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de la Monte SM, Tong M, Hapel AJ. Concordant and Discordant Cerebrospinal Fluid and Plasma Cytokine and Chemokine Responses in Mild Cognitive Impairment and Early-Stage Alzheimer's Disease. Biomedicines 2023; 11:2394. [PMID: 37760836 PMCID: PMC10525668 DOI: 10.3390/biomedicines11092394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/18/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
Neuroinflammation may be a pathogenic mediator and biomarker of neurodegeneration at the boundary between mild cognitive impairment (MCI) and early-stage Alzheimer's disease (AD). Whether neuroinflammatory processes are endogenous to the central nervous system (CNS) or originate from systemic (peripheral blood) sources could impact strategies for therapeutic intervention. To address this issue, we measured cytokine and chemokine immunoreactivities in simultaneously obtained lumbar puncture cerebrospinal fluid (CSF) and serum samples from 39 patients including 18 with MCI or early AD and 21 normal controls using a 27-plex XMAP bead-based enzyme-linked immunosorbent assay (ELISA). The MCI/AD combined group had significant (p < 0.05 or better) or statistically trend-wise (0.05 ≤ p ≤ 0.10) concordant increases in CSF and serum IL-4, IL-5, IL-9, IL-13, and TNF-α and reductions in GM-CSF, b-FGF, IL-6, IP-10, and MCP-1; CSF-only increases in IFN-y and IL-7 and reductions in VEGF and IL-12p70; serum-only increases in IL-1β, MIP-1α, and eotaxin and reductions in G-CSF, IL-2, IL-8 and IL-15; and discordant CSF-serum responses with reduced CSF and increased serum PDGF-bb, IL-17a, and RANTES. The results demonstrate simultaneously parallel mixed but modestly greater pro-inflammatory compared to anti-inflammatory or neuroprotective responses in CSF and serum. In addition, the findings show evidence that several cytokines and chemokines are selectively altered in MCI/AD CSF, likely corresponding to distinct neuroinflammatory responses unrelated to systemic pathologies. The aggregate results suggest that early management of MCI/AD neuroinflammation should include both anti-inflammatory and pro-neuroprotective strategies to help prevent disease progression.
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Affiliation(s)
- Suzanne M. de la Monte
- Departments of Pathology (Neuropathology), Neurology, and Neurosurgery, Rhode Island Hospital, The Alpert Medical School of Brown University, Providence, RI 02903, USA
- Department of Medicine, Rhode Island Hospital, The Alpert Medical School of Brown University, Providence, RI 02903, USA;
| | - Ming Tong
- Department of Medicine, Rhode Island Hospital, The Alpert Medical School of Brown University, Providence, RI 02903, USA;
| | - Andrew J. Hapel
- Department of Genome Biology, John Curtin School of Medical Research, Australian National University, Canberra 2601, Australia;
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2
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Shanazz K, Nalloor R, Lucas R, Vazdarjanova A. Neuroinflammation is a susceptibility factor in developing a PTSD-like phenotype. Front Behav Neurosci 2023; 17:1112837. [PMID: 37064304 PMCID: PMC10090279 DOI: 10.3389/fnbeh.2023.1112837] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 03/07/2023] [Indexed: 03/31/2023] Open
Abstract
IntroductionPost-Traumatic Stress Disorder (PTSD) is a psychological disorder that occurs after a traumatic event in a subset of exposed individuals. This implies the existence of susceptibility factors that foster the development of PTSD. Susceptibility factors are present before trauma and can contribute to the development and maintenance of PTSD after trauma. Manipulation of susceptibility factors may decrease the probability of developing PTSD. A putative susceptibility factor is inflammation. Patients with PTSD have been documented to have a higher pro-inflammatory profile compared to non-PTSD subjects. In addition, they are more likely to develop and die from cardiovascular disease which has a strong inflammation component. It is not known, however, whether inflammation plays a role in developing PTSD or whether reducing inflammation can prevent PTSD.MethodsWe used the Revealing Individual Susceptibility to a PTSD-like phenotype (RISP) model to behaviorally classify male rats as resilient or susceptible before trauma and tested their serum and prefrontal cortical (mPFC) levels of IL-1β, IL-6, TNFα, IL-10, IFN IFNγ, and KC/GRO to determine whether inflammation represents a putative susceptibility factor for PTSD.ResultsWe found elevated IL-6 levels in the mPFC, but not serum, of susceptible rats compared to resilient animals before trauma. Serum and mPFC levels were not correlated in any of the cytokines/chemokines. Rats with high anxiety-like behavior had elevated IL-6 and IL-10 mPFC levels. Acoustic startle responses were not associated with cytokine/chemokine levels.DiscussionNeuroinflammation, rather than systemic inflammation exists in susceptible male rats before trauma and is thus a putative susceptibility factor for PTSD. Thus, susceptibility appears neurogenic in its pathogenesis. The lack of differences between susceptible and resilient rats in serum cytokine/chemokine levels infers that peripheral markers will not be useful in determining susceptibility. Chronic neuroinflammation appears more broadly associated with anxiety rather than startle responses.
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Affiliation(s)
- Khadijah Shanazz
- VA Research Service, Charlie Norwood VA Medical Center, Augusta, GA, United States
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Rebecca Nalloor
- VA Research Service, Charlie Norwood VA Medical Center, Augusta, GA, United States
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Rudolf Lucas
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Division of Pulmonary and Critical Care Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Almira Vazdarjanova
- VA Research Service, Charlie Norwood VA Medical Center, Augusta, GA, United States
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
- *Correspondence: Almira Vazdarjanova,
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Li Z, Zhu Y, Kang Y, Qin S, Chai J. Neuroinflammation as the Underlying Mechanism of Postoperative Cognitive Dysfunction and Therapeutic Strategies. Front Cell Neurosci 2022; 16:843069. [PMID: 35418837 PMCID: PMC8995749 DOI: 10.3389/fncel.2022.843069] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/28/2022] [Indexed: 12/11/2022] Open
Abstract
Postoperative cognitive dysfunction (POCD) is a common neurological complication following surgery and general anesthesia, especially in elderly patients. Severe cases delay patient discharge, affect the patient’s quality of life after surgery, and are heavy burdens to society. In addition, as the population ages, surgery is increasingly used for older patients and those with higher prevalences of complications. This trend presents a huge challenge to the current healthcare system. Although studies on POCD are ongoing, the underlying pathogenesis is still unclear due to conflicting results and lack of evidence. According to existing studies, the occurrence and development of POCD are related to multiple factors. Among them, the pathogenesis of neuroinflammation in POCD has become a focus of research in recent years, and many clinical and preclinical studies have confirmed the correlation between neuroinflammation and POCD. In this article, we reviewed how central nervous system inflammation occurred, and how it could lead to POCD with changes in peripheral circulation and the pathological pathways between peripheral circulation and the central nervous system (CNS). Furthermore, we proposed some potential therapeutic targets, diagnosis and treatment strategies at the cellular and molecular levels, and clinical applications. The goal of this article was to provide a better perspective for understanding the occurrence of POCD, its development, and preventive strategies to help manage these vulnerable geriatric patients.
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Affiliation(s)
- Zhichao Li
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Youzhuang Zhu
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yihan Kang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shangyuan Qin
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jun Chai
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Jun Chai,
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4
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Vore AS, Deak T. Alcohol, inflammation, and blood-brain barrier function in health and disease across development. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2021; 161:209-249. [PMID: 34801170 DOI: 10.1016/bs.irn.2021.06.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Alcohol is the most commonly used drug of abuse in the world and binge drinking is especially harmful to the brain, though the mechanisms by which alcohol compromises overall brain health remain somewhat elusive. A number of brain diseases and pathological states are accompanied by perturbations in Blood-Brain Barrier (BBB) function, ultimately exacerbating disease progression. The BBB is critical for coordinating activity between the peripheral immune system and the brain. Importantly, BBB integrity is responsive to circulating cytokines and other immune-related signaling molecules, which are powerfully modulated by alcohol exposure. This review will highlight key cellular components of the BBB; discuss mechanisms by which permeability is achieved; offer insight into methodological approaches for assessing BBB integrity; and forecast how alcohol-induced changes in the peripheral and central immune systems might influence BBB function in individuals with a history of binge drinking and ultimately Alcohol Use Disorders (AUD).
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Affiliation(s)
- A S Vore
- Behavioral Neuroscience Program, Department of Psychology, Developmental Exposure Alcohol Research Center, Binghamton, NY, United States
| | - T Deak
- Behavioral Neuroscience Program, Department of Psychology, Developmental Exposure Alcohol Research Center, Binghamton, NY, United States.
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Brakel K, Aceves M, Garza A, Yoo C, Escobedo G, Panchani N, Shapiro L, Hook M. Inflammation increases the development of depression behaviors in male rats after spinal cord injury. Brain Behav Immun Health 2021; 14:100258. [PMID: 34589764 PMCID: PMC8474513 DOI: 10.1016/j.bbih.2021.100258] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/01/2021] [Accepted: 04/08/2021] [Indexed: 02/08/2023] Open
Abstract
Following spinal cord injury, 18-26% of patients are diagnosed with depressive disorders, compared to 8-12% in the general population. As increased inflammation strongly correlates with depression in both animal and human studies, we hypothesized that the immune activation inherent to SCI could increase depression-like behavior. Thus, we proposed that reducing immune activation with minocycline, a microglial inhibitor, would decrease depression-like behavior following injury. Male Sprague-Dawley rats were given minocycline in their drinking water for 14 days following a moderate, mid-thoracic (T12) spinal contusion. An array of depression-like behaviors (social activity, sucrose preference, forced swim, open field activity) were examined prior to injury as well as on days 9-10, 19-20, and 29-30 post-injury. Peripheral cytokine levels were analyzed in serum collected prior to injury and 10 days post-injury. Hierarchical cluster analysis divided subjects into two groups based on behavior: depressed and not-depressed. Depressed subjects displayed lower levels of open field activity and social interaction relative to their not-depressed counterparts. Depressed subjects also showed significantly greater expression of pro-inflammatory cytokines both before and after injury and displayed lower levels of hippocampal neurogenesis than not-depressed subjects. Intriguingly, subjects who later showed depressive behaviors had higher baseline levels of the pro-inflammatory cytokine IL-6, which persisted throughout the duration of the experiment. Minocycline, however, did not affect serum cytokine levels and did not block the development of depression; equal numbers of minocycline versus vehicle-treated subjects appeared in both phenotypic groups. Despite this, these data overall suggest that molecular correlates of inflammation prior to injury could predict the development of depression after a physical stressor.
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Affiliation(s)
- Kiralyn Brakel
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Medical Research and Education Building, Ste. 1005 8447 Riverside Pkwy, Bryan, TX, 77807, United States
- Texas A&M Institute of Neuroscience, Texas A&M University, Interdisciplinary Life Sciences Building, Rm 3148, 3474, TAMU, College Station, TX, United States
| | - Miriam Aceves
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Medical Research and Education Building, Ste. 1005 8447 Riverside Pkwy, Bryan, TX, 77807, United States
- Texas A&M Institute of Neuroscience, Texas A&M University, Interdisciplinary Life Sciences Building, Rm 3148, 3474, TAMU, College Station, TX, United States
- Department of Biology, Texas A&M University, Interdisciplinary Life Sciences Building, College Station, TX, United States
| | - Aryana Garza
- Texas A&M Institute of Neuroscience, Texas A&M University, Interdisciplinary Life Sciences Building, Rm 3148, 3474, TAMU, College Station, TX, United States
| | - Chaeyoung Yoo
- Texas A&M Institute of Neuroscience, Texas A&M University, Interdisciplinary Life Sciences Building, Rm 3148, 3474, TAMU, College Station, TX, United States
| | - Gabriel Escobedo
- Texas A&M Institute of Neuroscience, Texas A&M University, Interdisciplinary Life Sciences Building, Rm 3148, 3474, TAMU, College Station, TX, United States
| | - Nishah Panchani
- Texas A&M Institute of Neuroscience, Texas A&M University, Interdisciplinary Life Sciences Building, Rm 3148, 3474, TAMU, College Station, TX, United States
| | - Lee Shapiro
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Medical Research and Education Building, Ste. 1005 8447 Riverside Pkwy, Bryan, TX, 77807, United States
- Texas A&M Institute of Neuroscience, Texas A&M University, Interdisciplinary Life Sciences Building, Rm 3148, 3474, TAMU, College Station, TX, United States
| | - Michelle Hook
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Medical Research and Education Building, Ste. 1005 8447 Riverside Pkwy, Bryan, TX, 77807, United States
- Texas A&M Institute of Neuroscience, Texas A&M University, Interdisciplinary Life Sciences Building, Rm 3148, 3474, TAMU, College Station, TX, United States
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Salavrakos M, Leclercq S, De Timary P, Dom G. Microbiome and substances of abuse. Prog Neuropsychopharmacol Biol Psychiatry 2021; 105:110113. [PMID: 32971216 DOI: 10.1016/j.pnpbp.2020.110113] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 09/07/2020] [Accepted: 09/14/2020] [Indexed: 12/12/2022]
Abstract
There is a growing amount of evidence showing a reciprocal relation between the gut microbiota and the brain. Substance use disorders (SUD), which are a major cause of preventable morbidity and mortality worldwide, have an influence on the gut microbiota and on the gut-brain axis. The communication between the microbiota and the brain exists through different pathways: (1) the immune response elicited by bacterial products, coupled with alterations of the intestinal barrier allowing these products to enter the bloodstream, (2) the direct and indirect effects of bacterial metabolites such as short chain fatty acids (SCFAs) or tryptophan on the brain, (3) and the hypothalamic-pituitary-adrenal (HPA) axis, whose peripheral afferents can be influenced by the microbiota, and can in turn activate microglia. Among substances of abuse, alcohol has been the subject of the greatest number of studies in this field. In some but not all patients suffering from alcohol-use-disorder (AUD), alcohol alters the composition of the gut microbiota and the permeability of the intestinal barrier, directly and through dysbiosis. It has also been well demonstrated that alcohol induces a peripheral inflammation; it is still unclear whether it induces a central inflammation, as there are contradictory results in human studies. In animal studies, it has been shown that neuroinflammation increases during alcohol withdrawal. Literature on opioids and stimulants is less numerous. Chronic morphine intake induces dysbiosis, increased intestinal permeability and a probable neuroinflammation, which could explain symptoms such as tolerance, hyperalgesia and deficit in reward behavior. Cocaine induces a dysbiosis and conversely the microbiome can modulate the behavioral response to stimulant drugs. Tobacco cessation is associated with an increase in microbiota diversity. Taken together, the findings of our narrative literature review suggest a bidirectional influence in the pathogenesis of substance use disorders.
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Affiliation(s)
- M Salavrakos
- Target Journal Progress in Neuropsychopharmacology and Biological Psychiatry, Belgium
| | - S Leclercq
- Target Journal Progress in Neuropsychopharmacology and Biological Psychiatry, Belgium
| | - P De Timary
- Target Journal Progress in Neuropsychopharmacology and Biological Psychiatry, Belgium
| | - G Dom
- Target Journal Progress in Neuropsychopharmacology and Biological Psychiatry, Belgium.
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Kim YS, Choi J, Yoon BE. Neuron-Glia Interactions in Neurodevelopmental Disorders. Cells 2020; 9:cells9102176. [PMID: 32992620 PMCID: PMC7601502 DOI: 10.3390/cells9102176] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/24/2020] [Accepted: 09/24/2020] [Indexed: 12/12/2022] Open
Abstract
Recent studies have revealed synaptic dysfunction to be a hallmark of various psychiatric diseases, and that glial cells participate in synapse formation, development, and plasticity. Glial cells contribute to neuroinflammation and synaptic homeostasis, the latter being essential for maintaining the physiological function of the central nervous system (CNS). In particular, glial cells undergo gliotransmission and regulate neuronal activity in tripartite synapses via ion channels (gap junction hemichannel, volume regulated anion channel, and bestrophin-1), receptors (for neurotransmitters and cytokines), or transporters (GLT-1, GLAST, and GATs) that are expressed on glial cell membranes. In this review, we propose that dysfunction in neuron-glia interactions may contribute to the pathogenesis of neurodevelopmental disorders. Understanding the mechanisms of neuron-glia interaction for synapse formation and maturation will contribute to the development of novel therapeutic targets of neurodevelopmental disorders.
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Affiliation(s)
- Yoo Sung Kim
- Department of Molecular Biology, Dankook University, Cheonan 31116, Korea; (Y.S.K.); (J.C.)
| | - Juwon Choi
- Department of Molecular Biology, Dankook University, Cheonan 31116, Korea; (Y.S.K.); (J.C.)
| | - Bo-Eun Yoon
- Department of Molecular Biology, Dankook University, Cheonan 31116, Korea; (Y.S.K.); (J.C.)
- Department of Nanobiomedical science, Dankook University, Cheonan 31116, Korea
- Correspondence: ; Tel.: +82-41-529-6085
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8
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Behura SK, Kelleher AM, Spencer TE. Regulation of uterine genes during the peri‐implantation period, and its relationship to the maternal brain in gestating mice. Mol Reprod Dev 2020; 87:482-492. [DOI: 10.1002/mrd.23338] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 03/11/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Susanta K. Behura
- Division of Animal SciencesUniversity of MissouriColumbia Missouri
- Institute for Data Science and InformaticsUniversity of MissouriColumbia Missouri
| | | | - Thomas E. Spencer
- Division of Animal SciencesUniversity of MissouriColumbia Missouri
- Department of Obstetrics, Gynecology and Women's HealthUniversity of MissouriColumbia Missouri
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Brunoni AR, Supasitthumrong T, Teixeira AL, Vieira EL, Gattaz WF, Benseñor IM, Lotufo PA, Lafer B, Berk M, Carvalho AF, Maes M. Differences in the immune-inflammatory profiles of unipolar and bipolar depression. J Affect Disord 2020; 262:8-15. [PMID: 31693974 DOI: 10.1016/j.jad.2019.10.037] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 09/27/2019] [Accepted: 10/27/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND Major depressive disorder (MDD) and bipolar depression (BD) both share increased immune-inflammatory activation. However, there are unclear patterns of differences in peripheral immune profiles between them. METHODS We examined such differences in 245 MDD and 59 BD patients, recruited in the same center, who were in an acute depressive episode of moderate severity. Hierarchical binary logistic regression analyses and generalized linear models were used to compare levels of plasma biomarkers between groups and to predict dichotomous classification. RESULTS Interleukin (IL)-1β, tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1, IL-12 and IL-10 were significantly higher in MDD than in BD, whereas IL-6, sTNFR2, IL-18, IL-33, ST2 (IL1R Like 1) and KLOTHO were significantly higher in BD than in MDD. Moreover, logistic regression analyses correctly classified BD and MDD patients with 98.1% accuracy, using a combination of IL-6, IL-8, ST2, sTNFR2 (directly associated with BD) and IL-12 and TNF-α (directly associated with MDD). Patients with MDD with melancholic features showed higher IL-1β levels than those without melancholia. The sTNFR1 / sTNFR2 ratio significantly predicted MDD and state and trait anxiety and negative affect. Results remained significant after covariate adjustment, including drug use. LIMITATIONS Cross-sectional study. Lack of control comparison group. Differences in exposure to medications among participants. CONCLUSIONS Differences in immune profiles between BD and MDD patients exist, especially for the compensatory immune-regulatory system (CIRS): increased IL-10 is the primary immune-regulatory mechanism in MDD, while increased sTNFR2 and KLOTHO are the primary regulatory mechanisms in BD.
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Affiliation(s)
- Andre R Brunoni
- Department of Internal Medicine, Faculdade de Medicina da Universidade de São Paulo & Hospital Universitário, Universidade de São Paulo, Av. Prof Lineu Prestes 2565, 05508-000 São Paulo, Brazil; Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry, Faculdade de Medicina da Universidade de São Paulo, R Dr Ovidio Pires de Campos 785, 2o andar, 05403-000 São Paulo, Brazil
| | | | - Antonio Lucio Teixeira
- Interdisciplinary Laboratory of Medical Investigation, Faculdade de Medicina da Universidade Federal de Minas Gerais, Brazil; Neuropsychiatry Program, Department of Psychiatry & Behavioral Sciences, UT Health Houston, United States
| | - Erica Lm Vieira
- Interdisciplinary Laboratory of Medical Investigation, Faculdade de Medicina da Universidade Federal de Minas Gerais, Brazil; Neuropsychiatry Program, Department of Psychiatry & Behavioral Sciences, UT Health Houston, United States
| | - Wagner F Gattaz
- Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry, Faculdade de Medicina da Universidade de São Paulo, R Dr Ovidio Pires de Campos 785, 2o andar, 05403-000 São Paulo, Brazil
| | - Isabela M Benseñor
- Department of Internal Medicine, Faculdade de Medicina da Universidade de São Paulo & Hospital Universitário, Universidade de São Paulo, Av. Prof Lineu Prestes 2565, 05508-000 São Paulo, Brazil
| | - Paulo A Lotufo
- Department of Internal Medicine, Faculdade de Medicina da Universidade de São Paulo & Hospital Universitário, Universidade de São Paulo, Av. Prof Lineu Prestes 2565, 05508-000 São Paulo, Brazil
| | - Beny Lafer
- Bipolar Disorder Research Program, Department and Institute of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil
| | - Michael Berk
- Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia
| | - Andre F Carvalho
- Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Centre for Addiction & Mental Health (CAMH), Toronto, Canada.
| | - Michael Maes
- Department of Psychiatry, Chulalongkorn University, Faculty of Medicine, Bangkok, Thailand; Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
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10
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Guo G, Gong K, Puliyappadamba VT, Panchani N, Pan E, Mukherjee B, Damanwalla Z, Bharia S, Hatanpaa KJ, Gerber DE, Mickey BE, Patel TR, Sarkaria JN, Zhao D, Burma S, Habib AA. Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma. Neuro Oncol 2019; 21:1529-1539. [PMID: 31363754 PMCID: PMC6917414 DOI: 10.1093/neuonc/noz127] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM. METHODS We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ. RESULTS The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. CONCLUSION EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.
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Affiliation(s)
- Gao Guo
- Department of Neurology and Neurotherapeutics, Division of Hematology-Oncology, Dallas, Texas
| | - Ke Gong
- Department of Neurology and Neurotherapeutics, Division of Hematology-Oncology, Dallas, Texas
| | | | - Nishah Panchani
- Department of Pathology, Division of Hematology-Oncology, Dallas, Texas
| | - Edward Pan
- Department of Neurology and Neurotherapeutics, Division of Hematology-Oncology, Dallas, Texas
| | - Bipasha Mukherjee
- Department of Radiation Oncology, Division of Hematology-Oncology, Dallas, Texas
| | - Ziba Damanwalla
- Department of Neurology and Neurotherapeutics, Division of Hematology-Oncology, Dallas, Texas
| | - Sabrina Bharia
- Department of Neurology and Neurotherapeutics, Division of Hematology-Oncology, Dallas, Texas
- Department of Radiation Oncology, Division of Hematology-Oncology, Dallas, Texas
| | - Kimmo J Hatanpaa
- Department of Pathology, Division of Hematology-Oncology, Dallas, Texas
| | - David E Gerber
- Department of Internal Medicine, Division of Hematology-Oncology, Dallas, Texas
- Harold C. Simmons Comprehensive Cancer Center, VA North Texas Health Care System, Dallas, Texas
| | - Bruce E Mickey
- Department of Neurosurgery, VA North Texas Health Care System, Dallas, Texas
| | - Toral R Patel
- Department of Neurosurgery, VA North Texas Health Care System, Dallas, Texas
| | - Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Dawen Zhao
- Departments of Biomedical Engineering and Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Sandeep Burma
- Department of Neurology and Neurotherapeutics, Division of Hematology-Oncology, Dallas, Texas
- Department of Radiation Oncology, Division of Hematology-Oncology, Dallas, Texas
| | - Amyn A Habib
- Department of Neurology and Neurotherapeutics, Division of Hematology-Oncology, Dallas, Texas
- Harold C. Simmons Comprehensive Cancer Center, VA North Texas Health Care System, Dallas, Texas
- University of Texas Southwestern Medical Center, Dallas, Texas; VA North Texas Health Care System, Dallas, Texas
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11
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Zeun P, Scahill RI, Tabrizi SJ, Wild EJ. Fluid and imaging biomarkers for Huntington's disease. Mol Cell Neurosci 2019; 97:67-80. [PMID: 30807825 DOI: 10.1016/j.mcn.2019.02.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/25/2019] [Accepted: 02/12/2019] [Indexed: 01/18/2023] Open
Abstract
Huntington's disease is a chronic progressive neurodegenerative condition for which there is no disease-modifying treatment. The known genetic cause of Huntington's disease makes it possible to identify individuals destined to develop the disease and instigate treatments before the onset of symptoms. Multiple trials are already underway that target the cause of HD, yet clinical measures are often insensitive to change over typical clinical trial duration. Robust biomarkers of drug target engagement, disease severity and progression are required to evaluate the efficacy of treatments and concerted efforts are underway to achieve this. Biofluid biomarkers have potential advantages of direct quantification of biological processes at the molecular level, whilst imaging biomarkers can quantify related changes at a structural level in the brain. The most robust biofluid and imaging biomarkers can offer complementary information, providing a more comprehensive evaluation of disease stage and progression to inform clinical trial design and endpoints.
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Affiliation(s)
- Paul Zeun
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, United Kingdom.
| | - Rachael I Scahill
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, United Kingdom.
| | - Sarah J Tabrizi
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, United Kingdom.
| | - Edward J Wild
- Huntington's Disease Centre, University College London (UCL) Institute of Neurology, London WC1N 3BG, United Kingdom.
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Ignatowski TA, Spengler RN. Targeting tumor necrosis factor in the brain relieves neuropathic pain. World J Anesthesiol 2018; 7:10-19. [DOI: 10.5313/wja.v7.i2.10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/28/2018] [Accepted: 06/02/2018] [Indexed: 02/06/2023] Open
Abstract
Neuropathic pain is a chronic syndrome caused by direct damage to or disease of the somatosensory nervous system. The lack of safe, adequate and sustained pain relief offered by present analgesic treatments is most alarming. While many treatment options are available to manage chronic pain, such as antidepressants, non-steroidal anti-inflammatory agents, opioids, and anticonvulsants, chronic neuropathic pain remains largely unmanaged. Compounding the dilemma of ineffective chronic pain treatments is the need to provide relief from suffering and yet not contribute to the scourge of drug abuse. A recent epidemic of addiction and accidental drug prescription overdoses parallel the increased use of opioid treatment, even though opioids are rarely an effective treatment of relieving chronic pain. To make matters worse, opioids may contribute to exacerbating pain, and side-effects such as cognitive impairment, nausea, constipation, development of tolerance, as well as their potential for addiction and overdose deaths exist. Clearly, there is an urgent need for alternative, non-opiate treatment of chronic pain. Innovative discoveries of pertinent brain mechanisms and functions are key to developing effective, safe treatments. Pioneering work has revealed the essential effects of the pleiotropic mediator tumor necrosis factor (TNF) on brain functioning. These studies establish that TNF inhibits norepinephrine release from hippocampal neurons, and show that excess TNF production within the hippocampus occurs during neuropathic pain, which mobilizes additional mechanisms that further inhibit norepinephrine release. Significantly, it has been verified that elevated levels of TNF in the brain are actually required for neuropathic pain development. Since TNF decreases norepinephrine release in the brain, enhanced TNF levels would prevent engagement of the norepinephrine descending inhibitory neuronal pain pathways. Increased levels of TNF in the brain are therefore critical to the development of neuropathic pain. Therefore, strategies that decrease this enhanced TNF expression in the brain will have superior analgesic efficacy. We propose this novel approach of targeting the pathologically high levels of brain TNF as an effective strategy in the treatment of the devastating syndrome of chronic pain.
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Affiliation(s)
- Tracey A Ignatowski
- Department of Pathology and Anatomical Sciences and Program for Neuroscience, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14203, United States
- NanoAxis, LLC, Clarence, NY 14031, United States
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Valacchi G, Virgili F, Cervellati C, Pecorelli A. OxInflammation: From Subclinical Condition to Pathological Biomarker. Front Physiol 2018; 9:858. [PMID: 30038581 PMCID: PMC6046448 DOI: 10.3389/fphys.2018.00858] [Citation(s) in RCA: 132] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 06/15/2018] [Indexed: 12/18/2022] Open
Abstract
Inflammation is a complex systemic response evolved to cope with cellular injury, either due to infectious agents or, in general, with sporadic events challenging tissue integrity and function. Researchers involved in different fields have the tendency to look at the inflammatory response with different angles, according to their specific interest. Established its complexity, one of the most evident features of the inflammatory response is the generation of a pro-oxidative environment due to the production of high fluxes of pro-oxidant species. This production begins locally, close to the sites of tissue damage or infection, but eventually becomes a chronic challenge for the organism, if the inflammatory response is not properly controlled. In this review, we focus on this specific aspect of chronic, low-level sub-clinical inflammatory response. We propose the term "OxInflammation" as a novel operative term describing a permanent pro-oxidative feature that interact, in a positive feed-back manner, to a not yet clinically detectable inflammatory process, leading in a long run (chronically) to a systemic/local damage, as a consequence of the cross talk between inflammatory, and oxidative stress mediators. Therefore, it could be useful to analyze inflammatory markers in pathologies where there is an alteration of the redox homeostasis, although an inflammatory status is not clinically evident.
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Affiliation(s)
- Giuseppe Valacchi
- Plants for Human Health Institute, Department of Animal Sciences, North Carolina State University, Kannapolis, NC, United States
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Fabio Virgili
- Council for Agricultural Research and Economics - Food and Nutrition Research Centre (C.R.E.A.-AN), Rome, Italy
| | - Carlo Cervellati
- Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Ferrara, Italy
| | - Alessandra Pecorelli
- Plants for Human Health Institute, Department of Animal Sciences, North Carolina State University, Kannapolis, NC, United States
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Myotube-derived factor promotes oligodendrocyte precursor cell proliferation. Biochem Biophys Res Commun 2018; 500:609-613. [PMID: 29679562 DOI: 10.1016/j.bbrc.2018.04.118] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 04/14/2018] [Indexed: 11/22/2022]
Abstract
Muscle cells secrete numerous molecules that function as endocrine hormones and regulate the functions of distant organs. Myelination in the central nervous system (CNS) is regulated by peripheral hormones. However, the effects of muscle-derived molecules on myelination have not been sufficiently analyzed. In this study, we show that muscle-releasing factors promote proliferation of oligodendrocyte precursor cells (OPCs), which is an element of myelination process. Supernatants of mouse myotube cultures stimulated bromodeoxyuridine (BrdU) incorporation into mouse OPCs. Mouse myotube supernatants did not enhance mouse OPC transmigration and myelin basic protein (MBP) expression. RNA sequencing identified candidate genes with hormonal functions that were expressed in mouse myotubes. These data support the possibility that hormonal molecules secreted by myotubes contribute to OPC proliferation and myelination.
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Maes M, Carvalho AF. The Compensatory Immune-Regulatory Reflex System (CIRS) in Depression and Bipolar Disorder. Mol Neurobiol 2018; 55:8885-8903. [DOI: 10.1007/s12035-018-1016-x] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 03/16/2018] [Indexed: 12/11/2022]
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Sowa-Kućma M, Styczeń K, Siwek M, Misztak P, Nowak RJ, Dudek D, Rybakowski JK, Nowak G, Maes M. Are there differences in lipid peroxidation and immune biomarkers between major depression and bipolar disorder: Effects of melancholia, atypical depression, severity of illness, episode number, suicidal ideation and prior suicide attempts. Prog Neuropsychopharmacol Biol Psychiatry 2018; 81:372-383. [PMID: 28867391 DOI: 10.1016/j.pnpbp.2017.08.024] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 08/09/2017] [Accepted: 08/30/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND There is evidence that major depression (MDD) and bipolar disorder (BD) are accompanied by activated immune & oxidative (I&O) pathways. METHODS To compare I&O biomarkers between MDD and BD we assessed serum levels of thiobarbituric acid reactive substances (TBARS; a lipid peroxidation marker), soluble interleukin-2 receptor (sIL-2R), sIL-6R, IL-α, sIL-1R antagonist (sIL-1RA), tumor necrosis factor receptor 60kDa/80kDa (sTNFR60/R80) in 114 MDD and 133 BD patients, and 50 healthy controls. We computed z-unit weighted indices reflecting the 5 cytokine receptor levels (zCytR), cell-mediated immunity (zCMI) and I&O pathways (zCMI+TBARS). RESULTS There are no significant differences in biomarkers between MDD and BD. BD/MDD with atypical features is characterized by increased sIL-6R and TBARS, whereas melancholia is associated with higher TBARS and lower sTNFR60 levels. Severity of illness, as measured with the Hamilton Depression Rating Scale, is correlated with increased sIL-6R, sTNFR80, TBARS, zCytR and zCMI+TBARS. The number of episodes the year prior to blood sampling is positively associated with sTNFR80, TBARS, zCMI, zCMI+TBARS, while number of hospitalizations is positively associated with sIL-1RA. Prior suicidal attempts are associated with increased sIL-1RA, IL-1α, zCMI, TBARS and zCMI+TBARS, while TBARS is associated with current suicidal ideation. CONCLUSIONS There are no I&O biomarker differences between MDD and BD. Atypical depression is associated with increased IL-6 trans-signaling and lipid peroxidation. Severity of depression, number of episodes and suicidal attempts are associated with activated I&O pathways. Increased TBARS is the single best predictor of BD/MDD, atypical depression, melancholia and current suicidal ideation.
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Affiliation(s)
- Magdalena Sowa-Kućma
- Institute of Pharmacology, Polish Academy of Sciences, Laboratory of Trace Elements Neurobiology, Department of Neurobiology, Smetna Street 12, 31-343 Krakow, Poland; Department of Human Physiology, Institute of Clinical and Experimental Medicine, Medical Faculty, University of Rzeszow, Al. Kopisto Street 2a, 35-959 Rzeszów, Poland.
| | - Krzysztof Styczeń
- Department of Affective Disorders, Chair of Psychiatry, Jagiellonian University Medical College, Kopernika 21a, 31-501 Krakow, Poland
| | - Marcin Siwek
- Department of Affective Disorders, Chair of Psychiatry, Jagiellonian University Medical College, Kopernika 21a, 31-501 Krakow, Poland
| | - Paulina Misztak
- Institute of Pharmacology, Polish Academy of Sciences, Laboratory of Trace Elements Neurobiology, Department of Neurobiology, Smetna Street 12, 31-343 Krakow, Poland; Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland
| | - Rafał J Nowak
- Department of Drug Management, Jagiellonian University Medical College, Grzegórzecka 20, 31-531 Krakow, Poland
| | - Dominika Dudek
- Department of Affective Disorders, Chair of Psychiatry, Jagiellonian University Medical College, Kopernika 21a, 31-501 Krakow, Poland
| | - Janusz K Rybakowski
- Department of Adult Psychiatry, Poznań University of Medical Sciences, Szpitalna 27/33, 60-572 Poznań, Poland
| | - Gabriel Nowak
- Institute of Pharmacology, Polish Academy of Sciences, Laboratory of Trace Elements Neurobiology, Department of Neurobiology, Smetna Street 12, 31-343 Krakow, Poland; Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; IMPACT Strategic Research Centre, Deakin University, School of Medicine and Barwon Health, Geelong, VIC, Australia; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria; Revitalis, Waalre, The Netherlands
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Abstract
Huntington's disease (HD) is a chronic progressive neurodegenerative condition where new markers of disease progression are needed. So far no disease-modifying interventions have been found, and few interventions have been proven to alleviate symptoms. This may be partially explained by the lack of reliable indicators of disease severity, progression, and phenotype.Biofluid biomarkers may bring advantages in addition to clinical measures, such as reliability, reproducibility, price, accuracy, and direct quantification of pathobiological processes at the molecular level; and in addition to empowering clinical trials, they have the potential to generate useful hypotheses for new drug development.In this chapter we review biofluid biomarker reports in HD, emphasizing those we feel are likely to be closest to clinical applicability.
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Affiliation(s)
- Filipe B Rodrigues
- Huntington's Disease Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK
| | - Lauren M Byrne
- Huntington's Disease Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK
| | - Edward J Wild
- Huntington's Disease Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
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Taghipour M, Ghaffarpasand F, Saffarrian A. Circumventricular Organ Origin of Hemangioblastoama; Hypothesis for Pathogenesis of Disease. World Neurosurg 2017; 108:980. [PMID: 29179425 DOI: 10.1016/j.wneu.2017.08.173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 08/26/2017] [Indexed: 11/17/2022]
Affiliation(s)
- Mousa Taghipour
- Shiraz Neurosciences Research Center, Department of Neurosurgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Arash Saffarrian
- Department of Neurosurgery, Shiraz University of Medical Sciences, Shiraz, Iran
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Lai KSP, Liu CS, Rau A, Lanctôt KL, Köhler CA, Pakosh M, Carvalho AF, Herrmann N. Peripheral inflammatory markers in Alzheimer's disease: a systematic review and meta-analysis of 175 studies. J Neurol Neurosurg Psychiatry 2017; 88:876-882. [PMID: 28794151 DOI: 10.1136/jnnp-2017-316201] [Citation(s) in RCA: 310] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 06/23/2017] [Accepted: 07/17/2017] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Increasing evidence suggests that inflammation is involved in Alzheimer's disease (AD) pathology. This study quantitatively summarised the data on peripheral inflammatory markers in patients with AD compared with healthy controls (HC). METHODS Original reports containing measurements of peripheral inflammatory markers in AD patients and HC were included for meta-analysis. Standardised mean differences were calculated using a random effects model. Meta-regression and exploration of heterogeneity was performed using publication year, age, gender, Mini-Mental State Examination (MMSE) scores, plasma versus serum measurements and immunoassay type. RESULTS A total of 175 studies were combined to review 51 analytes in 13 344 AD and 12 912 HC patients. Elevated peripheral interleukin (IL)-1β, IL-2, IL-6, IL-18, interferon-γ, homocysteine, high-sensitivity C reactive protein, C-X-C motif chemokine-10, epidermal growth factor, vascular cell adhesion molecule-1, tumour necrosis factor (TNF)-α converting enzyme, soluble TNF receptors 1 and 2, α1-antichymotrypsin and decreased IL-1 receptor antagonist and leptin were found in patients with AD compared with HC. IL-6 levels were inversely correlated with mean MMSE scores. CONCLUSIONS These findings suggest that AD is accompanied by a peripheral inflammatory response and that IL-6 may be a useful biological marker to correlate with the severity of cognitive impairment. Further studies are needed to determine the clinical utility of these markers.
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Affiliation(s)
- Ka Sing P Lai
- Neuropsychopharmacology Research Group, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Celina S Liu
- Neuropsychopharmacology Research Group, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Allison Rau
- Neuropsychopharmacology Research Group, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Krista L Lanctôt
- Neuropsychopharmacology Research Group, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Departments of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Cristiano A Köhler
- Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Maureen Pakosh
- Toronto Rehabilitation Institute, University Health Network, Toronto, Ontario, Canada
| | - André F Carvalho
- Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Nathan Herrmann
- Neuropsychopharmacology Research Group, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Departments of Psychiatry, University of Toronto, Toronto, Ontario, Canada
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DMARD use is associated with a higher risk of dementia in patients with rheumatoid arthritis: A propensity score-matched case-control study. Toxicol Appl Pharmacol 2017; 334:217-222. [PMID: 28927738 DOI: 10.1016/j.taap.2017.09.014] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 08/17/2017] [Accepted: 09/15/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND Patients with rheumatoid arthritis (RA) exhibit an increased risk of dementia. Disease-modifying antirheumatic drugs (DMARDs) are commonly used to slow RA progression, but studies investigating the relationship between DMARDs and dementia in patients with RA are lacking. We investigated the relationship between DMARDs and dementia in patients with RA. METHODS Using the National Health Insurance Research Database, patients aged ≥20years, who were newly diagnosed with RA between 2000 and 2011 were identified. Patients with RA who had dementia comprised the dementia group, and patients with RA who did not have dementia comprised the control group. The groups were matched at a 1:1 ratio by the propensity score. DMARDs were categorized into conventional synthetic DMARDs (csDMARDs) and biological DMARDs (bDMARDs). Logistic regression models were used to calculate the odds ratio and 95% confidence interval (CI) to evaluate the association between DMARD use and the risk of dementia in patients with RA. RESULTS A total of 957 patients with RA and dementia, and 957 patients with RA but not dementia, were enrolled. The risk of dementia was determined to be 1.63-fold higher in patients with RA with csDMARD use than in those without csDMARD use (95% CI=1.33-2.00). No significant risk of dementia was observed in patients with RA who used bDMARDs compared with their counterparts. However, patients with RA who used hydroxychloroquine, methotrexate, and sulfasalazine exhibited significant risks of dementia, irrespective of cumulative exposure days. CONCLUSION Patients with RA who used csDMARDs exhibit significant association with dementia.
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Folic acid supplementation improves cognitive function by reducing the levels of peripheral inflammatory cytokines in elderly Chinese subjects with MCI. Sci Rep 2016; 6:37486. [PMID: 27876835 PMCID: PMC5120319 DOI: 10.1038/srep37486] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 10/31/2016] [Indexed: 12/23/2022] Open
Abstract
This study aimed to evaluate whether folic acid supplementation would improve cognitive performance by reducing serum inflammatory cytokine concentrations. This RCT was performed in Tianjin, China. Participants with mild cognitive impairment (MCI) were randomly assigned to the folic acid (400 μg/day) or conventional treatment groups. Neuropsychological tests were administered, and folate, homocysteine, vitamin B12, IL-6, TNF-α, Aβ-42, and Aβ-40 were measured at baseline and at 6- and 12-month time points.152 participants (folic acid: 77, conventional: 75) completed the trial. Significant improvements in folate (ηp2 = 0.703, P = 0.011), homocysteine (ηp2 = 0.644, P = 0.009), Aβ-42 (ηp2 = 0.687, P = 0.013), peripheral IL-6 (ηp2 = 0.477, P = 0.025), TNF-α (ηp2 = 0.709, P = 0.009) levels were observed in folic acid group compared with conventional group. Folic acid supplementation improved the Full Scale Intelligence Quotient (P = 0.028; effect size d = 0.153), Information (P = 0.031; d = 0.157) and Digit Span (P = 0.009; d = 0.172) scores at 12 months compared with conventional treatment. Based on these findings, daily oral administration of a 400-μg folic acid supplement to MCI subjects for 12 months can significantly improve cognitive performance and reduce peripheral inflammatory cytokine levels.
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22
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Klaus F, Paterna JC, Marzorati E, Sigrist H, Götze L, Schwendener S, Bergamini G, Jehli E, Azzinnari D, Fuertig R, Fontana A, Seifritz E, Pryce CR. Differential effects of peripheral and brain tumor necrosis factor on inflammation, sickness, emotional behavior and memory in mice. Brain Behav Immun 2016; 58:310-326. [PMID: 27515532 DOI: 10.1016/j.bbi.2016.08.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 07/22/2016] [Accepted: 08/01/2016] [Indexed: 12/21/2022] Open
Abstract
Tumor necrosis factor alpha (TNF) is increased in depression and clinical-trial evidence indicates that blocking peripheral TNF has some antidepressant efficacy. In rodents, peripheral or intracerebroventricular TNF results in sickness e.g. reduced body weight, altered emotional behavior and impaired memory. However, the underlying pathways and responsible brain regions are poorly understood. The aim of this mouse study was to increase understanding by comparing the effects of sustained increases in TNF in the circulation, in brain regions impacted by increased circulating TNF, or specific brain regions. Increased peripheral TNF achieved by repeated daily injection (IP-TNF) or osmotic pump resulted in decreased body weight, decreased saccharin (reward) consumption, and increased memory of an aversive conditioned stimulus. These effects co-occurred with increased plasma interleukin-6 and increased IP-derived TNF in brain peri-ventricular regions. An adenovirus-associated viral TNF vector (AAV-TNF) was constructed, brain injection of which resulted in dose-dependent, sustained and region-specific TNF expression, and was without effect on blood cytokine levels. Lateral ventricle AAV-TNF yielded increased TNF in the same brain regions as IP-TNF. In contrast to IP-TNF it was without effect on body weight, saccharin consumption and fear memory, although it did increase anxiety. Hippocampal AAV-TNF led to decreased body weight. It increased conditioning to but not subsequent memory of an aversive context, suggesting impaired consolidation; it also increased anxiety. Amygdala AAV-TNF was without effect on body weight and aversive stimulus learning-memory, but reduced saccharin consumption and increased anxiety. This study adds significantly to the evidence that both peripheral and brain region-specific increases in TNF lead to both sickness and depression- and anxiety disorder-relevant behavior and do so via different pathways. It thereby highlights the complexity in terms of indirect and direct pathways via which increased TNF can act and which need to be taken into account when considering it as a therapeutic target.
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Affiliation(s)
- Federica Klaus
- Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland
| | - Jean-Charles Paterna
- Viral Vector Facility, Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland
| | - Elisa Marzorati
- Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland
| | - Hannes Sigrist
- Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland
| | - Lea Götze
- Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland
| | | | - Giorgio Bergamini
- Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland
| | - Elisabeth Jehli
- Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland
| | - Damiano Azzinnari
- Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland
| | - René Fuertig
- CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Adriano Fontana
- Institute of Experimental Immunology, Inflammation and Sickness Behaviour, University of Zurich, Switzerland
| | - Erich Seifritz
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland
| | - Christopher R Pryce
- Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland.
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Rodrigues FB, Byrne LM, McColgan P, Robertson N, Tabrizi SJ, Zetterberg H, Wild EJ. Cerebrospinal Fluid Inflammatory Biomarkers Reflect Clinical Severity in Huntington's Disease. PLoS One 2016; 11:e0163479. [PMID: 27657730 PMCID: PMC5033331 DOI: 10.1371/journal.pone.0163479] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 09/09/2016] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Immune system activation is involved in Huntington's disease (HD) pathogenesis and biomarkers for this process could be relevant to study the disease and characterise the therapeutic response to specific interventions. We aimed to study inflammatory cytokines and microglial markers in the CSF of HD patients. METHODS CSF TNF-α, IL-1β, IL-6, IL-8, YKL-40, chitotriosidase, total tau and neurofilament light chain (NFL) from 23 mutation carriers and 14 healthy controls were assayed. RESULTS CSF TNF-α and IL-1β were below the limit of detection. Mutation carriers had higher YKL-40 (p = 0.003), chitotriosidase (p = 0.015) and IL-6 (p = 0.041) than controls. YKL-40 significantly correlated with disease stage (p = 0.007), UHDRS total functional capacity score (r = -0.46, p = 0.016), and UHDRS total motor score (r = 0.59, p = 4.5*10-4) after adjustment for age. CONCLUSION YKL-40 levels in CSF may, after further study, come to have a role as biomarkers for some aspects of HD. Further investigation is needed to support our exploratory findings.
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Affiliation(s)
| | - Lauren M. Byrne
- Huntington’s Disease Centre, Institute of Neurology, University College London, London, United Kingdom
| | - Peter McColgan
- Huntington’s Disease Centre, Institute of Neurology, University College London, London, United Kingdom
| | - Nicola Robertson
- Huntington’s Disease Centre, Institute of Neurology, University College London, London, United Kingdom
| | - Sarah J. Tabrizi
- Huntington’s Disease Centre, Institute of Neurology, University College London, London, United Kingdom
| | - Henrik Zetterberg
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
- Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom
| | - Edward J. Wild
- Huntington’s Disease Centre, Institute of Neurology, University College London, London, United Kingdom
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Sheen JM, Chen YC, Hsu MH, Tain YL, Yu HR, Huang LT. Combined Intraperitoneal and Intrathecal Etanercept Reduce Increased Brain Tumor Necrosis Factor-Alpha and Asymmetric Dimethylarginine Levels and Rescues Spatial Deficits in Young Rats after Bile Duct Ligation. Front Cell Neurosci 2016; 10:167. [PMID: 27445694 PMCID: PMC4917524 DOI: 10.3389/fncel.2016.00167] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 06/09/2016] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Rats subjected to bile duct ligation (BDL) exhibit increased systemic oxidative stress and brain dysfunction characteristic of hepatic encephalopathy (HE), including fatigue, neurotransmitter alterations, cognitive and motor impairment, and brain inflammation. The levels of tumor necrosis factor-alpha (TNF-α) and asymmetric dimethylarginine (ADMA) are both increased in plasma and brain in encephalopathy induced by chronic liver failure. This study first determined the temporal profiles of TNF-α and ADMA in the plasma, brain cortex, and hippocampus in young BDL rats. Next, we examined whether etanercept was beneficial in preventing brain damage. METHODS Young rats underwent sham ligation or BDL at day 17 ± 1 for 4 weeks. Treatment group rats were administered etanercept (10 mg/kg) intraperitoneally (IP) three times per week with or without etanercept (100 μg) intrathecally (IT) three times in total. RESULTS We found increased plasma TNF-α, soluble tumor necrosis factor receptor 1 (sTNFR1), soluble tumor necrosis factor receptor 2 (sTNFR2), and ADMA levels, increased cortical TNF-α mRNA and protein and ADMA, and hippocampal TNF-α mRNA and protein, and spatial defects in young BDL rats. The increase in cortex TNF-α mRNA and ADMA were reduced by IP etanercept or combined IP and IT etanercept. Dually IP/IT etanercept administration reduced the increased cortical and hippocampal TNF-α mRNA and protein level as well as spatial deficits. CONCLUSIONS We conclude that combined intraperitoneal and intrathecal etanercept reduce increased brain TNF-α and ADMA levels and rescues spatial deficits in young rats after BDL.
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Affiliation(s)
- Jiunn-Ming Sheen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan; Graduate Institute of Clinical Medical Sciences, Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Yu-Chieh Chen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan
| | - Mei-Hsin Hsu
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan
| | - You-Lin Tain
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan
| | - Hong-Ren Yu
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan
| | - Li-Tung Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan
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Wang Z, Young MRI. PTSD, a Disorder with an Immunological Component. Front Immunol 2016; 7:219. [PMID: 27375619 PMCID: PMC4893499 DOI: 10.3389/fimmu.2016.00219] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 05/23/2016] [Indexed: 12/27/2022] Open
Abstract
Post-traumatic stress disorder (PTSD) has been associated with an inflammatory state. However, few studies have addressed the mechanisms underlying this immune imbalance that favors inflammation or how this imbalance contributes to PTSD. Whether the immune imbalance influences responsiveness or unresponsiveness of patients to PTSD treatments is currently not known. This review brings forward an immune emphasis to a mental health disorder that is unprecedented in its prevalence among combat Veterans of the ongoing conflicts in Iraq and Afghanistan and which also afflicts civilians who have undergone extreme traumatic experiences, such as following natural disasters, serious accidents, or assaults. Included is an overview of the correlative associations in human subjects between PTSD and inflammation and studies in animal models of PTSD, demonstrating causal contributions of inflammation and immune dysregulation to PTSD-like behavior following stress exposure.
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Affiliation(s)
- Zhewu Wang
- Mental Health Service, Ralph H. Johnson VA Medical Center, Charleston, SC, USA; Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA
| | - M Rita I Young
- Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC, USA; Department of Otolaryngology - Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
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Gorky J, Schwaber J. The role of the gut-brain axis in alcohol use disorders. Prog Neuropsychopharmacol Biol Psychiatry 2016; 65:234-41. [PMID: 26188287 PMCID: PMC4679635 DOI: 10.1016/j.pnpbp.2015.06.013] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 06/23/2015] [Accepted: 06/24/2015] [Indexed: 02/08/2023]
Abstract
Neuroimmune and inflammatory processes have been locally associated with the amygdala in alcohol exposure and withdrawal. We and others have suggested that this inflammation in the amygdala may cause disturbance of neural function observed as anxiety and autonomic distress in withdrawal. Despite the potential importance of the robust neuroinflammatory response, the mechanisms contributing to this response are not well understood. We review literature that suggests the effects of alcohol, and other substances of abuse, cause dysbiosis of the gut microbiome. This peripheral response may modulate neuroprotective vagal afferent signaling that permits and exacerbates a neuroinflammatory response in the amygdala. We will examine the mounting evidence that suggests that (1) gut dysbiosis contributes to neuroinflammation, especially in the context of alcohol exposure and withdrawal, (2) the neuroinflammation in the amygdala involves the microglia and astrocytes and their effect on neural cells, and (3) amygdala neuroinflammation itself contributes directly to withdrawal behavior and symptoms. The contribution of the gut to an anxiogenic response is a promising therapeutic target for patients suffering with withdrawal symptoms given the safe and well-established methods of modulating the gut microbiome.
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Affiliation(s)
- Jonathan Gorky
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA
| | - James Schwaber
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
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Dell'Ovo V, Rosenzweig J, Burd I, Merabova N, Darbinian N, Goetzl L. An animal model for chorioamnionitis at term. Am J Obstet Gynecol 2015; 213:387.e1-10. [PMID: 25979619 PMCID: PMC4806536 DOI: 10.1016/j.ajog.2015.05.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Revised: 04/20/2015] [Accepted: 05/04/2015] [Indexed: 12/27/2022]
Abstract
OBJECTIVE The purpose of this study was to develop an animal model for intrapartum inflammation at term to investigate the interactions between maternal and fetal inflammatory responses and adverse neurologic outcome. STUDY DESIGN Lipopolysaccharide (160, 320, or 640 μg/kg) was administered intraperitoneally to day 20 term-pregnant Sprague Dawley rat dams 2, 4, and 6 hours before sample collection. Maternal outcomes included dam core temperature and plasma interleukin 6 (IL-6). Fetal outcomes included plasma IL-6, brain IL-6 messenger RNA expression, and brain IL-6 protein expression. Primary cortical cell cultures were prepared to examine neuronal morphologic condition. Neurite counts were obtained with the use of automated Sholl analysis. RESULTS Maternal plasma IL-6 levels peaked 2 hours after lipopolysaccharide stimulus and rapidly resolved, except for an observed low level persistence at 6 hours with 640 μg/kg. Fetal plasma and placental IL-6 expression also peaked rapidly but only persisted in placental samples. Fetal brain IL-6 RNA and protein expression was significantly higher than control litters at 6 hours after the exposure to both 320 μg/kg (P ≤ .05) and 640 μg/kg (P ≤ .01). Cortical cells from fetuses that were exposed for 6 hours to maternal systemic inflammation showed reduced neurite number and neurite length (P < .001) with increasing lipopolysaccharide dose. CONCLUSION Our results demonstrate that fetal brain injury follows isolated systemic maternal inflammation and that fetal brain inflammation lags after maternal stimulus, which creates a potential 4-hour clinical window for therapeutic intervention.
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Affiliation(s)
- Valeria Dell'Ovo
- Department of Obstetrics and Gynecology, Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center and Department of Obstetrics & Gynecology, Temple University School of Medicine, Philadelphia, PA
| | - Jason Rosenzweig
- Department of Obstetrics and Gynecology, Integrated Research Center for Fetal Medicine, Johns Hopkins University, Baltimore, MD
| | - Irina Burd
- Department of Obstetrics and Gynecology, Integrated Research Center for Fetal Medicine, Johns Hopkins University, Baltimore, MD
| | - Nana Merabova
- Department of Obstetrics and Gynecology, Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center and Department of Obstetrics & Gynecology, Temple University School of Medicine, Philadelphia, PA
| | - Nune Darbinian
- Department of Obstetrics and Gynecology, Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center and Department of Obstetrics & Gynecology, Temple University School of Medicine, Philadelphia, PA
| | - Laura Goetzl
- Department of Obstetrics and Gynecology, Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center and Department of Obstetrics & Gynecology, Temple University School of Medicine, Philadelphia, PA.
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Perez-Polo JR, Rea HC, Johnson KM, Parsley MA, Unabia GC, Xu GY, Prough D, DeWitt DS, Paulucci-Holthauzen AA, Werrbach-Perez K, Hulsebosch CE. Inflammatory cytokine receptor blockade in a rodent model of mild traumatic brain injury. J Neurosci Res 2015; 94:27-38. [PMID: 26172557 DOI: 10.1002/jnr.23617] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 05/24/2015] [Accepted: 06/15/2015] [Indexed: 12/14/2022]
Abstract
In rodent models of traumatic brain injury (TBI), both Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) levels increase early after injury to return later to basal levels. We have developed and characterized a rat mild fluid percussion model of TBI (mLFP injury) that results in righting reflex response times (RRRTs) that are less than those characteristic of moderate to severe LFP injury and yet increase IL-1α/β and TNFα levels. Here we report that blockade of IL-1α/β and TNFα binding to IL-1R and TNFR1, respectively, reduced neuropathology in parietal cortex, hippocampus, and thalamus and improved outcome. IL-1β binding to the type I IL-1 receptor (IL-1R1) can be blocked by a recombinant form of the endogenous IL-1R antagonist IL-1Ra (Kineret). TNFα binding to the TNF receptor (TNFR) can be blocked by the recombinant fusion protein etanercept, made up of a TNFR2 peptide fused to an Fc portion of human IgG1. There was no benefit from the combined blockades compared with individual blockades or after repeated treatments for 11 days after injury compared with one treatment at 1 hr after injury, when measured at 6 hr or 18 days, based on changes in neuropathology. There was also no further enhancement of blockade benefits after 18 days. Given that both Kineret and etanercept given singly or in combination showed similar beneficial effects and that TNFα also has a gliotransmitter role regulating AMPA receptor traffic, thus confounding effects of a TNFα blockade, we chose to focus on a single treatment with Kineret.
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Affiliation(s)
| | - H C Rea
- University of Texas Medical Branch, Galveston, Texas
| | - K M Johnson
- University of Texas Medical Branch, Galveston, Texas
| | - M A Parsley
- University of Texas Medical Branch, Galveston, Texas
| | - G C Unabia
- University of Texas Medical Branch, Galveston, Texas
| | - G-Y Xu
- University of Texas Medical Branch, Galveston, Texas
| | - D Prough
- University of Texas Medical Branch, Galveston, Texas
| | - D S DeWitt
- University of Texas Medical Branch, Galveston, Texas
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Hoeijmakers L, Lucassen PJ, Korosi A. The interplay of early-life stress, nutrition, and immune activation programs adult hippocampal structure and function. Front Mol Neurosci 2015; 7:103. [PMID: 25620909 PMCID: PMC4288131 DOI: 10.3389/fnmol.2014.00103] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 12/16/2014] [Indexed: 01/08/2023] Open
Abstract
Early-life adversity increases the vulnerability to develop psychopathologies and cognitive decline later in life. This association is supported by clinical and preclinical studies. Remarkably, experiences of stress during this sensitive period, in the form of abuse or neglect but also early malnutrition or an early immune challenge elicit very similar long-term effects on brain structure and function. During early-life, both exogenous factors like nutrition and maternal care, as well as endogenous modulators, including stress hormones and mediator of immunological activity affect brain development. The interplay of these key elements and their underlying molecular mechanisms are not fully understood. We discuss here the hypothesis that exposure to early-life adversity (specifically stress, under/malnutrition and infection) leads to life-long alterations in hippocampal-related cognitive functions, at least partly via changes in hippocampal neurogenesis. We further discuss how these different key elements of the early-life environment interact and affect one another and suggest that it is a synergistic action of these elements that shapes cognition throughout life. Finally, we consider different intervention studies aiming to prevent these early-life adversity induced consequences. The emerging evidence for the intriguing interplay of stress, nutrition, and immune activity in the early-life programming calls for a more in depth understanding of the interaction of these elements and the underlying mechanisms. This knowledge will help to develop intervention strategies that will converge on a more complete set of changes induced by early-life adversity.
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Affiliation(s)
- Lianne Hoeijmakers
- Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam Amsterdam, Netherlands
| | - Paul J Lucassen
- Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam Amsterdam, Netherlands
| | - Aniko Korosi
- Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam Amsterdam, Netherlands
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Fritze D, Zhang W, Li JY, Chai B, Mulholland MW. TNFα causes thrombin-dependent vagal neuron apoptosis in inflammatory bowel disease. J Gastrointest Surg 2014; 18:1632-41. [PMID: 24961441 PMCID: PMC4703123 DOI: 10.1007/s11605-014-2573-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 06/09/2014] [Indexed: 01/31/2023]
Abstract
BACKGROUND The role of peripheral tumor necrosis factor alpha (TNFα) in inflammatory bowel disease (IBD) is well established, but its central nervous system (CNS) effects are not understood. Thrombin, another mediator of inflammation in IBD, has been implicated in CNS vagal neuron apoptosis in the dorsal motor nucleus of the vagus (DMV). This study evaluates DMV TNFα exposure, characterizes effects of TNFα on DMV neurons, and identifies a relationship between DMV TNFα and thrombin in IBD. METHODS 2,4,6-Trinitrobenzene sulfonic acid was administered via enema to induce colonic inflammation in rats. TNFα in serum, cerebrospinal fluid (CSF), and DMV tissues were determined by ELISA and DMV TNFα expression by quantitative reverse transcription PCR (RT-PCR). TNFα was administered into the fourth intracerebral ventricle (4 V) adjacent to the DMV, with and without blockade of TNF receptor 1 (TNFR1) and the thrombin receptor proteinase-activated receptor 1 (PAR1). Immunofluorescence was used to evaluate microglial activation (Cd11b) and prothrombin presence in DMV sections. Apoptosis was examined using terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) and activated caspase-3 immunofluorescence. RESULTS IBD is associated with increased TNFα protein in serum, CSF, and DMV tissue; DMV TNFα transcription is also increased. TNFα (4 V) caused a 54 % increase in microglial activation, a 27 % increase in DMV prothrombin protein, and a 31 % increase in vagal neuron apoptosis by TUNEL. There was a 52 % increase in activated caspase-3 immunofluorescence in TNFα-treated animals (p < 0.05). All effects of 4 V TNFα were prevented by TNFR1 blockade. TNFα-induced apoptosis was prevented by PAR1 blockade. CONCLUSIONS IBD is associated with DMV exposure to TNFα, causing excess DMV prothrombin and vagal apoptosis.
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Affiliation(s)
- Danielle Fritze
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
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31
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Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother 2014; 10:985-1002. [DOI: 10.1586/ern.10.52] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Abstract
There is increasing recognition of the involvement of the immune signaling molecule, tumor necrosis factor (TNF), in the pathophysiology of stroke and chronic brain dysfunction. TNF plays an important role both in modulating synaptic function and in the pathogenesis of neuropathic pain. Etanercept is a recombinant therapeutic that neutralizes pathologic levels of TNF. Brain imaging has demonstrated chronic intracerebral microglial activation and neuroinflammation following stroke and other forms of acute brain injury. Activated microglia release TNF, which mediates neurotoxicity in the stroke penumbra. Recent observational studies have reported rapid and sustained improvement in chronic post-stroke neurological and cognitive dysfunction following perispinal administration of etanercept. The biological plausibility of these results is supported by independent evidence demonstrating reduction in cognitive dysfunction, neuropathic pain, and microglial activation following the use of etanercept, as well as multiple studies reporting improvement in stroke outcome and cognitive impairment following therapeutic strategies designed to inhibit TNF. The causal association between etanercept treatment and reduction in post-stroke disability satisfy all of the Bradford Hill Criteria: strength of the association; consistency; specificity; temporality; biological gradient; biological plausibility; coherence; experimental evidence; and analogy. Recognition that chronic microglial activation and pathologic TNF concentration are targets that may be therapeutically addressed for years following stroke and other forms of acute brain injury provides an exciting new direction for research and treatment.
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Rosenzweig JM, Lei J, Burd I. Interleukin-1 receptor blockade in perinatal brain injury. Front Pediatr 2014; 2:108. [PMID: 25340046 PMCID: PMC4187538 DOI: 10.3389/fped.2014.00108] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 09/23/2014] [Indexed: 12/13/2022] Open
Abstract
Interleukin-1 (IL-1) is a potent inflammatory cytokine that can be produced by a variety of cell types throughout the body. While IL-1 is a central mediator of inflammation and response to infection, the role of IL-1 signaling in adult and pediatric brain injury is becoming increasingly clear. Although the mechanisms of IL-1 expression are largely understood, the downstream effects and contributions to excitotoxicity and oxidative stress are poorly defined. Here, we present a review of mechanisms of IL-1 signaling with a focus on the role of IL-1 in perinatal brain injury. We highlight research models of perinatal brain injury and the use of interleukin-1 receptor antagonist (IL-1RA) as an agent of therapeutic potential in preventing perinatal brain injury due to exposure to inflammation.
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Affiliation(s)
- Jason M Rosenzweig
- Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine , Baltimore, MD , USA
| | - Jun Lei
- Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine , Baltimore, MD , USA
| | - Irina Burd
- Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine , Baltimore, MD , USA ; Department of Neuroscience, Kennedy Krieger Institute , Baltimore, MD , USA ; Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, MD , USA
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Metti AL, Cauley JA. How predictive of dementia are peripheral inflammatory markers in the elderly? Neurodegener Dis Manag 2012; 2:609-622. [PMID: 23441140 DOI: 10.2217/nmt.12.68] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Dementia is a huge public health concern today owing to the exponentially increasing number of older adults it affects each year, and there has been a large number of investigators looking at potential biomarkers of dementia. Peripheral inflammatory markers have emerged as one potential class of markers that may be useful in predicting those individuals at a greater risk of developing dementia, or in expounding the underlying mechanisms or pathways of this complex disease. Although some evidence has been promising, indicating that peripheral inflammatory markers are indeed crucial in brain changes that occur in both normal aging and in dementia, results have been mixed on their usefulness for predicting dementia or cognitive decline in older adults. Here, the authors present a review of existing studies investigating inflammatory markers as potential biomarkers of dementia, highlighting some strengths and limitations of the current research and discuss the future directions for this field.
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Affiliation(s)
- Andrea L Metti
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, PA, USA ; University of Pittsburgh Department of Epidemiology, Center for Aging & Population Health, 130 N Bellefield, Room 456, Pittsburgh, PA 15213, USA
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Tobinick E, Kim NM, Reyzin G, Rodriguez-Romanacce H, DePuy V. Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs 2012; 26:1051-70. [PMID: 23100196 DOI: 10.1007/s40263-012-0013-2] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Brain injury from stroke and traumatic brain injury (TBI) may result in a persistent neuroinflammatory response in the injury penumbra. This response may include microglial activation and excess levels of tumour necrosis factor (TNF). Previous experimental data suggest that etanercept, a selective TNF inhibitor, has the ability to ameliorate microglial activation and modulate the adverse synaptic effects of excess TNF. Perispinal administration may enhance etanercept delivery across the blood-CSF barrier. OBJECTIVE The objective of this study was to systematically examine the clinical response following perispinal administration of etanercept in a cohort of patients with chronic neurological dysfunction after stroke and TBI. METHODS After approval by an independent external institutional review board (IRB), a chart review of all patients with chronic neurological dysfunction following stroke or TBI who were treated open-label with perispinal etanercept (PSE) from November 1, 2010 to July 14, 2012 at a group medical practice was performed. RESULTS The treated cohort included 629 consecutive patients. Charts of 617 patients following stroke and 12 patients following TBI were reviewed. The mean age of the stroke patients was 65.8 years ± 13.15 (range 13-97). The mean interval between treatment with PSE and stroke was 42.0 ± 57.84 months (range 0.5-419); for TBI the mean interval was 115.2 ± 160.22 months (range 4-537). Statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioural function, aphasia and pain were noted in the stroke group, with a wide variety of additional clinical improvements noted in individuals, such as reductions in pseudobulbar affect and urinary incontinence. Improvements in multiple domains were typical. Significant improvement was noted irrespective of the length of time before treatment was initiated; there was evidence of a strong treatment effect even in the subgroup of patients treated more than 10 years after stroke and TBI. In the TBI cohort, motor impairment and spasticity were statistically significantly reduced. DISCUSSION Irrespective of the methodological limitations, the present results provide clinical evidence that stroke and TBI may lead to a persistent and ongoing neuroinflammatory response in the brain that is amenable to therapeutic intervention by selective inhibition of TNF, even years after the acute injury. CONCLUSION Excess TNF contributes to chronic neurological, neuropsychiatric and clinical impairment after stroke and TBI. Perispinal administration of etanercept produces clinical improvement in patients with chronic neurological dysfunction following stroke and TBI. The therapeutic window extends beyond a decade after stroke and TBI. Randomized clinical trials will be necessary to further quantify and characterize the clinical response.
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Affiliation(s)
- Edward Tobinick
- Institute of Neurological Recovery, 100 UCLA Medical Plaza, Suites 205-210, Los Angeles, CA 90095, USA.
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Ashok BK, Ravishankar B, Prajapati PK, Bhat SD. Antipyretic activity of Guduchi Ghrita formulations in albino rats. Ayu 2012; 31:367-70. [PMID: 22131741 PMCID: PMC3221073 DOI: 10.4103/0974-8520.77162] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The present pharmacological investigation was undertaken to study the anti-pyretic activity of Guduchi ghrita formulations in albino rats against yeast induced pyrexia. Seven groups of six animals were used for the experiment. The yeast induced pyrexia method was standardized first by injecting 12.5% yeast suspension (s.c) followed by recording the rectal temperature at regular intervals. Then the evaluation of anti-pyretic activity of Guduchi ghrita formulations was carried out by using this standard procedure. Both the Guduchi ghrita samples including vehicle significantly attenuated the raise in temperature after three hours of yeast injection. After 6 and 9 hours of yeast injection also both the Guduchi ghrita samples attenuated the raise in temperature in a highly significant manner in comparison to both yeast control and vehicle control groups. The data generated during study shows that both the Guduchi ghrita formulations having significant anti-pyretic activity.
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Affiliation(s)
- B K Ashok
- Pharmacology laboratory, Institute for Post Graduate Teaching and Research in Ayurveda, Gujarat Ayurved University, Gujarat, India
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A systematic review of the association between immunogenomic markers and cancer-related fatigue. Brain Behav Immun 2012; 26:830-48. [PMID: 22595751 PMCID: PMC3398196 DOI: 10.1016/j.bbi.2012.05.004] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 04/24/2012] [Accepted: 05/08/2012] [Indexed: 01/04/2023] Open
Abstract
Fatigue, which is one of the most commonly reported symptoms in cancer, can negatively impact the functional status and the health-related quality of life of individuals. This paper systematically reviews 34 studies to determine patterns of associations between immunogenomic markers and levels of cancer-related fatigue (CRF). Findings from the longitudinal studies revealed that elevated fatigue symptoms especially of women with early stages of breast cancer were associated with high levels of neutrophil/monocyte, IL-1ra, and IL-6 during radiation therapy; high levels of CD4+, IL-1β, and IL-6 with stressing stimuli; high levels of IL-1β during chemotherapy; low NK cell levels after chemotherapy; and presence of homozygous IL-6 and TNF alleles. In the cross-sectional studies, associations between levels of fatigue and immune/inflammatory markers were not consistently found, especially when covariates such as BMI, ethnicity, menopausal status, and educational level were controlled in the statistical analyses. However, a number of genomic markers were observed to be elevated mostly in fatigued breast cancer survivors in the cross-sectional studies. Gaps in knowledge and recommendations for future research are discussed.
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Piras F, Salani F, Bossù P, Caltagirone C, Spalletta G. High serum levels of transforming growth factor β1 are associated with increased cortical thickness in cingulate and right frontal areas in healthy subjects. J Neuroinflammation 2012; 9:42. [PMID: 22373370 PMCID: PMC3359165 DOI: 10.1186/1742-2094-9-42] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Accepted: 02/28/2012] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Transforming growth factor β (TGF-β) is a cytokine having multiple functions in the central nervous system such as promoting repair mechanisms in degenerative diseases and stroke. To date, however, its neuroprotective effects in non-disease conditions have not been studied METHODS With the aim of exploring the relationship between peripheral TGF-β1 expression and brain structural integrity, 70 healthy participants underwent high-resolution structural T1-weighted magnetic resonance imaging scans and blood sampling. Data were processed to obtain brain cortical thickness and serum concentrations of TGF-β1. We investigated the correlation between TGF-β1 and cortical thickness using both region-of-interest- and vertex-based approaches. FINDINGS Region-of-interest-based analysis of the cortical mantle showed a correlation between TGF-β1 serum concentrations and cortical thickness bilaterally in cingulate and right frontal and temporal areas. Similar results emerged in the vertex-based analysis, where significant correlations were found bilaterally in cingulate and right frontal cortices. CONCLUSIONS These results suggest that TGF-β1, through its role in down-regulating inflammatory processes, might have a beneficial effect on the structural integrity of the brain in physiological states.
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Affiliation(s)
- Fabrizio Piras
- Fondazione IRCCS Santa Lucia, Via Ardeatina 306, 00179 Rome, Italy.
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Etanercept for sleep in patients with alcohol use disorder--mechanisms need to be elucidated. Biol Psychiatry 2010; 67:e1; author reply e3. [PMID: 19683705 DOI: 10.1016/j.biopsych.2009.06.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2009] [Revised: 05/29/2009] [Accepted: 06/01/2009] [Indexed: 11/22/2022]
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Tobinick E. Tumour necrosis factor modulation for treatment of Alzheimer's disease: rationale and current evidence. CNS Drugs 2009; 23:713-25. [PMID: 19689163 DOI: 10.2165/11310810-000000000-00000] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Tumour necrosis factor (TNF), a key regulator of varied physiological mechanisms in multiple organ systems, is an immune signalling molecule produced by glia, neurons, macrophages and other immune cells. In the brain, among other functions, TNF serves as a gliotransmitter, secreted by glial cells that envelope and surround synapses, which regulates synaptic communication between neurons. The role of TNF as a gliotransmitter may help explain the profound synaptic effects of TNF that have been demonstrated in the hippocampus, in the spinal cord and in a variety of experimental models. Excess TNF is present in the CSF of individuals with Alzheimer's disease (AD), and has been implicated as a mediator of the synaptic dysfunction that is hypothesized to play a central role in the pathogenesis of AD. TNF may also play a role in endothelial and microvascular dysfunction in AD, and in amyloidogenesis and amyloid-induced memory dysfunction in AD. Genetic and epidemiological evidence has implicated increased TNF production as a risk factor for AD. Perispinal administration of etanercept, a potent anti-TNF fusion protein, produced sustained clinical improvement in a 6-month, open-label pilot study in patients with AD ranging from mild to severe. Subsequent case studies have documented rapid clinical improvement following perispinal etanercept in both AD and primary progressive aphasia, providing evidence of rapidly reversible, TNF-dependent, pathophysiological mechanisms in AD and related disorders. Perispinal etanercept for AD merits further study in randomized clinical trials.
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Affiliation(s)
- Edward Tobinick
- Institute for Neurological Research, Los Angeles, California 90095, USA.
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Rapid intracerebroventricular delivery of Cu-DOTA-etanercept after peripheral administration demonstrated by PET imaging. BMC Res Notes 2009; 2:28. [PMID: 19284700 PMCID: PMC2651903 DOI: 10.1186/1756-0500-2-28] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2008] [Accepted: 02/27/2009] [Indexed: 02/07/2023] Open
Abstract
Background The cytokines interleukin-1 and tumor necrosis factor (TNF), and the cytokine blocker interleukin-1 receptor antagonist, all have been demonstrated to enter the cerebrospinal fluid (CSF) following peripheral administration. Recent reports of rapid clinical improvement in patients with Alzheimer's disease and related forms of dementia following perispinal administration of etanercept, a TNF antagonist, suggest that etanercept also has the ability to reach the brain CSF. To investigate, etanercept was labeled with a positron emitter to enable visualization of its intracranial distribution following peripheral administration by PET in an animal model. Findings Radiolabeling of etanercept with the PET emitter 64Cu was performed by DOTA (1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid) conjugation of etanercept, followed by column purification and 64Cu labeling. MicroPET imaging revealed accumulation of 64Cu-DOTA-etanercept within the lateral and third cerebral ventricles within minutes of peripheral perispinal administration in a normal rat anesthesized with isoflurane anesthesia, with concentration within the choroid plexus and into the CSF. Conclusion Synthesis of 64Cu-DOTA-etanercept enabled visualization of its intracranial distribution by microPET imaging. MicroPET imaging documented rapid accumulation of 64Cu-DOTA-etanercept within the choroid plexus and the cerebrospinal fluid within the cerebral ventricles of a living rat after peripheral administration. Further study of the effects of etanercept and TNF at the level of the choroid plexus may yield valuable insights into the pathogenesis of Alzheimer's disease.
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Abstract
Nosocomial hyperthermia (fever) occurs in about 30% of all medical patients at some time during their hospital stay. In patients admitted to the intensive care unit with severe sepsis the incidence of hyperthermia is greater than 90%, while in a specialized neurological critical care unit the incidence is reported as 47%. In contrast, hyperthermia during anaesthesia is rare owing to the impairment of thermoregulation by anaesthetic agents. This article is designed to give an overview on the various causes of hyperthermia with special emphasis on fever during general and regional anaesthesia in general and neurological critical care patients.
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Tobinick E. Perispinal etanercept for neuroinflammatory disorders. Drug Discov Today 2009; 14:168-77. [DOI: 10.1016/j.drudis.2008.10.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2008] [Revised: 10/13/2008] [Accepted: 10/22/2008] [Indexed: 12/31/2022]
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Smith MW, Gumbleton M. Endocytosis at the blood–brain barrier: From basic understanding to drug delivery strategies. J Drug Target 2008; 14:191-214. [PMID: 16777679 DOI: 10.1080/10611860600650086] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
The blood-brain barrier (BBB) protects the central nervous system (CNS) from potentially harmful xenobiotics and endogenous molecules. Anatomically, it comprises the brain microvasculature whose functionality is nevertheless influenced by associated astrocyte, pericyte and neuronal cells. The highly restrictive paracellular pathway within brain microvasculature restricts significant CNS penetration to only those drugs whose physicochemical properties afford ready penetration into hydrophobic cell membranes or are capable of exploiting endogenous active transport processes such as solute carriers or endocytosis pathways. Endocytosis at the BBB is an essential pathway by which the brain obtains its nutrients and affords communication with the periphery. The development of strategies to exploit these endocytic pathways for the purposes of drug delivery to the CNS is still an immature field although some impressive results have been documented with the targeting of particular receptors. This current article initially provides an overview of general endocytosis processes and pathways showing evidence of their functional existence within the BBB. Subsequent sections provide, in an entity-specific manner, comprehensive reviews on BBB transport investigations of endocytosis involving: transferrin and the targeting of the transferrin receptor; hormones; cytokines; cell penetrating peptides; microorganisms and toxins, and nanoparticles aimed at more effectively delivering drugs to the CNS.
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Affiliation(s)
- Mathew W Smith
- Pharmaceutical Cell Biology, Welsh School of Pharmacy, Cardiff University, Redwood Building, Cardiff CF10 3XF, UK
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Tobinick EL, Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease. BMC Neurol 2008; 8:27. [PMID: 18644112 PMCID: PMC2500042 DOI: 10.1186/1471-2377-8-27] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2008] [Accepted: 07/21/2008] [Indexed: 12/31/2022] Open
Abstract
Background Recent clinical studies point to rapid and sustained clinical, cognitive, and behavioral improvement in both Alzheimer's disease and primary progressive aphasia following weekly perispinal administration of etanercept, a TNF-alpha inhibitor that acts by blocking the binding of this cytokine to its receptors. This outcome is concordant with recent basic science studies suggesting that TNF-alpha functions in vivo as a gliotransmitter that regulates synaptic function in the brain. We hypothesized that perispinal etanercept had the potential to improve verbal function in Alzheimer's disease, so we included several standarized measures of verbal ability to evaluate language skills in a clinical trial of perispinal etanercept for Alzheimer's disease. Methods This was a prospective, single-center, open-label, pilot study, in which 12 patients with mild-to-severe Alzheimer's disease were administered etanercept, 25–50 mg, weekly by perispinal administration for six months. Two additional case studies are presented. Results Two-tailed, paired t-tests were conducted comparing baseline performance to 6-month performance on all neuropsychological measures. Test batteries included the California Verbal Learning Test-Second Edition, Adult Version; Logical Memory I and II(WMS-LM-II) from the Wechsler Memory Scale-Abbreviated; the Comprehensive Trail Making Test (TMT); Boston Naming Test; and letter(FAS) and category verbal fluency. All measures revealed a significant effect except for the Boston Naming Test and the TMT-4, with WMS-LM-II being marginally significant at p = .05. The FAS test for letter fluency was most highly significant with a p < 0.0007. In addition, rapid improvement in verbal fluency and aphasia in two patients with dementia, beginning minutes after perispinal etanercept administration, is documented. Conclusion In combination with the previously reported results of perispinal etanercept in Alzheimer's disease and primary progressive aphasia, these results further argue that larger scale studies of this therapeutic intervention, including Phase 3 trials, are warranted in dementias. In addition, these results may provide insight into the basic pathophysiologic mechanisms underlying Alzheimer's disease and related forms of dementia, and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in Alzheimer's disease which are worthy of further investigation.
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Affiliation(s)
- Edward L Tobinick
- Institute for Neurological Research, a private medical group, inc., Los Angeles, USA.
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Conti B, Tabarean I, Sanchez-Alavez M, Davis C, Brownell S, Behrens M, Bartfai T. Cytokine Receptors in the Brain. CYTOKINES AND THE BRAIN 2008. [DOI: 10.1016/s1567-7443(07)10002-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Abstract
Evidence both from mice and cultured cells suggests an important role of soluble leptin receptors in obesity and leptin signaling. However, the direct effects of soluble receptors on leptin uptake by cells are not clear. This study shows that soluble leptin receptors antagonize the permeation of leptin across the mouse blood-brain barrier by reducing the binding and endocytosis of leptin. This is illustrated by analysis of radioactively labeled and fluorescent-tagged leptin in normal mice and in cultured cells overexpressing various forms of leptin receptors. Three constructs of soluble leptin receptors were generated in this study: ObRe (805 aa), ObR839, and ObR852. (125)I-leptin was injected intravenously and its influx rate from blood to brain determined by multiple-time regression analysis. Pre-incubation with ObR839 caused a significant reduction of leptin influx across the blood-brain barrier. Endocytosis assays and fluorescent image analysis further showed that ObRe, ObR839, and ObR852 failed to mediate leptin internalization and trafficking within the cells. Instead, these soluble receptors inhibited surface binding and endocytosis of leptin. Thus, we provide novel direct evidence both in vivo and in vitro that soluble receptors of leptin serve as antagonists of the transport of leptin.
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Affiliation(s)
- Hong Tu
- Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA
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Endogenous antipyretics. Clin Chim Acta 2006; 371:13-24. [DOI: 10.1016/j.cca.2006.02.013] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2005] [Revised: 01/21/2006] [Accepted: 02/09/2006] [Indexed: 11/23/2022]
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Johnson AB, Bake S, Lewis DK, Sohrabji F. Temporal expression of IL-1beta protein and mRNA in the brain after systemic LPS injection is affected by age and estrogen. J Neuroimmunol 2006; 174:82-91. [PMID: 16530273 DOI: 10.1016/j.jneuroim.2006.01.019] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2005] [Revised: 01/19/2006] [Accepted: 01/27/2006] [Indexed: 11/17/2022]
Abstract
Estrogen has been shown to suppress neural inflammation in vivo in response to intracerebral LPS injections or by intraparenchymal injections of NMDA. Using the latter approach, we have shown that estrogen suppresses inflammatory cytokine expression in lesioned ovariectomized young adult females but not reproductive senescent animals. However, in cultured microglia derived from either young or senescent animals, estrogen fails to suppress LPS-induced cytokine expression. These data suggest that estrogen's effects on the neural inflammatory response may result from its actions on blood-borne immune cells or its actions at the blood brain barrier or both. This hypothesis was directly tested here using a systemic injury model and comparing the neural inflammatory response in the olfactory bulb, which is protected by the blood brain barrier, and in the pituitary gland, which is incompletely protected by the blood brain barrier. Young and senescent Sprague-Dawley female rats were ovariectomized and replaced with either an estrogen or placebo pellet. Three weeks later, animals received a single i.p. injection of LPS (or vehicle) and were terminated 0.5, 2 or 3h later. Systemic injections of LPS increased IL-1beta expression in the liver in a time-dependent manner in young and senescent females. In young adults, LPS increased cytokine expression in both the bulb and the pituitary gland. However, estrogen treatment attenuated IL-1beta expression in the olfactory bulb but not in the pituitary gland. In senescent animals, estrogen completely suppressed IL-1beta expression in the bulb and the pituitary gland, while placebo-replaced animals responded normally. This age-related difference in cytokine induction by LPS was also seen in mRNA regulation, such that LPS induced IL-1beta mRNA in the olfactory bulb of young adults but not in the senescent female. Age and hormone effects on pituitary cytokines were also mirrored in plasma corticosterone (CORT) levels, such that estrogen treatment to senescent females attenuated LPS-induced CORT. These data suggest that the central inflammatory response to a systemic insult can be modulated by estrogen although the mechanism underlying the initiation of this response varies with reproductive age.
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Affiliation(s)
- Adam B Johnson
- Department of Anatomy and Medical Neurobiology, TAMUS Health Science Center, 228 Reynolds Medical Building, College Station, TX 77843-1114, USA
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