected] (D.S.-C.); [email protected] (G.A.P.) 2 Department of Pharmacology, Long School of Medicine, UT Health San Antonio, Mail Code 8864, San Antonio, TX 78229, USA 3 Department of Research, Audie L. Murphy VA Hospital, South Texas Veterans Heath System, San Antonio, TX 78229, USA * Correspondence: [email protected]; Tel.: +1-(210)-567-4232 Abstract: Diseases of the central nervous system (CNS) remain a significant health, social and eco- nomic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Un- derstanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neu- ropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation Citation: Mithaiwala, M.N.; in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that Santana-Coelho, D.; Porter, G.A.; ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide O’Connor, J.C.
    [Show full text]
  • Neuroinflammation Neurotrophic Cytokines in Autoimmune Demyelination: a New Role for Modulates the Immune Response and Limits Le
    Leukemia Inhibitory Factor Deficiency Modulates the Immune Response and Limits Autoimmune Demyelination: A New Role for Neurotrophic Cytokines in This information is current as Neuroinflammation of September 26, 2021. Ralf A. Linker, Niels Kruse, Stephanie Israel, Tao Wei, Silvia Seubert, Anja Hombach, Bettina Holtmann, Fred Luhder, Richard M. Ransohoff, Michael Sendtner and Ralf Gold Downloaded from J Immunol 2008; 180:2204-2213; ; doi: 10.4049/jimmunol.180.4.2204 http://www.jimmunol.org/content/180/4/2204 http://www.jimmunol.org/ References This article cites 43 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/180/4/2204.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Leukemia Inhibitory Factor Deficiency Modulates the Immune Response and Limits Autoimmune Demyelination: A New Role for Neurotrophic Cytokines in Neuroinflammation1 Ralf A.
    [Show full text]
  • Defining the Contribution of Neuroinflammation to Parkinson's
    Manocha et al. Molecular Neurodegeneration (2017) 12:17 DOI 10.1186/s13024-017-0158-z RESEARCH ARTICLE Open Access Defining the contribution of neuroinflammation to Parkinson’s disease in humanized immune system mice Gunjan Dhawan Manocha1, Angela Marie Floden1, Kendra Lynn Puig1, Kumi Nagamoto-Combs2, Clemens R. Scherzer3 and Colin Kelly Combs1* Abstract Background: Reactive microglia have been associated with the histological changes that occur in Parkinson’sdisease brains and mouse models of the disease. Multiple studies from autopsy brains have verified the presence of microgliosis in several brain regions including substantia nigra, striatum, hippocampus and various cortical areas. MPTP injections in rodents have also shown striato-nigral microgliosis correlating with the loss of dopaminergic neurons. However, consistent data with respect to cytokine and immune cell changes during Parkinson’s disease have not been fully defined. Results: In order to improve understanding of the role of neuroinflammation in Parkinson’sdisease,weemployedthe MPTP injection model using humanized CD34+ mice along with age-matched C57BL/6 mice. NSG mice engrafted with hu-CD34+ hematopoietic stem cells were injected with MPTP to quantify cytokine changes, neuron loss, gliosis, and behavioral dysfunction. The mice were also treated with or without the calcineurin/NFAT inhibitor, FK506, to determine whether modulating the immune response could attenuate disease. MPTP injections produced impairment of motor performance, increased microgliosis, elevated brain cytokine levels, and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum of both humanized CD34+ mice and C57BL/6 mice with a strikingly different profile of human versus mouse cytokine elevations observed in each. Interestingly, FK506 injections significantly attenuated the MPTP-induced effects in the humanized CD34+ mice compared the C57BL/6 mice.
    [Show full text]