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Gordh, T
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Publications (10 of 65) Show all publications
Emami Khoonsari, P., Musunri, S., Herman, S., Svensson, C. I., Tanum, L., Gordh, T. & Kultima, K. (2019). Systematic Analysis of the Cerebrospinal Fluid Proteome of Fibromyalgia patients. Journal of Proteomics, 35-43
Open this publication in new window or tab >>Systematic Analysis of the Cerebrospinal Fluid Proteome of Fibromyalgia patients
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2019 (English)In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, p. 35-43Article in journal (Refereed) Published
Abstract [en]

Fibromyalgia (FM) is a syndrome characterized by widespread muscular pain, fatigue and functional symptoms, which is known to be difficult to diagnose as the various symptoms overlap with many other conditions. Currently, there are no biomarkers for FM, and the diagnosis is made subjectively by the clinicians. We have performed shotgun proteomics on cerebrospinal fluid (CSF) from FM patients and non-pain controls to find potential biomarker candidates for this syndrome. Based on our multivariate and univariate analyses, we found that the relative differences in the CSF proteome between FM patients and controls were moderate. Four proteins, important to discriminate FM patients from non-pain controls, were found: Apolipoprotein C-III, Galectin-3-binding protein, Malate dehydrogenase cytoplasmic and the neuropeptide precursor protein ProSAAS. These proteins are involved in lipoprotein lipase (LPL) activity, inflammatory signaling, energy metabolism and neuropeptide signaling.

Keywords
cerebrospinal fluid, biomarker, chronic pain, fibromyalgia, inflammation, neuroinflammation, mass spectrometry
National Category
Neurosciences Clinical Laboratory Medicine Biomedical Laboratory Science/Technology
Research subject
Bioinformatics; Biology with specialization in Molecular Biology; Chemistry with specialization in Analytical Chemistry; Medical Science; Clinical Chemistry
Identifiers
urn:nbn:se:uu:diva-331615 (URN)10.1016/j.jprot.2018.04.014 (DOI)000450381500006 ()29656018 (PubMedID)
Funder
Magnus Bergvall FoundationLars Hierta Memorial FoundationÅke Wiberg FoundationThe Karolinska Institutet's Research Foundation
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2018-12-20Bibliographically approved
Philippot, G., Hallgren, S., Gordh, T., Fredriksson, A., Fredriksson, R. & Viberg, H. (2018). A Cannabinoid Receptor Type 1 (CB1R) Agonist Enhances the Developmental Neurotoxicity of Acetaminophen (Paracetamol). Toxicological Sciences, 166(1), 203-212
Open this publication in new window or tab >>A Cannabinoid Receptor Type 1 (CB1R) Agonist Enhances the Developmental Neurotoxicity of Acetaminophen (Paracetamol)
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2018 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 166, no 1, p. 203-212Article in journal (Refereed) Published
Abstract [en]

Acetaminophen (AAP; also known as paracetamol) is the most used and only recommended analgesic and antipyretic among pregnant women and young children. However, recent findings in both humans and rodents suggest a link between developmental exposure to AAP and adverse neurobehavioral effects later in life. We hypothesized that the cannabinoid receptor type 1 (CB1R) may be involved in the developmental neurotoxicity of AAP, owing to its interaction with the endocannabinoid system. Here we test if CB1R agonist WIN 55 212-2 (WIN) and AAP can interact when exposure occurs during a neurodevelopmental stage known for increased growth rate and for its vulnerability to AAP exposure. We exposed male NMRI mice on postnatal day 10 to different combinations of AAP and WIN. Adult mice, neonatally co-exposed to AAP and WIN, displayed a significant lack of habituation in the spontaneous behavior test, when compared with controls and single agent exposed mice. These adult adverse effects may at least in part be explained by a reduction of transcript levels of hippocampal synaptophysin (Syp) and tropomyosin receptor kinase B (Trkb), and cerebral cortical fatty acid amide hydroxylase (Faah), 24h after exposure. These findings are consistent with our hypothesis that AAP and WIN can interact when exposure occurs during early postnatal brain development in mice. Assuming our results are relevant for humans, they raise concerns on AAP safety because it is the only recommended analgesic and antipyretic during pregnancy and early life.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
Keywords
developmental toxicity, acetaminophen (paracetamol), CB1R, spontaneous behavior, habituation
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-372828 (URN)10.1093/toxsci/kfy199 (DOI)000453585900016 ()30165669 (PubMedID)
Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2019-01-09Bibliographically approved
Lesniak, A., Aarnio, M., Diwakarla, S., Norberg, T., Nyberg, F. & Gordh, T. (2018). Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.. Life Sciences, 194, 26-33
Open this publication in new window or tab >>Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.
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2018 (English)In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 194, p. 26-33Article in journal (Refereed) Published
Abstract [en]

Aims: D-Deprenyl when used as a positron emission tomography tracer visualizes peripheral inflammation. The major aim of the current study was to identify and investigate the properties of the binding target for D-deprenyl in synovial membrane explants from arthritic patients.

Main methods: Thirty patients diagnosed with arthritis or osteoarthritis were enrolled into the study. Homologous and competitive radioligand binding assays utilizing [H-3]D-deprenyl were performed to investigate the biochemical characteristics of the binding site and assess differences in the binding profile in synovial membranes exhibiting varying levels of inflammation.

Key findings: The [H-3]D-deprenyl binding assay confirmed the existence of a single, saturable population of membrane-bound protein binding sites in synovial membrane homogenates. The macroscopically determined level of inflammation correlated with an increase in [H-3]D-deprenyl binding affinity, without significant alterations in binding site density. Selective monoamine oxidase B inhibitor, selegiline competed for the same site as [H-3]D-deprenyl, but failed to differentiate the samples with regard to their inflammation grade. A monoamine oxidase A inhibitor, pirlindole mesylate showed only weak displacement of [H-3]D-deprenyl binding. No significant alterations in monoamine oxidase B expression was detected, thus it was not confirmed whether it could serve as a marker for ongoing inflammation.

Significance: Our study was the first to show the biochemical characteristics of the [H-3]D-deprenyl binding site in inflamed human synovium. We confirmed that d-deprenyl could differentiate between patients with varying severity of synovitis in the knee joint by binding to a protein target distinct from monoamine oxidase B.

Keywords
Arthritis, Binding target, Monoamine oxidase B, Synovium, d-Deprenyl
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Biochemistry; Medical Biochemistry
Identifiers
urn:nbn:se:uu:diva-347601 (URN)10.1016/j.lfs.2017.12.003 (DOI)000425052000004 ()29221756 (PubMedID)
Funder
Swedish Research Council, 9459
Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2018-04-18Bibliographically approved
Buratovic, S., Stenerlöw, B., Sundell-Bergman, S., Fredriksson, A., Viberg, H., Gordh, T. & Eriksson, P. (2018). Effects on adult cognitive function after neonatal exposure to clinically relevant doses of ionising radiation and ketamine in mice. British Journal of Anaesthesia, 120(3), 546-554
Open this publication in new window or tab >>Effects on adult cognitive function after neonatal exposure to clinically relevant doses of ionising radiation and ketamine in mice
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2018 (English)In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 120, no 3, p. 546-554Article in journal (Refereed) Published
Abstract [en]

Background: Radiological methods for screening, diagnostics and therapy are frequently used in healthcare. In infants and children, anaesthesia/sedation is often used in these situations to relieve the patients' perception of stress or pain. Both ionising radiation (IR) and ketamine have been shown to induce developmental neurotoxic effects and this study aimed to identify the combined effects of these in a murine model. Methods: Male mice were exposed to a single dose of ketamine (7.5 mg kg(-1) body weight) s.c. on postnatal day 10. One hour after ketamine exposure, mice were whole body irradiated with 50-200 mGy gamma radiation (Cs-137). Behavioural observations were performed at 2, 4 and 5 months of age. At 6 months of age, cerebral cortex and hippocampus tissue were analysed for neuroprotein levels. Results: Animals co-exposed to IR and ketamine displayed significant (P <= 0.01) lack of habituation in the spontaneous behaviour test, when compared with controls and single agent exposed mice. In the Morris Water Maze test, co-exposed animals showed significant (P <= 0.05) impaired learning and memory capacity in both the spatial acquisition task and the relearning test compared with controls and single agent exposed mice. Furthermore, in co-exposed mice a significantly (P <= 0.05) elevated level of tau protein in cerebral cortex was observed. Single agent exposure did not cause any significant effects on the investigated endpoints. Conclusion: Co-exposure to IR and ketamine can aggravate developmental neurotoxic effects at doses where the single agent exposure does not impact on the measured variables. These findings show that estimation of risk after paediatric low-dose IR exposure, based upon radiation dose alone, may underestimate the consequences for this vulnerable population.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2018
Keywords
cognition, gamma rays, ketamine, mice, tau proteins
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-360552 (URN)10.1016/j.bja.2017.11.099 (DOI)000438191300019 ()29452811 (PubMedID)
Funder
Swedish Radiation Safety Authority
Available from: 2018-09-14 Created: 2018-09-14 Last updated: 2018-09-14Bibliographically approved
Solheim, N., Gregersen, I., Halvorsen, B., Bjerkeli, V., Stubhaug, A., Gordh, T. & Rosseland, L. A. (2018). Randomized controlled trial of intra-articular ketorolac on pain and inflammation after minor arthroscopic knee surgery. Acta Anaesthesiologica Scandinavica, 62(6), 829-838
Open this publication in new window or tab >>Randomized controlled trial of intra-articular ketorolac on pain and inflammation after minor arthroscopic knee surgery
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2018 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 62, no 6, p. 829-838Article in journal (Refereed) Published
Abstract [en]

Background: Ketorolac is an effective non-steroidal anti-inflammatory drug, commonly used with local anaesthetics as part of local infiltration analgesia protocols following orthopaedic surgery. However, systemic uptake and drug action may be the major mechanism after local infiltration. The aims of this project were to study the effects of a small, systemically ineffective dose of ketorolac given intra-articularly for post-operative pain and also to study synovial inflammatory biomarkers. We investigated whether ketorolac affects pro-inflammatory biomarkers in an invitro model, as well.

Methods: In this placebo-controlled, blind, randomized study, we analysed intra-articular ketorolac (5mg) in ambulatory minor knee surgery patients with moderate or severe pain (n=44). We assessed post-operative pain intensity (n=44) and analysed microdialysis samples taken from knee synovial tissue every 20min (n=34). We also tested cyclooxygenase-independent effects of ketorolac in synovial cells stimulated by prostaglandin E-2 and chondroitin sulphate invitro.

Results: Intra-articular ketorolac (5mg) administration did not reduce pain or synovial pro-inflammatory cytokines CXCL1, IL-8, and MCP-1, 0-120min after knee arthroscopy. Female gender was a risk factor for moderate or severe pain (relative risk 1.45, 95% confidence interval 1.04-2.01). Paradoxically, ketorolac increased the release of CXCL1 and IL-8 in prostaglandin E-2 and chondroitin sulphate-stimulated synovial cells invitro.

Conclusion: Ketorolac prescribed at a low dose intra-articularly does not produce any detectable analgesic effect after minor knee surgery.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-358365 (URN)10.1111/aas.13104 (DOI)000434205100013 ()29512121 (PubMedID)
Available from: 2018-08-29 Created: 2018-08-29 Last updated: 2018-08-29Bibliographically approved
Gordh, T. (2017). A possible biomarker of low back pain: 18F-FDeoxyGlucose uptake in PETscan and CT of the spinal cord. Scandinavian Journal of Pain, 15, 79-80
Open this publication in new window or tab >>A possible biomarker of low back pain: 18F-FDeoxyGlucose uptake in PETscan and CT of the spinal cord
2017 (English)In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 15, p. 79-80Article in journal, Editorial material (Other academic) Published
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-345645 (URN)10.1016/j.sjpain.2017.01.004 (DOI)000405971800016 ()28850353 (PubMedID)
Available from: 2018-03-12 Created: 2018-03-12 Last updated: 2018-03-12Bibliographically approved
Philippot, G., Gordh, T., Fredriksson, A. & Viberg, H. (2017). Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period. Journal of Applied Toxicology, 37(10), 1174-1181
Open this publication in new window or tab >>Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period
2017 (English)In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 37, no 10, p. 1174-1181Article in journal (Refereed) Published
Abstract [en]

Paracetamol (acetaminophen) is a widely used non-prescription drug with analgesic and antipyretic properties. Among pregnant women and young children, paracetamol is one of the most frequently used drugs and is considered the first-choice treatment for pain and/or fever. Recent findings in both human and animal studies have shown associations between paracetamol intake during brain development and adverse behavioral outcomes later in life. The present study was undertaken to investigate if the induction of these effects depend on when the exposure occurs during a critical period of brain development and if male and female mice are equally affected. Mice of both sexes were exposed to two doses of paracetamol (30 + 30 mg kg – 1 , 4 h apart) on postnatal days (PND) 3, 10 or 19. Spontaneous behavior, when introduced to a new home environment, was observed at the age of 2 months. We show that adverse effects on adult behavior and cognitive function occurred in both male and female mice exposed to paracetamol on PND 3 and 10, but not when exposed on PND 19. These neurodevelopmental time points in mice correspond to the beginning of the third trimester of pregnancy and the time around birth in humans, supporting existing human data. Considering that paracetamol is the first choice treatment for pain and/or fever during pregnancy and early life, these results may be of great importance for future research and, ultimately, for clinical practice

Keywords
Paracetamol (acetaminophen), developmental neurotoxicity, neonatal mice, critical period, spontaneous behavior, habituation, cognitive impairments
National Category
Neurosciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-334493 (URN)10.1002/jat.3473 (DOI)000409913500005 ()28448685 (PubMedID)
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-01-13Bibliographically approved
Backryd, E., Tanum, L., Lind, A.-L., Larsson, A. & Gordh, T. (2017). Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. Journal of Pain Research, 10
Open this publication in new window or tab >>Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma
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2017 (English)In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 10Article in journal (Refereed) Published
Abstract [en]

In addition to central hyperexcitability and impaired top-down modulation, chronic inflammation probably plays a role in the pathophysiology of fibromyalgia (FM). Indeed, on the basis of both animal experiments and human studies involving the analysis of cytokines and other inflammation-related proteins in different body fluids, neuroinflammatory mechanisms are considered to be central to the pathophysiology of many chronic pain conditions. However, concerning FM, previous human plasma/serum and/or cerebrospinal fluid (CSF) cytokine studies have looked only at a few predetermined cytokine candidates. Instead of analyzing only a few substances at a time, we used a new multiplex protein panel enabling simultaneous analysis of 92 inflammation-related proteins. Hence, we investigated the CSF and plasma inflammatory profiles of 40 FM patients compared with CSF from healthy controls (n= 10) and plasma from blood donor controls (n= 46). Using multivariate data analysis by projection, we found evidence of both neuroinflammation (as assessed in CSF) and chronic systemic inflammation (as assessed in plasma). Two groups of proteins (one for CSF and one for plasma) highly discriminating between patients and controls are presented. Notably, we found high levels of CSF chemokine CX3CL1 (also known as fractalkine). In addition, previous findings concerning IL-8 in FM were replicated, in both CSF and plasma. This is the first time that such an extensive inflammatory profile has been described for FM patients. Hence, FM seems to be characterized by objective biochemical alterations, and the lingering characterization of its mechanisms as essentially idiopathic or even psychogenic should be seen as definitively outdated.

Place, publisher, year, edition, pages
DOVE MEDICAL PRESS LTD, 2017
Keywords
cerebrospinal fluid, chemokines, chronic pain, cytokines, fibromyalgia, inflammation
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-319693 (URN)10.2147/JPR.S128508 (DOI)000396320700001 ()
Funder
VINNOVASwedish Research Council, P29797-1
Note

The two first authors contributed equally to this work

Available from: 2017-04-06 Created: 2017-04-06 Last updated: 2017-11-29Bibliographically approved
Tanum, L., Backryd, E., Lind, A.-L., Larsson, A. & Gordh, T. (2017). Evidence of both Systemic Inflammation and Neuroinflammation in Patients with Chronic Widespread Pain. Paper presented at 72nd Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry (SOBP), MAY 18-20, 2017, San Diego, CA. Biological Psychiatry, 81(10), S231-S232
Open this publication in new window or tab >>Evidence of both Systemic Inflammation and Neuroinflammation in Patients with Chronic Widespread Pain
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2017 (English)In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 81, no 10, p. S231-S232Article in journal, Meeting abstract (Other academic) Published
Keywords
Cytokines and Chemokines, chronic pain, Neuroinflammation, immunoinflammation, cerebrospinal fluid
National Category
Neurology Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-331810 (URN)10.1016/j.biopsych.2017.02.443 (DOI)000400348700570 ()
Conference
72nd Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry (SOBP), MAY 18-20, 2017, San Diego, CA
Funder
Swedish Research Council
Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2017-10-18Bibliographically approved
Bäckryd, E., Lind, A.-L., Thulin, M., Larsson, A., Gerdle, B. & Gordh, T. (2017). High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls. Pain, 158(12), 2487-2495
Open this publication in new window or tab >>High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls
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2017 (English)In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, no 12, p. 2487-2495Article in journal (Refereed) Published
Abstract [en]

Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called "gliotransmitters," a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n = 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-335278 (URN)10.1097/j.pain.0000000000001061 (DOI)000419133700022 ()28930774 (PubMedID)
Available from: 2017-12-02 Created: 2017-12-02 Last updated: 2018-02-09Bibliographically approved
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