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de Tommaso M, Scannicchio S, Paparella G, Clemente L, Libro G. Efficacy of monoclonal antibodies against CGRP in migraine patients with fibromyalgia comorbidity: a retrospective monocentric observational study. J Headache Pain 2025; 26:102. [PMID: 40329175 PMCID: PMC12057166 DOI: 10.1186/s10194-025-02034-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Accepted: 04/11/2025] [Indexed: 05/08/2025] Open
Abstract
BACKGROUND Migraine is a common comorbidity with fibromyalgia (FM). CGRP is a potent inflammatory neuropeptide that may play a role in somatic and visceral pain either inflammatory or neuropathic. Previous studies have reported a significant number of migraine patients with FM responding to anti-CGRP therapies. The potential impact on diffuse pain and global disability associated with fibromyalgia is still unclear. In this retrospective, observational, cross-sectional study, we aimed to analyze the effects of a monoclonal antibody therapy in a subpopulation of migraineurs with FM compared to patients without this comorbidity by assessing the headache frequency and disability as well as the severity of FM (assessed by the Fibromyalgia Impact Questionnaire (FIQ). METHODS Among 1088 patients came for the first visit to our headache Center between January 1, 2021, and December 31, 2022, we examined six-month outcomes of 148 migraine patients prescribed various monoclonal antibodies to CGRP, erenumab, galcanezumab, and fremanezumab. One hundred and twenty-two patients were selected, 26 of whom suffered from FM. We retrospectively evaluated the following characteristics at baseline (T0) and after 6 months (T1),headache frequency and severity, number of days with symptomatic medication, and MIDAS score. In the FM patients, we evaluated the FIQ and the intensity of somatic pain using a numerical rating scale from 0 to 10. RESULTS Headache characteristics improved similarly in patients with and without FM comorbidity. The number of patients in whom headache frequency decreased by at least 50% was similar in the two migraine groups. In patients with FM, both fibromyalgia-related disability and somatic pain improved. The improvement in fibromyalgia disability was significantly correlated with the improvement in migraine-related disability. CONCLUSIONS We found that in migraine suffereres with FM, anti-CGRP monoclonal antibodies had a similar beneficial effect on migraine as in non-fibromyalgia patients, in addition to reducing somatic pain and global disability from the disease. The anti-CGRP agents, represent a good option for the treatment of migraineurs with fibromyalgia, for which no resolutive therapy is yet available.
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Affiliation(s)
- Marina de Tommaso
- Neurophysiopathology Unit, Headache Center, DiBrain Department, Bari Aldo Moro University, Policlinico General Hospital, Piazza Giulio Cesare 11, 70124, Bari, Italy.
| | - Stefania Scannicchio
- Neurophysiopathology Unit, Headache Center, DiBrain Department, Bari Aldo Moro University, Policlinico General Hospital, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Giulia Paparella
- Neurophysiopathology Unit, Headache Center, DiBrain Department, Bari Aldo Moro University, Policlinico General Hospital, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Livio Clemente
- Neurophysiopathology Unit, Headache Center, DiBrain Department, Bari Aldo Moro University, Policlinico General Hospital, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Giuseppe Libro
- Neurophysiopathology Unit, Headache Center, DiBrain Department, Bari Aldo Moro University, Policlinico General Hospital, Piazza Giulio Cesare 11, 70124, Bari, Italy
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Caparaso SM, Sankaranarayanan I, Lillyman DJ, Price TJ, Wachs RA. Single-nuclei RNA Sequencing Reveals Distinct Transcriptomic Signatures of Rat Dorsal Root Ganglia in a Chronic Discogenic Low Back Pain Model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.19.639130. [PMID: 40060537 PMCID: PMC11888191 DOI: 10.1101/2025.02.19.639130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
Chronic low back pain (LBP), often correlated with intervertebral disc degeneration, is a leading source of disability worldwide yet remains poorly understood. Current treatments often fail to provide sustained relief, highlighting the need to better understand the mechanisms driving discogenic LBP. During disc degeneration, the extracellular matrix degrades, allowing nociceptive nerve fibers to innervate previously aneural disc regions. Persistent mechanical and inflammatory stimulation of nociceptors can induce plastic changes within dorsal root ganglia (DRG) neurons, characterized by altered gene expression, enhanced excitability, and lowered activation thresholds. Although these transcriptional changes have been described in other pain states, including osteoarthritis, they remain underexplored in discogenic LBP. To address this gap, this study represents the first application of comprehensive single-nuclei RNA sequencing of DRG neurons in a rat model of chronic discogenic LBP. Eighteen distinct DRG subpopulations were identified and mapped to existing mouse and cross-species atlases revealing strong similarities in neuronal populations with the mouse. Differential expression analysis revealed increased expression of pain-associated genes, including Scn9a and Piezo2, and neuroinflammatory mediators such as Fstl1 and Ngfr, in LBP animals. Axial hypersensitivity, measured using grip strength, significantly correlated with increased expression of Scn9a, Fstl1, and Ngfr, which suggests their role in maintaining axial hypersensitivity in this model. These findings establish a relationship between DRG transcriptomic changes and axial hypersensitivity in a discogenic LBP model, identifying potential molecular targets for non-opioid treatments and advancing understanding of discogenic LBP mechanisms.
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Affiliation(s)
- Sydney M Caparaso
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, USA
| | - Ishwarya Sankaranarayanan
- Department of Neuroscience, Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, USA
| | - David J Lillyman
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, USA
| | - Theodore J Price
- Department of Neuroscience, Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, USA
| | - Rebecca A Wachs
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, USA
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3
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Al-Kuraishy HM, Al-Gareeb AI, Alexiou A, Mukerjee N, Al-Hamash SMJ, Al-Maiahy TJ, Batiha GES. 5-HT/CGRP pathway and Sumatriptan role in Covid-19. Biotechnol Genet Eng Rev 2024; 40:3148-3173. [PMID: 36042570 DOI: 10.1080/02648725.2022.2108996] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/21/2022] [Indexed: 12/27/2022]
Abstract
Coronavirus disease 2019 (Covid-19) is a pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In Covid-19, there is uncontrolled activation of immune cells with a massive release of pro-inflammatory cytokines and the development of cytokine storm. These inflammatory changes induce impairment of different organ functions, including the central nervous system (CNS), leading to acute brain injury and substantial changes in the neurotransmitters, including serotonin (5-HT) and calcitonin gene-related peptide (CGRP), which have immunomodulatory properties through modulation of central and peripheral immune responses. In Covid-19, 5-HT neurotransmitters and CGRP could contribute to abnormal and atypical vascular reactivity. Sumatriptan is a pre-synaptic 5-HT (5-HT1D and 5-HT1B) agonist and inhibits the release of CGRP. Both 5-HT and CGRP seem to be augmented in Covid-19 due to underlying activation of inflammatory signaling pathways and hyperinflammation. In virtue of its anti-inflammatory and antioxidant properties with inhibition release of 5-HT and CGRP, Sumatriptan may reduce Covid-19 hyperinflammation. Therefore, Sumatriptan might be a novel potential therapeutic strategy in managing Covid-19. In conclusion, Sumatriptan could be an effective therapeutic strategy in managing Covid-19 through modulation of 5-HT neurotransmitters and inhibiting CGRP.
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Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, AL-Mustansiriyah University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, AL-Mustansiriyah University, Baghdad, Iraq
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW, Australia
- AFNP Med, Wien, Austria
| | - Nobendu Mukerjee
- Department of Microbiology, Ramakrishna Mission Vivekananda Centenary College, Kolkata, India
- Department of Health Sciences, Novel Global Community Educational Foundation, Hebersham, NSW, Australia
| | | | - Thabat J Al-Maiahy
- Department of Gynecology and Obstetrics, College of Medicine, Al-Mustansiriyah University, Baghdad, Iraq
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
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Jones M, Jones E, Kouroupis D. The Use of Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles in the Treatment of Osteoarthritis: Insights from Preclinical Studies. Bioengineering (Basel) 2024; 11:961. [PMID: 39451337 PMCID: PMC11504680 DOI: 10.3390/bioengineering11100961] [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: 08/21/2024] [Revised: 09/16/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024] Open
Abstract
Osteoarthritis (OA) is a prominent cause of disability, and has severe social and economic ramifications across the globe. The main driver of OA's pervasiveness is the fact that no current medical interventions exist to reverse or even attenuate the degeneration of cartilage within the articular joint. Crucial for cell-to-cell communication, extracellular vesicles (EVs) contribute to OA progression through the delivery of bioactive molecules in the inflammatory microenvironment. By repurposing this acellular means of signal transmission, therapeutic drugs may be administered to degenerated cartilage tissue in the hopes of encouraging regeneration. Positive outcomes are apparent in in vivo studies on this subject; however, for this therapy to prove itself in the clinical world, efforts towards standardizing the characterization, application, biological contents, and dosage are essential.
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Affiliation(s)
- Mitch Jones
- Department of Chemistry, Loughborough University, Loughborough LE11 3TU, UK;
| | - Elena Jones
- Leeds Institute of Rheumatic and Musculoskeletal Disease, University of Leeds, Leeds LS2 9JT, UK
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA
- Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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Pyeon GH, Kim JH, Choi JS, Jo YS. Activation of CGRP neurons in the parabrachial nucleus suppresses addictive behavior. Proc Natl Acad Sci U S A 2024; 121:e2401929121. [PMID: 38843183 PMCID: PMC11181112 DOI: 10.1073/pnas.2401929121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 03/12/2024] [Indexed: 06/18/2024] Open
Abstract
Punishment such as electric shock or physical discipline employs a mixture of physical pain and emotional distress to induce behavior modification. However, a neural circuit that produces behavior modification by selectively focusing the emotional component, while bypassing the pain typically induced by peripheral nociceptor activation, is not well studied. Here, we show that genetically silencing the activity of neurons expressing calcitonin gene-related peptide (CGRP) in the parabrachial nucleus blocks the suppression of addictive-like behavior induced by footshock. Furthermore, activating CGRP neurons suppresses not only addictive behavior induced by self-stimulating dopamine neurons but also behavior resulting from self-administering cocaine, without eliciting nocifensive reactions. Moreover, among multiple downstream targets of CGRP neurons, terminal activation of CGRP in the central amygdala is effective, mimicking the results of cell body stimulation. Our results indicate that unlike conventional electric footshock, stimulation of CGRP neurons does not activate peripheral nociceptors but effectively curb addictive behavior.
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Affiliation(s)
- Gyeong Hee Pyeon
- School of Psychology, Korea University, Seoul02841, Republic of Korea
| | - Joung-Hun Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang37673, Republic of Korea
| | - June-Seek Choi
- School of Psychology, Korea University, Seoul02841, Republic of Korea
| | - Yong Sang Jo
- School of Psychology, Korea University, Seoul02841, Republic of Korea
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Jiang S, Xie W, Knapstein PR, Donat A, Albertsen LC, Sevecke J, Erdmann C, Appelt J, Fuchs M, Hildebrandt A, Maleitzke T, Frosch KH, Baranowsky A, Keller J. Transcript-dependent effects of the CALCA gene on the progression of post-traumatic osteoarthritis in mice. Commun Biol 2024; 7:223. [PMID: 38396204 PMCID: PMC10891124 DOI: 10.1038/s42003-024-05889-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Osteoarthritis represents a chronic degenerative joint disease with exceptional clinical relevance. Polymorphisms of the CALCA gene, giving rise to either a procalcitonin/calcitonin (PCT/CT) or a calcitonin gene-related peptide alpha (αCGRP) transcript by alternative splicing, were reported to be associated with the development of osteoarthritis. The objective of this study was to investigate the role of both PCT/CT and αCGRP transcripts in a mouse model of post-traumatic osteoarthritis (ptOA). WT, αCGRP-/- and CALCA-/- mice were subjected to anterior cruciate ligament transection (ACLT) to induce ptOA of the knee. Mice were sacrificed 4 and 8 weeks post-surgery, followed by micro-CT and histological evaluation. Here we show that the expression of both PCT/CT and αCGRP transcripts is induced in ptOA knees. CALCA-/- mice show increased cartilage degeneration and subchondral bone loss with elevated osteoclast numbers compared to αCGRP-/- and WT mice. Osteophyte formation is reduced to the same extent in CALCA-/- and αCGRP-/- mice compared to WT controls, while a reduced synovitis score is noticed exclusively in mice lacking CALCA. Our data show that expression of the PCT/CT transcript protects from the progression of ptOA, while αCGRP promotes osteophyte formation, suggesting that CALCA-encoded peptides may represent novel targets for the treatment of ptOA.
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Affiliation(s)
- Shan Jiang
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Weixin Xie
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Paul Richard Knapstein
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Antonia Donat
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lilly-Charlotte Albertsen
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan Sevecke
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Cordula Erdmann
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jessika Appelt
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Melanie Fuchs
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Alexander Hildebrandt
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany
| | - Tazio Maleitzke
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin, Germany
- Department of Orthopaedic Surgery, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Karl-Heinz Frosch
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Trauma Surgery, Orthopedics and Sports Traumatology, BG Hospital Hamburg, Hamburg, Germany
| | - Anke Baranowsky
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Keller
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Lee W, Georgas E, Komatsu DE, Qin YX. Daily low-intensity pulsed ultrasound stimulation mitigates joint degradation and pain in a post-traumatic osteoarthritis rat model. J Orthop Translat 2024; 44:9-18. [PMID: 38161708 PMCID: PMC10753057 DOI: 10.1016/j.jot.2023.09.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 08/22/2023] [Accepted: 09/12/2023] [Indexed: 01/03/2024] Open
Abstract
Objectives The aim of this study was to investigate the effects of low-intensity pulsed ultrasound (LIPUS) in a post-traumatic osteoarthritis (OA) rat model and in vitro. Methods Thirty-eight male, four-month-old Sprague Dawley rats were randomly assigned to Sham, Sham + US, OA, and OA + US. Sham surgery was performed to serve as a negative control, and anterior cruciate ligament transection was used to induce OA. Three days after the surgical procedures, Sham + US and OA + US animals received daily LIPUS treatment, while the rest of the groups received sham ultrasound (US) signals. Behavioral pain tests were performed at baseline and every week thereafter. After 31 days, the tissues were collected, and histological analyses were performed on knees and innervated dorsal root ganglia (DRG) neurons traced by retrograde labeling. Furthermore, to assess the activation of osteoclasts by LIPUS treatment, RAW264.7 cells were differentiated into osteoclasts and treated with LIPUS. Results Joint degradation in cartilage and bone microarchitecture were mitigated in OA + US compared to OA. OA + US showed improvements in behavioral pain tests. A significant increase of large soma-sized DRG neurons was located in OA compared to Sham. In addition, a greater percentage of large soma-sized innervated neurons were calcitonin gene-related peptide-positive. Daily LIPUS treatment suppressed osteoclastogenesis in vitro, which was confirmed via histological analyses and mRNA expression. Finally, lower expression of netrin-1, a sensory innervation-related protein, was found in the LIPUS treated cells. Conclusion Our findings demonstrate that early intervention using LIPUS treatment has protective effects from the progression of knee OA, including reduced tissue degradation, mitigated pain characteristics, improved subchondral bone microarchitecture, and less sensory innervation. Furthermore, daily LIPUS treatment has a suppressive effect on osteoclastogenesis, which may be linked to the suppression of sensory innervation in OA. The translational potential of this article This study presents a new potential for early intervention in treating OA symptoms through the use of LIPUS, which involves the suppression of osteoclastogenesis and the alteration of DRG profiles. This intervention aims to delay joint degradation and reduce pain.
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Affiliation(s)
- Wonsae Lee
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA
| | - Elias Georgas
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA
| | - David E. Komatsu
- Department of Orthopaedics and Rehabilitation, Stony Brook University, Stony Brook, NY, USA
| | - Yi-Xian Qin
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA
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Shumnalieva R, Kotov G, Ermencheva P, Monov S. Pathogenic Mechanisms and Therapeutic Approaches in Obesity-Related Knee Osteoarthritis. Biomedicines 2023; 12:9. [PMID: 38275369 PMCID: PMC10812969 DOI: 10.3390/biomedicines12010009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 12/10/2023] [Accepted: 12/14/2023] [Indexed: 01/27/2024] Open
Abstract
The knee is the joint most frequently involved in osteoarthritis, a common joint disorder in the adult population that is associated with significant chronic joint pain, reduced mobility and quality of life. Recent studies have established an association between obesity and the development of knee osteoarthritis that goes beyond the increased mechanical load on the knees as weight-bearing joints. This link is based on the maintenance of a chronic low-grade inflammation, altered secretion of adipokines by the adipose tissue and development of sarcopenia. Major adipokines involved in the pathogenesis of obesity-related knee osteoarthritis include adiponectin, which appears to have a protective effect, as well as leptin, resistin and visfatin, which are associated with higher pain scores and more severe structural damage. Joint pain in knee osteoarthritis may be both nociceptive and neuropathic and is the result of complex mechanisms driven by nerve growth factor, calcitonin gene-related peptide and pro-inflammatory cytokines. The role of endogenous cannabinoids and gut microbiota in common mechanisms between obesity and knee pain has recently been studied. The aim of the present review is to highlight major pathogenic mechanisms in obesity-related knee osteoarthritis with special attention on pain and to comment on possible therapeutic approaches.
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Affiliation(s)
- Russka Shumnalieva
- Department of Rheumatology, Medical University of Sofia, 1431 Sofia, Bulgaria; (R.S.); (S.M.)
- Clinic of Rheumatology, University Hospital ‘St. Ivan Rilski’, 1612 Sofia, Bulgaria;
| | - Georgi Kotov
- Department of Rheumatology, Medical University of Sofia, 1431 Sofia, Bulgaria; (R.S.); (S.M.)
- Clinic of Rheumatology, University Hospital ‘St. Ivan Rilski’, 1612 Sofia, Bulgaria;
| | - Plamena Ermencheva
- Clinic of Rheumatology, University Hospital ‘St. Ivan Rilski’, 1612 Sofia, Bulgaria;
| | - Simeon Monov
- Department of Rheumatology, Medical University of Sofia, 1431 Sofia, Bulgaria; (R.S.); (S.M.)
- Clinic of Rheumatology, University Hospital ‘St. Ivan Rilski’, 1612 Sofia, Bulgaria;
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Karuppagounder V, Chung J, Abdeen A, Thompson A, Bouboukas A, Pinamont WJ, Yoshioka NK, Sepulveda DE, Raup-Konsavage WM, Graziane NM, Vrana KE, Elbarbary RA, Kamal F. Therapeutic Effects of Non-Euphorigenic Cannabis Extracts in Osteoarthritis. Cannabis Cannabinoid Res 2023; 8:1030-1044. [PMID: 35994012 PMCID: PMC10714119 DOI: 10.1089/can.2021.0244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Introduction: Osteoarthritis (OA) is disabling and degenerative disease of the joints that is clinically characterized by pain and loss of function. With no disease-modifying treatment available, current therapies aim at pain management but are of limited efficacy. Cannabis products, specifically cannabinoids, are widely used to control pain and inflammation in many diseases with no scientific evidence demonstrating their efficacy in OA. Objective: We investigated the effects of non-euphorigenic cannabis extracts, CBD oil and cannabigerol oil (CBG oil), on pain and disease progression in OA mice. Methods and Results: Twelve-week-old male C57BL/6J mice received either sham or destabilization of the medial meniscus (DMM) surgery. DMM mice were treated with vehicle, CBD oil, or CBG oil. The gait of DMM mice was impaired as early as 2 weeks following surgery and continued deteriorating until week 8, which was restored by CBD oil and CBG oil treatments throughout the disease course. Mechanical allodynia developed in DMM mice, however, was not ameliorated by any of the treatments. On the other hand, both CBD oil and CBG oil ameliorated cold allodynia. In open field test, both oil treatments normalized changes in the locomotor activity of DMM mice. CBD oil and CBG oil treatments significantly reduced synovitis in DMM mice. Only CBG oil reduced cartilage degeneration, chondrocyte loss, and matrix metalloproteinase 13 expression, with a significant increase in the number of anabolic chondrocytes. Subchondral bone remodeling found in vehicle-treated DMM mice was not ameliorated by either CBD or CBG oil. Conclusions: Our results show evidence for the therapeutic efficacy of CBD oil and CBG oil, where both oils ameliorate pain and inflammation, and improve gait and locomotor activity in OA mice, representing clinical pain and function. Importantly, only CBG oil is chondroprotective, which may provide superior efficacy in future studies in OA patients.
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Affiliation(s)
- Vengadeshprabhu Karuppagounder
- Center for Orthopedic Research and Translational Science (CORTS), Penn State College of Medicine, Hershey, Pennsylvania, USA
- Department of Orthopedics and Rehabilitation, Departments of Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Juliet Chung
- Center for Orthopedic Research and Translational Science (CORTS), Penn State College of Medicine, Hershey, Pennsylvania, USA
- Department of Orthopedics and Rehabilitation, Departments of Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Ahmed Abdeen
- Center for Orthopedic Research and Translational Science (CORTS), Penn State College of Medicine, Hershey, Pennsylvania, USA
- Department of Orthopedics and Rehabilitation, Departments of Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Amy Thompson
- Center for Orthopedic Research and Translational Science (CORTS), Penn State College of Medicine, Hershey, Pennsylvania, USA
- Department of Orthopedics and Rehabilitation, Departments of Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Andreas Bouboukas
- Center for Orthopedic Research and Translational Science (CORTS), Penn State College of Medicine, Hershey, Pennsylvania, USA
- Department of Orthopedics and Rehabilitation, Departments of Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - William J. Pinamont
- Center for Orthopedic Research and Translational Science (CORTS), Penn State College of Medicine, Hershey, Pennsylvania, USA
- Department of Orthopedics and Rehabilitation, Departments of Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Natalie K. Yoshioka
- Center for Orthopedic Research and Translational Science (CORTS), Penn State College of Medicine, Hershey, Pennsylvania, USA
- Department of Orthopedics and Rehabilitation, Departments of Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Diana E. Sepulveda
- Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, USA
- Anesthesiology and Perioperative Medicine, and Penn State College of Medicine, Hershey, Pennsylvania, USA
| | | | - Nicholas M. Graziane
- Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, USA
- Anesthesiology and Perioperative Medicine, and Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Kent E. Vrana
- Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Reyad A. Elbarbary
- Center for Orthopedic Research and Translational Science (CORTS), Penn State College of Medicine, Hershey, Pennsylvania, USA
- Department of Orthopedics and Rehabilitation, Departments of Penn State College of Medicine, Hershey, Pennsylvania, USA
- Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Fadia Kamal
- Center for Orthopedic Research and Translational Science (CORTS), Penn State College of Medicine, Hershey, Pennsylvania, USA
- Department of Orthopedics and Rehabilitation, Departments of Penn State College of Medicine, Hershey, Pennsylvania, USA
- Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, USA
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Park EH, Seo J, Lee Y, Park K, Kim KR, Kim S, Mobasheri A, Choi H. TissueGene-C induces long-term analgesic effects through regulation of pain mediators and neuronal sensitization in a rat monoiodoacetate-induced model of osteoarthritis pain. Osteoarthritis Cartilage 2023; 31:1567-1580. [PMID: 37544583 DOI: 10.1016/j.joca.2023.07.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 06/21/2023] [Accepted: 07/27/2023] [Indexed: 08/08/2023]
Abstract
OBJECTIVE TissueGene-C (TG-C), a combination of human allogeneic chondrocytes and irradiated GP2-293 cells engineered to overexpress transforming growth factor-β1 (TGF-β1), has been developed as a novel cell-based gene therapy and a candidate for disease modifying osteoarthritis drug (DMOAD). We aim to investigate analgesic mechanism of TG-C in a pre-clinical animal model with monoiodoacetate (MIA)-induced pain. DESIGN We used a rat MIA model of osteoarthritis (OA) pain. We examined that TG-C can regulate pain by inhibiting the upregulation of various pain mediators in both knee joint tissue and dorsal root ganglia (DRG) (n = 112) and alleviating pain behavior (n = 41) and neuronal hyperexcitability in DRG (n = 60), afferent nerve fiber (n = 24), and spinal cord (n = 35). RESULTS TG-C significantly alleviated pain-related behavior by restoring altered dynamic weight bearing and reduced mechanical threshold of the affected hindlimb. TG-C significantly suppressed the expression of nerve growth factor (NGF) and calcitonin gene-related peptide (CGRP) in inflamed joint tissue. TG-C significantly suppressed the upregulation of tropomyosin receptor kinase A (TrkA) and nerve injury/regeneration protein (GAP43) and activation of Iba1-positive microglial cells in DRG. TG-C significantly recovered neuronal hyperexcitability by restoring RMP and firing threshold and frequency of DRG neurons, attenuating firing rates of mechanosensitive C- or Aδ-nerve fiber innervating knee joint, and lowering increased miniature and evoked excitatory postsynaptic currents (mEPSCs and eEPSCs) in the spinal cord. CONCLUSION Our results demonstrated that TG-C exerted potent analgesic effects in a rat MIA model of OA pain by inhibiting the upregulation of pain mediators and modulating neuronal sensitization.
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Affiliation(s)
- Eui Ho Park
- Department of Physiology, College of Medicine and Neuroscience Research Institute, Korea University, Seoul, South Korea
| | - Jinwon Seo
- Institute of BioInnovation Research, Kolon Life Science, Inc., Magok-dong, Gangseo-gu, Seoul, South Korea
| | - Yunsin Lee
- Institute of BioInnovation Research, Kolon Life Science, Inc., Magok-dong, Gangseo-gu, Seoul, South Korea
| | - Kiwon Park
- Institute of BioInnovation Research, Kolon Life Science, Inc., Magok-dong, Gangseo-gu, Seoul, South Korea
| | - Kyung-Ran Kim
- Institute of BioInnovation Research, Kolon Life Science, Inc., Magok-dong, Gangseo-gu, Seoul, South Korea
| | - Sujeong Kim
- Institute of BioInnovation Research, Kolon Life Science, Inc., Magok-dong, Gangseo-gu, Seoul, South Korea
| | - Ali Mobasheri
- Research Unit of Health Sciences and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland; Department of Regenerative Medicine, State Research Institute Center for Innovative Medicine, Vilnius, Lithuania; World Health Organization Collaborating Center for Public Health Aspects of Musculoskeletal Health and Aging, Université de Liège, Liège, Belgium; Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Heonsik Choi
- Healthcare Research Institute, Kolon Advanced Research Cluster, Magok-dong, Gangseo-gu, Seoul, South Korea.
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11
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Qu Z, Koga H, Tsuji K, Tang G, Yang Y, Yoshihara A, Katakura M, Katagiri H, Miyatake K, Nakamura T, Sekiya I, Nakagawa Y. Hyaluronic acid sheet transplantation attenuates infrapatellar fat pad fibrosis and pain in a rat arthritis model. J Orthop Res 2023; 41:2442-2454. [PMID: 37087680 DOI: 10.1002/jor.25580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 03/02/2023] [Accepted: 04/17/2023] [Indexed: 04/24/2023]
Abstract
Fibrosis of the infrapatellar fat pad (IFP) occurs after knee joint surgery or during knee osteoarthritis (KOA) and causes persistent pain and limited mobility. Previous studies demonstrated that treating IFP fibrosis alleviated pain in animal models. In this study, we examined the effects of hyaluronic acid (HA) sheet transplantation on IFP fibrosis and articular cartilage degeneration in a monoiodoacetic acid (MIA) rat arthritis model (95 male rats). Rats received bilateral intra-articular MIA injections (1.0 mg/30 μL) and underwent surgery 4 days later. HA sheets were transplanted on the right knee of each rat (HA group), with the left knee receiving sham surgery (sham group). Incapacitance tests were performed at multiple time points up to 28 days after MIA injection. Macroscopic, histological, and immunohistochemical analyzes were performed 14 and 28 days after injection. The concentrations of HA and interleukin-1β (IL-1β) in the synovial fluid were measured using ELISA. Transplantation of HA sheets could alleviate persistent pain 10-28 days after injection. The HA sheets inhibited articular cartilage degeneration at 14 days. Fibrosis and the invasion of calcitonin gene-related peptide-positive nerve fiber endings in the IFP were inhibited at both 14 and 28 days. Moreover, the HA sheets remained histologically until 10 days after transplantation. The concentration of HA reached its peak on Day 10 after transplantation; the concentration of IL-1β in the sham group was significantly higher than that in the HA group on Day 7. Therefore, HA sheets could be a promising option to treat IFP fibrosis occurring in KOA and after knee joint surgery.
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Affiliation(s)
- Zhen Qu
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kunikazu Tsuji
- Department of Nano-bioscience, Tokyo Medical and Dental University, Tokyo, Japan
| | - Guo Tang
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yang Yang
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Aritoshi Yoshihara
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mai Katakura
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroki Katagiri
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazumasa Miyatake
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomomasa Nakamura
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yusuke Nakagawa
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Cartilage Regeneration, Tokyo Medical and Dental University, Tokyo, Japan
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12
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Rahimi K, Riyahi M, Sajedianfard J, Nazifi S. Effects of intracerebroventricular administration of calcitonin gene-related peptide (CGRP) on sex hormones and sperm quality in rats. Ann Med Surg (Lond) 2023; 85:5454-5458. [PMID: 37915664 PMCID: PMC10617940 DOI: 10.1097/ms9.0000000000001252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 08/19/2023] [Indexed: 11/03/2023] Open
Abstract
Background Therapeutic strategies with calcitonin gene-related peptide (CGRP) or its receptor have been investigated, but there are few studies regarding the possible harmful effects of CGRP in other body organs. Objective This study aimed to investigate the effect of intracerebroventricular (ICV) injection of CGRP on sex hormones and sperm quality in rats. Methods Twelve male rats were divided into two groups (n=6 per group). The first group (control) rats were injected with 5 µl artificial cerebrospinal fluid intra-ICV; the second group rats, 5 µl (1.5 nmol) CGRP. The levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone were measured. Epididymal sperms were used to determine the sperm parameters. Results The levels of testosterone, LH and FSH in CGRP group was significantly lower than in artificial cerebrospinal fluid (ACSF) group (P<0.05). The concentration and motility of sperm in CGRP group was significantly lower than in ACSF group (P<0.05). In CGRP group live spermatozoa and intact acrosome significantly reduced compared to the ACSF group (P<0.05). In addition, in CGRP group dead spermatozoa and lose acrosome significantly increased compared to the ACSF group (P<0.05). Conclusion ICV injection of CGRP may reduce sperm quality, probably through induction of an imbalance in FSH and LH production as well as testosterone.
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Affiliation(s)
- Kaveh Rahimi
- Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz
| | | | | | - Saeed Nazifi
- Clinical Science, School of Veterinary Science, Shiraz University, Shiraz, Iran
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13
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Noor-Mohammadi E, Ligon CO, Mackenzie KD, Stratton J, Shnider SJ, Greenwood-Van Meerveld B. Antinociceptive Effects of an Anti-CGRP Antibody in Rat Models of Colon-Bladder Cross-Organ Sensitization. J Pharmacol Exp Ther 2023; 387:4-14. [PMID: 37164371 DOI: 10.1124/jpet.122.001480] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 04/10/2023] [Accepted: 04/22/2023] [Indexed: 05/12/2023] Open
Abstract
Irritable bowel syndrome (IBS) and bladder pain syndrome/interstitial cystitis (BPS/IC) are comorbid visceral pain disorders seen commonly in women with unknown etiology and limited treatment options and can involve visceral organ cross-sensitization. Calcitonin gene-related peptide (CGRP) is a mediator of nociceptive processing and may serve as a target for therapy. In three rodent models, we employed a monoclonal anti-CGRP F(ab')2 to investigate the hypothesis that visceral organ cross-sensitization is mediated by abnormal CGRP signaling. Visceral organ cross-sensitization was induced in adult female rats via transurethral infusion of protamine sulfate (PS) into the urinary bladder or infusion into the colon of trinitrobenzene sulfonic acid (TNBS). Colonic sensitivity was assessed via the visceromotor response to colorectal distension (CRD). Bladder sensitivity was assessed as the frequency of abdominal withdrawal reflexes to von Frey filaments applied to the suprapubic region. PS- or TNBS-induced changes in colonic and bladder permeability were investigated in vitro via quantification of transepithelial electrical resistance (TEER). Peripheral administration of an anti-CGRP F(ab')2 inhibited PS-induced visceral pain behaviors and colon hyperpermeability. Similarly, TNBS-induced pain behaviors and colon and bladder hyperpermeability were attenuated by anti-CGRP F(ab')2 treatment. PS into the bladder or TNBS into the colon significantly increased the visceromotor response to CRD and abdominal withdrawal reflexes to suprapubic stimulation and decreased bladder and colon TEER. These findings suggest an important role of peripheral CGRP in visceral nociception and organ cross-sensitization and support the evaluation of CGRP as a therapeutic target for visceral pain in patients with IBS and/or BPS/IC. SIGNIFICANCE STATEMENT: A monoclonal antibody against calcitonin gene-related peptide (CGRP) was found to reduce concomitant colonic and bladder hypersensitivity and hyperpermeability. The results of this study suggest that CGRP-targeting antibodies, in addition to migraine prevention, may provide a novel treatment strategy for multiorgan abdominopelvic pain following injury or inflammation.
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Affiliation(s)
- Ehsan Noor-Mohammadi
- Department of Physiology (E.N.-M., C.O.L., B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and TEVA Pharmaceuticals Ltd. (K.D.M., J.S., S.J.S.), Redwood City, California
| | - Casey O Ligon
- Department of Physiology (E.N.-M., C.O.L., B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and TEVA Pharmaceuticals Ltd. (K.D.M., J.S., S.J.S.), Redwood City, California
| | - Kimberly D Mackenzie
- Department of Physiology (E.N.-M., C.O.L., B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and TEVA Pharmaceuticals Ltd. (K.D.M., J.S., S.J.S.), Redwood City, California
| | - Jennifer Stratton
- Department of Physiology (E.N.-M., C.O.L., B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and TEVA Pharmaceuticals Ltd. (K.D.M., J.S., S.J.S.), Redwood City, California
| | - Sara J Shnider
- Department of Physiology (E.N.-M., C.O.L., B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and TEVA Pharmaceuticals Ltd. (K.D.M., J.S., S.J.S.), Redwood City, California
| | - Beverley Greenwood-Van Meerveld
- Department of Physiology (E.N.-M., C.O.L., B.G.-V.M.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; and TEVA Pharmaceuticals Ltd. (K.D.M., J.S., S.J.S.), Redwood City, California
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14
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Nekomoto A, Nakasa T, Ikuta Y, Ding C, Miyaki S, Adachi N. Feasibility of administration of calcitonin gene-related peptide receptor antagonist on attenuation of pain and progression in osteoarthritis. Sci Rep 2023; 13:15354. [PMID: 37717108 PMCID: PMC10505157 DOI: 10.1038/s41598-023-42673-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 09/13/2023] [Indexed: 09/18/2023] Open
Abstract
Suppressing inflammation and abnormal subchondral bone turnover is essential for reducing osteoarthritis (OA) progression and pain relief. This study focused on calcitonin gene-related peptide (CGRP), which is involved in inflammation and bone metabolism, and investigated whether a CGRP receptor antagonist (rimegepant) could suppress OA progression and relieve pain in two OA models. C57BL/6 mice (10-week-old) underwent surgical destabilization of the medial meniscus, and Rimegepant (1.0 mg/kg/100 μL) or phosphate-buffered saline (100 μL) was administered weekly intraperitoneally after OA surgery and evaluated at 4, 8, and 12 weeks. In the senescence-accelerated mice (SAM)-prone 8 (SAMP8), rimegepant was administered weekly before and after subchondral bone sclerosis and sacrificed at 9 and 23 weeks, respectively. Behavioral assessment and immunohistochemical staining (CGRP) of the dorsal root ganglion (DRG) were conducted to assess pain. In DMM mice, synovitis, cartilage degeneration, and osteosclerosis were significantly suppressed in the rimegepant group. In SAMP8, synovitis, cartilage degeneration, and osteosclerosis were significantly suppressed by rimegepant at 9 weeks; however, not at 23 weeks. Behavioral assessment shows the traveled distance and the number of standings in the rimegepant group were significantly longer and higher. In addition, CGRP expression of the DRG was significantly lower in the rimegepant group at 8 and 12 weeks of DMM and 9 weeks of SAMP8 treatment. No adverse effects were observed in either of the mouse models. Inhibition of CGRP signaling has the potential to be a therapeutic target to prevent OA progression and suppress pain through the attenuation of subchondral bone sclerosis and synovitis.
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Affiliation(s)
- Akinori Nekomoto
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, Hiroshima, 734-8551, Japan
| | - Tomoyuki Nakasa
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, Hiroshima, 734-8551, Japan.
| | - Yasunari Ikuta
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, Hiroshima, 734-8551, Japan
| | - Chenyang Ding
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, Hiroshima, 734-8551, Japan
| | - Shigeru Miyaki
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, Hiroshima, 734-8551, Japan
- Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
| | - Nobuo Adachi
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, Hiroshima, 734-8551, Japan
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15
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Shin Y, Cho D, Kim SK, Chun JS. STING mediates experimental osteoarthritis and mechanical allodynia in mouse. Arthritis Res Ther 2023; 25:90. [PMID: 37259103 DOI: 10.1186/s13075-023-03075-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 05/24/2023] [Indexed: 06/02/2023] Open
Abstract
BACKGROUND This study was performed to develop therapeutic targets of osteoarthritis (OA) that can be targeted to alleviate OA development (i.e., cartilage destruction) and relieve the OA-associated joint pain. METHODS The candidate molecule, STING (stimulator of interferon genes, encoded by Sting1), was identified by microarray analysis of OA-like mouse chondrocytes. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM). STING functions in OA and hindpaw mechanical allodynia were evaluated by gain-of-function (intra-articular injection of a STING agonist) and loss-of-function (Sting1-/- mice) approaches. RESULTS DNA damage was observed in OA-like chondrocytes. Cytosolic DNA sensors, STING and its upstream molecule, cGAS (cyclic GMP-AMP synthase), were upregulated in OA chondrocytes and cartilage of mouse and human. Genetic ablation of STING in mice (Sting1-/-) alleviated OA manifestations (cartilage destruction and subchondral bone sclerosis) and hindpaw mechanical allodynia. In contrast, stimulation of STING signaling in joint tissues by intra-articular injection of cGAMP exacerbated OA manifestations and mechanical sensitization. Mechanistic studies on the regulation of hindpaw mechanical allodynia revealed that STING regulates the expression of peripheral sensitization molecules in the synovium and meniscus of mouse knee joints. CONCLUSION Our results indicated that STING, which senses damaged cytosolic DNA and accordingly activates the innate immune response, regulates OA pathogenesis and hindpaw mechanical allodynia. Therefore, inhibition of STING could be a therapeutic approach to inhibit OA cartilage destruction and relieve the associated mechanical sensitization in model mice.
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Affiliation(s)
- Youngnim Shin
- National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Deborah Cho
- National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Seul Ki Kim
- National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Jang-Soo Chun
- National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
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16
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Sunzini F, Schrepf A, Clauw DJ, Basu N. The Biology of Pain: Through the Rheumatology Lens. Arthritis Rheumatol 2023; 75:650-660. [PMID: 36599071 DOI: 10.1002/art.42429] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 11/07/2022] [Accepted: 12/20/2022] [Indexed: 01/06/2023]
Abstract
Chronic pain is a major socioeconomic burden globally. The most frequent origin of chronic pain is musculoskeletal. In inflammatory musculoskeletal diseases such as rheumatoid arthritis (RA), chronic pain is a primary determinant of deleterious quality of life. The pivotal role of peripheral inflammation in the initiation and perpetuation of nociceptive pain is well-established among patients with musculoskeletal diseases. However, the persistence of pain, even after the apparent resolution of peripheral inflammation, alludes to the coexistence of different pain states. Recent advances in neurobiology have highlighted the importance of nociplastic pain mechanisms. In this review we aimed to explore the biology of pain with a particular focus on nociplastic pain in RA.
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Affiliation(s)
- Flavia Sunzini
- Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
| | - Andrew Schrepf
- Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan Medical School, Ann Arbor
| | - Daniel J Clauw
- Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan Medical School, Ann Arbor
| | - Neil Basu
- Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
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17
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Almahasneh F, Abu-El-Rub E, Khasawneh RR. Mechanisms of analgesic effect of mesenchymal stem cells in osteoarthritis pain. World J Stem Cells 2023; 15:196-208. [PMID: 37181003 PMCID: PMC10173815 DOI: 10.4252/wjsc.v15.i4.196] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/25/2023] [Accepted: 03/27/2023] [Indexed: 04/26/2023] Open
Abstract
Osteoarthritis (OA) is the most common musculoskeletal disease, and it is a major cause of pain, disability and health burden. Pain is the most common and bothersome presentation of OA, but its treatment is still suboptimal, due to the short-term action of employed analgesics and their poor adverse effect profile. Due to their regenerative and anti-inflammatory properties, mesenchymal stem cells (MSCs) have been extensively investigated as a potential therapy for OA, and numerous preclinical and clinical studies found a significant improvement in joint pathology and function, pain scores and/or quality of life after administration of MSCs. Only a limited number of studies, however, addressed pain control as the primary end-point or investigated the potential mechanisms of analgesia induced by MSCs. In this paper, we review the evidence reported in literature that support the analgesic action of MSCs in OA, and we summarize the potential mechanisms of these antinociceptive effects.
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Affiliation(s)
- Fatimah Almahasneh
- Basic Medical Sciences, Faculty of Medicine -Yarmouk University, Irbid 21163, Jordan
| | - Ejlal Abu-El-Rub
- Basic Medical Sciences, Faculty of Medicine -Yarmouk University, Irbid 21163, Jordan.
| | - Ramada R Khasawneh
- Basic Medical Sciences, Faculty of Medicine -Yarmouk University, Irbid 21163, Jordan
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18
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Faur FI, Clim IA, Dobrescu A, Isaic A, Prodan C, Florea S, Tarta C, Totolici B, Duţă C, Pasca P, Lazar G. The Use of Wound Infiltration for Postoperative Pain Management after Breast Cancer Surgery: A Randomized Clinical Study. Biomedicines 2023; 11:biomedicines11041195. [PMID: 37189812 DOI: 10.3390/biomedicines11041195] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/01/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
(1) Background: The present study aims to evaluate the reduction of postoperative pain in breast surgery using a series of local analgesics, which were infiltrated into the wound; (2) Methods: Envelopes containing allocation were prepared prior to the study. The patients involved were randomly assigned to the groups of local anesthesia infiltration (Group A) or normal pain management with intravenous analgesics (Group B). The random allocation sequence was generated using computer-generated random numbers. The normally distributed continuous data were expressed as the means (SD) and were assessed using the analysis of variance (ANOVA), independent-sample t-test, or paired t-test; (3) Results: The development of the postoperative pain stages was recorded using the VAS score. Therefore, for Group A, the following results were obtained: the VAS at 6 h postoperatively showed an average value of 0.63 and a maximum value of 3. The results for Group B were the following: the VAS score at 6 h postoperatively showed an average value of 4.92, a maximum of 8, and a minimum of 2; (4) Conclusions: We can confirm that there are favorable statistical indicators regarding the postoperative pain management process during the first 24-38 h after a surgical intervention for breast cancer using local infiltration of anesthetics.
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Affiliation(s)
- Flaviu Ionut Faur
- IInd Surgery Clinic, Timisoara Emergency County Hospital, 300723 Timișoara, Romania
- Department X of General Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Ioana Adelina Clim
- IInd Obstetric and Gynecology Clinic "Dominic Stanca", 400124 Cluj-Napoca, Romania
| | - Amadeus Dobrescu
- IInd Surgery Clinic, Timisoara Emergency County Hospital, 300723 Timișoara, Romania
- Department X of General Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Alexandru Isaic
- IInd Surgery Clinic, Timisoara Emergency County Hospital, 300723 Timișoara, Romania
- Department X of General Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Catalin Prodan
- IInd Surgery Clinic, Timisoara Emergency County Hospital, 300723 Timișoara, Romania
- Department X of General Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Sabrina Florea
- Central Military Emergency University Hospital "Dr. Carol Davila", 010825 Bucharest, Romania
| | - Cristi Tarta
- IInd Surgery Clinic, Timisoara Emergency County Hospital, 300723 Timișoara, Romania
- Department X of General Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Bogdan Totolici
- Ist Clinic of General Surgery, Arad County Emergency Clinical Hospital, 310158 Arad, Romania
- Department of General Surgery, Faculty of Medicine, "Vasile Goldiș" Western University of Arad, 310025 Arad, Romania
| | - Ciprian Duţă
- IInd Surgery Clinic, Timisoara Emergency County Hospital, 300723 Timișoara, Romania
- Department X of General Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Paul Pasca
- IInd Surgery Clinic, Timisoara Emergency County Hospital, 300723 Timișoara, Romania
| | - Gabriel Lazar
- Department of Oncology Surgery, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania
- Ist Clinic of Oncological Surgery, Oncological Institute "Prof Dr I Chiricuta" Cluj-Napoca, 400015 Cluj-Napoca, Romania
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19
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Maleitzke T, Dietrich T, Hildebrandt A, Weber J, Appelt J, Jahn D, Otto E, Zocholl D, Jiang S, Baranowsky A, Duda GN, Tsitsilonis S, Keller J. Inactivation of the gene encoding procalcitonin prevents antibody-mediated arthritis. Inflamm Res 2023; 72:1069-1081. [PMID: 37039837 DOI: 10.1007/s00011-023-01719-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/25/2023] [Accepted: 03/09/2023] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND Procalcitonin (PCT) is applied as a sensitive biomarker to exclude bacterial infections in patients with rheumatoid arthritis (RA) flare-ups. Beyond its diagnostic value, little is known about the pathophysiological role of PCT in RA. METHODS Collagen antibody-induced arthritis (CAIA) was induced in Calca-deficient mice (Calca-/-), lacking PCT (n = 15), and wild-type (WT) mice (n = 13), while control (CTRL) animals (n = 8 for each genotype) received phosphate-buffered saline. Arthritis severity and grip strength were assessed daily for 10 or 48 days. Articular inflammation, cartilage degradation, and bone lesions were assessed by histology, gene expression analysis, and µ-computed tomography. RESULTS Serum PCT levels and intra-articular PCT expression increased following CAIA induction. While WT animals developed a full arthritic phenotype, Calca-deficient mice were protected from clinical and histological signs of arthritis and grip strength was preserved. Cartilage turnover markers and Tnfa were exclusively elevated in WT mice. Calca-deficient animals expressed increased levels of Il1b. Decreased bone surface and increased subchondral bone porosity were observed in WT mice, while Calca-deficiency preserved bone integrity. CONCLUSION The inactivation of Calca and thereby PCT provided full protection from joint inflammation and arthritic bone loss in mice exposed to CAIA. Together with our previous findings on the pathophysiological function of Calca-derived peptides, these data indicate an independent pro-inflammatory role of PCT in RA.
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Affiliation(s)
- Tazio Maleitzke
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin, Germany
| | - Tamara Dietrich
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Alexander Hildebrandt
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Jérôme Weber
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Jessika Appelt
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Denise Jahn
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Ellen Otto
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Dario Zocholl
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biometry and Clinical Epidemiology, Berlin, Germany
| | - Shan Jiang
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, Hamburg, Germany
| | - Anke Baranowsky
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, Hamburg, Germany
| | - Georg N Duda
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Serafeim Tsitsilonis
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Johannes Keller
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, Hamburg, Germany.
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20
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Gil Alabarse P, Chen LY, Oliveira P, Qin H, Liu-Bryan R. Targeting CD38 to Suppress Osteoarthritis Development and Associated Pain After Joint Injury in Mice. Arthritis Rheumatol 2023; 75:364-374. [PMID: 36103412 PMCID: PMC9998345 DOI: 10.1002/art.42351] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 08/11/2022] [Accepted: 09/08/2022] [Indexed: 01/12/2023]
Abstract
OBJECTIVE This study was undertaken to determine the role of CD38, which can function as an enzyme to degrade NAD+ , in osteoarthritis (OA) development. METHODS Human knee cartilage from normal donors and OA donors were examined for CD38 expression. "Gain-of-function," through overexpression of CD38 via transient transfection, and "loss-of-function," through pharmacologic inhibition of CD38, approaches were used to assess the effects of CD38 on intracellular NAD+ :NADH ratio and catabolic activity in chondrocytes. We also initiated joint injury-induced OA by surgical destabilization of the medial meniscus (DMM) in CD38 knockout mice and wild-type (WT; C57BL/6) mice and in WT male mice in the presence or absence of apigenin treatment. Cartilage degradation, synovial inflammation, subchondral bone changes, and pain behavior were evaluated after DMM surgery. We also examined expression of CD38 and the neuropeptide calcitonin gene-related peptide (CGRP) in knee sections from these mice. RESULTS CD38 expression was up-regulated in human knee OA cartilage and in chondrocytes stimulated with the proinflammatory cytokine interleukin-1β (IL-1β). Overexpression of CD38 in chondrocytes resulted in reduced cellular NAD+ :NADH ratio and augmented catabolic responses to IL-1β. These effects were reversed by pharmacologic inhibition of CD38. Cartilage degradation and synovial inflammation, associated with increased CD38 expression in cartilage and synovium, osteophyte formation and subchondral bone sclerosis, and pain-like behavior linked to increased CGRP expression in the synovium were observed in WT mice after joint injury. Such effects were significantly reduced in mice deficient in CD38 through either genetic knockout or pharmacologic inhibition. CONCLUSION CD38 deficiency exerts OA disease-modifying effects. Inhibition of CD38 has the potential to be a novel therapeutic approach for OA treatment.
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Affiliation(s)
| | - Liang-Yu Chen
- VA San Diego Healthcare System and University of California San Diego
| | - Patricia Oliveira
- VA San Diego Healthcare System and University of California San Diego
| | | | - Ru Liu-Bryan
- VA San Diego Healthcare System and University of California San Diego
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21
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The FKBP51 Inhibitor SAFit2 Restores the Pain-Relieving C16 Dihydroceramide after Nerve Injury. Int J Mol Sci 2022; 23:ijms232214274. [PMID: 36430751 PMCID: PMC9695264 DOI: 10.3390/ijms232214274] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/14/2022] [Accepted: 11/16/2022] [Indexed: 11/19/2022] Open
Abstract
Neuropathic pain is a pathological pain state with a broad symptom scope that affects patients after nerve injuries, but it can also arise after infections or exposure to toxic substances. Current treatment possibilities are still limited because of the low efficacy and severe adverse effects of available therapeutics, highlighting an emerging need for novel analgesics and for a detailed understanding of the pathophysiological alterations in the onset and maintenance of neuropathic pain. Here, we show that the novel and highly specific FKBP51 inhibitor SAFit2 restores lipid signaling and metabolism in nervous tissue after nerve injury. More specifically, we identify that SAFit2 restores the levels of the C16 dihydroceramide, which significantly reduces the sensitization of the pain-mediating TRPV1 channel and subsequently the secretion of the pro-inflammatory neuropeptide CGRP in primary sensory neurons. Furthermore, we show that the C16 dihydroceramide is capable of reducing acute thermal hypersensitivity in a capsaicin mouse model. In conclusion, we report for the first time the C16 dihydroceramide as a novel and crucial lipid mediator in the context of neuropathic pain as it has analgesic properties, contributing to the pain-relieving properties of SAFit2.
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22
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Chao D, Tran H, Hogan QH, Pan B. Analgesic dorsal root ganglion field stimulation blocks both afferent and efferent spontaneous activity in sensory neurons of rats with monosodium iodoacetate-induced osteoarthritis. Osteoarthritis Cartilage 2022; 30:1468-1481. [PMID: 36030058 PMCID: PMC9588581 DOI: 10.1016/j.joca.2022.08.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 08/03/2022] [Accepted: 08/18/2022] [Indexed: 02/02/2023]
Abstract
OBJECTIVES Chronic joint pain is common in patients with osteoarthritis (OA). Non-steroidal anti-inflammatory drugs and opioids are used to relieve OA pain, but they are often inadequately effective. Dorsal root ganglion field stimulation (GFS) is a clinically used neuromodulation approach, although it is not commonly employed for patients with OA pain. GFS showed analgesic effectiveness in our previous study using the monosodium iodoacetate (MIA) - induced OA rat pain model. This study was to evaluate the mechanism of GFS analgesia in this model. METHODS After osteoarthritis was induced by intra-articular injection of MIA, pain behavioral tests were performed. Effects of GFS on the spontaneous activity (SA) were tested with in vivo single-unit recordings from teased fiber saphenous nerve, sural nerve, and dorsal root. RESULTS Two weeks after intra-articular MIA injection, rats developed pain-like behaviors. In vivo single unit recordings from bundles teased from the saphenous nerve and third lumbar (L3) dorsal root of MIA-OA rats showed a higher incidence of SA than those from saline-injected control rats. GFS at the L3 level blocked L3 dorsal root SA. MIA-OA reduced the punctate mechanical force threshold for inducing AP firing in bundles teased from the L4 dorsal root, which reversed to normal with GFS. After MIA-OA, there was increased retrograde SA (dorsal root reflex), which can be blocked by GFS. CONCLUSIONS These results indicate that GFS produces analgesia in MIA-OA rats at least in part by producing blockade of afferent inputs, possibly also by blocking efferent activity from the dorsal horn.
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Affiliation(s)
- D Chao
- Department of Anesthesiology, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI 53226, USA
| | - H Tran
- Department of Anesthesiology, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI 53226, USA
| | - Q H Hogan
- Department of Anesthesiology, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI 53226, USA
| | - B Pan
- Department of Anesthesiology, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI 53226, USA.
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23
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Sun K, Jiang J, Wang Y, Sun X, Zhu J, Xu X, Sun J, Shi J. The role of nerve fibers and their neurotransmitters in regulating intervertebral disc degeneration. Ageing Res Rev 2022; 81:101733. [PMID: 36113765 DOI: 10.1016/j.arr.2022.101733] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/11/2022] [Accepted: 09/11/2022] [Indexed: 01/31/2023]
Abstract
Intervertebral disc degeneration (IVDD) has been the major contributor to chronic lower back pain (LBP). Abnormal apoptosis, senescence, and pyroptosis of IVD cells, extracellular matrix (ECM) degradation, and infiltration of immune cells are the major molecular alternations during IVDD. Changes at tissue level frequently occur at advanced IVD tissue. Ectopic ingrowth of nerves within inner annulus fibrosus (AF) and nucleus pulposus (NP) tissue has been considered as the primary cause for LBP. Innervation at IVD tissue mainly included sensory and sympathetic nerves, and many markers for these two types of nerves have been detected since 1940. In fact, in osteoarthritis (OA), beyond pain transmission, the direct regulation of neuropeptides on functions of chondrocytes have attracted researchers' great attention recently. Many physical and pathological similarities between joint and IVD have shed us the light on the neurogenic mechanism involved in IVDD. Here, an overview of the advances in the nervous system within IVD tissue will be performed, with a discussion on in the role of nerve fibers and their neurotransmitters in regulating IVDD. We hope this review can attract more research interest to address neuromodulation and IVDD itself, which will enhance our understanding of the contribution of neuromodulation to the structural changes within IVD tissue and inflammatory responses and will help identify novel therapeutic targets and enable the effective treatment of IVDD disease.
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Affiliation(s)
- Kaiqiang Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China; Department of Orthopedics, Naval Medical Center of PLA, China
| | - Jialin Jiang
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Yuan Wang
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Xiaofei Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Jian Zhu
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Ximing Xu
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Jingchuan Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China.
| | - Jiangang Shi
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China.
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24
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Wedel S, Mathoor P, Rauh O, Heymann T, Ciotu CI, Fuhrmann DC, Fischer MJM, Weigert A, de Bruin N, Hausch F, Geisslinger G, Sisignano M. SAFit2 reduces neuroinflammation and ameliorates nerve injury-induced neuropathic pain. J Neuroinflammation 2022; 19:254. [PMID: 36217203 PMCID: PMC9552419 DOI: 10.1186/s12974-022-02615-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 10/04/2022] [Indexed: 01/17/2024] Open
Abstract
Background Neuropathic pain is experienced worldwide by patients suffering from nerve injuries, infectious or metabolic diseases or chemotherapy. However, the treatment options are still limited because of low efficacy and sometimes severe side effects. Recently, the deficiency of FKBP51 was shown to relieve chronic pain, revealing FKBP51 as a potential therapeutic target. However, a specific and potent FKBP51 inhibitor was not available until recently which hampered targeting of FKBP51. Methods In this study, we used the well-established and robust spared nerve injury model to analyze the effect of SAFit2 on nerve injury-induced neuropathic pain and to elucidate its pharmacodynamics profile. Therefore, the mice were treated with 10 mg/kg SAFit2 after surgery, the mice behavior was assessed over 21 days and biochemical analysis were performed after 14 and 21 days. Furthermore, the impact of SAFit2 on sensory neurons and macrophages was investigated in vitro. Results Here, we show that the FKBP51 inhibitor SAFit2 ameliorates nerve injury-induced neuropathic pain in vivo by reducing neuroinflammation. SAFit2 reduces the infiltration of immune cells into neuronal tissue and counteracts the increased NF-κB pathway activation which leads to reduced cytokine and chemokine levels in the DRGs and spinal cord. In addition, SAFit2 desensitizes the pain-relevant TRPV1 channel and subsequently reduces the release of pro-inflammatory neuropeptides from sensory neurons. Conclusions SAFit2 ameliorates neuroinflammation and counteracts enhanced neuronal activity after nerve injury leading to an amelioration of nerve injury-induced neuropathic pain. Based on these findings, SAFit2 constitutes as a novel and promising drug candidate for the treatment of nerve injury-induced neuropathic pain. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02615-7.
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Affiliation(s)
- Saskia Wedel
- Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe-University, 60590, Frankfurt am Main, Germany
| | - Praveen Mathoor
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590, Frankfurt am Main, Germany
| | - Oliver Rauh
- Membrane Biophysics, Department of Biology, Technical University of Darmstadt, 64287, Darmstadt, Germany
| | - Tim Heymann
- Department of Chemistry, Technical University of Darmstadt, 64287, Darmstadt, Germany
| | - Cosmin I Ciotu
- Center of Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria
| | - Dominik C Fuhrmann
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590, Frankfurt am Main, Germany
| | - Michael J M Fischer
- Center of Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria
| | - Andreas Weigert
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590, Frankfurt am Main, Germany
| | - Natasja de Bruin
- Center of Physiology and Pharmacology, Medical University of Vienna, 1090, Vienna, Austria
| | - Felix Hausch
- Department of Chemistry, Technical University of Darmstadt, 64287, Darmstadt, Germany
| | - Gerd Geisslinger
- Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe-University, 60590, Frankfurt am Main, Germany.,Fraunhofer Institute for Translational Medicine and Pharmacology ITMP and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, 60596, Frankfurt am Main, Germany
| | - Marco Sisignano
- Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe-University, 60590, Frankfurt am Main, Germany. .,Fraunhofer Institute for Translational Medicine and Pharmacology ITMP and Fraunhofer Cluster of Excellence for Immune Mediated Diseases CIMD, 60596, Frankfurt am Main, Germany.
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25
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Guo Y, Schon L, Paudel S, Feltham T, Manandhar L, Zhang Z. Increased synovial expression of calcitonin gene-related peptide and its potential roles in Charcot Neuroarthropathy. Exp Mol Pathol 2022; 128:104835. [PMID: 36195300 DOI: 10.1016/j.yexmp.2022.104835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 09/19/2022] [Accepted: 09/28/2022] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Joint destruction in Charcot neuroarthropathy (CNA) is accompanied with abundant hyperplastic synovium. This study aimed to characterize the expression patterns of a group of neuropeptides in the CNA synovium. METHODS Synovial specimens were collected during surgery from the CNA (n = 6) and non-CNA joints (n = 14). Tissue samples were processed for protein extraction and western blot for vasoactive intestinal peptide (VIP), galanin, and calcitonin gene-related peptide (CGRP). Immunohistochemistry was performed to localize CGRP in the CNA synovium. Additionally, CGRP was applied to fibroblast-like synoviocytes (FLS) isolated from CNA synovium for its effects on cell proliferation and collagenolysis in vitro. RESULTS Western blot detected light bands of VIP in the CNA samples but abundant galanin in both CNA and non-CNA samples. Most of the CNA samples (5/6) increased expression of CGRP, with an average band density about 2 times that in the non-CNA group (p < .05). Immunohistochemistry of CGRP demonstrated intense staining in the intimal layer of the CNA synovium. In tissue culture, adding CGRP (10 nM) in the medium promoted FLS proliferation. In combination with TNF-α, CGRP enhanced FLS-mediated collagenolysis in vitro. CONCLUSION This study revealed an increased expression of CGRP in the CNA synovium and demonstrated that CGRP regulates FLS proliferation and collagenolytic activity, suggesting CGRP may contribute to the bone and cartilage destruction in CNA.
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Affiliation(s)
- Yi Guo
- Department of Orthopaedic Surgery, Montefiore Medical Center, Bronx, NY, USA
| | - Lew Schon
- Institute for Foot and Ankle Reconstruction, Mercy Medical Center, Baltimore, MD, USA; Center for Orthopaedic Innovation, Mercy Medical Center, Baltimore, MD, USA
| | - Sharada Paudel
- Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Tyler Feltham
- Philadelphia College of Osteopathic Medicine-GA, Suwanee, GA, USA
| | | | - Zijun Zhang
- Center for Orthopaedic Innovation, Mercy Medical Center, Baltimore, MD, USA.
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26
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Zhou S, Maleitzke T, Geissler S, Hildebrandt A, Fleckenstein FN, Niemann M, Fischer H, Perka C, Duda GN, Winkler T. Source and hub of inflammation: The infrapatellar fat pad and its interactions with articular tissues during knee osteoarthritis. J Orthop Res 2022; 40:1492-1504. [PMID: 35451170 DOI: 10.1002/jor.25347] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 02/28/2022] [Accepted: 04/20/2022] [Indexed: 02/04/2023]
Abstract
Knee osteoarthritis, the most prevalent degenerative joint disorder worldwide, is driven by chronic low-grade inflammation and subsequent cartilage degradation. Clinical data on the role of the Hoffa or infrapatellar fat pad in knee osteoarthritis are, however, scarce. The infrapatellar fat pad is a richly innervated intracapsular, extrasynovial adipose tissue, and an abundant source of adipokines and proinflammatory and catabolic cytokines, which may contribute to chronic synovial inflammation, cartilage destruction, and subchondral bone remodeling during knee osteoarthritis. How the infrapatellar fat pad interacts with neighboring tissues is poorly understood. Here, we review available literature with regard to the infrapatellar fat pad's interactions with cartilage, synovium, bone, menisci, ligaments, and nervous tissue during the development and progression of knee osteoarthritis. Signaling cascades are described with a focus on immune cell populations, pro- and anti-inflammatory cytokines, adipokines, mesenchymal stromal cells, and molecules derived from conditioned media from the infrapatellar fat pad. Understanding the complex interplay between the infrapatellar fat pad and its neighboring articular tissues may help to better understand and treat the multifactorial pathogenesis of osteoarthritis.
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Affiliation(s)
- Sijia Zhou
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany.,Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Tazio Maleitzke
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany.,Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany.,Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin, Germany
| | - Sven Geissler
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany.,Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
| | - Alexander Hildebrandt
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany.,Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Florian Nima Fleckenstein
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin, Germany.,Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Diagnostic and Interventional Radiology, Berlin, Germany
| | - Marcel Niemann
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany.,Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany.,Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
| | - Heilwig Fischer
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany.,Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany
| | - Carsten Perka
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany
| | - Georg N Duda
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany.,Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
| | - Tobias Winkler
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Berlin, Germany.,Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Berlin, Germany.,Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
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27
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Anti-Inflammatory, Analgesic and Antioxidant Potential of New (2S,3S)-2-(4-isopropylbenzyl)-2-methyl-4-nitro-3-phenylbutanals and Their Corresponding Carboxylic Acids through In Vitro, In Silico and In Vivo Studies. Molecules 2022; 27:molecules27134068. [PMID: 35807316 PMCID: PMC9268591 DOI: 10.3390/molecules27134068] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 02/07/2023] Open
Abstract
In the current study, a series of new (2S,3S)-2-(4-isopropylbenzyl)-2-methyl-4-nitro-3-phenylbutanals (FM1-6) with their corresponding carboxylic acid analogues (FM7-12) has been synthesized. Initially, the aldehydic derivatives were isolated in the diastereomeric form, and the structures were confirmed with NMR, MS and elemental analysis. Based on the encouraging results in in vitro COX 1/2, 5-LOX and antioxidant assays, we oxidized the compounds and obtained the pure single (major) diastereomer for activities. Among all the compounds, FM4, FM10 and FM12 were the leading compounds based on their potent IC50 values. The IC50 values of compounds FM4, FM10 and FM12 were 0.74, 0.69 and 0.18 µM, respectively, in COX-2 assay. Similarly, the IC50 values of these three compounds were also dominant in COX-1 assay. In 5-LOX assay, the majority of our compounds were potent inhibitors of the enzyme. Based on the potency and safety profiles, FM10 and FM12 were subjected to the in vivo experiments. The compounds FM10 and FM12 were observed with encouraging results in in vivo analgesic and anti-inflammatory models. The molecular docking studies of the selected compounds show binding interactions in the minimized pocked of the target proteins. It is obvious from the overall results that FM10 and FM12 are potent analgesic and anti-inflammatory agents.
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28
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Xu W, Jiang Y, Wang N, Bai H, Xu S, Xia T, Xin H. Traditional Chinese Medicine as a Promising Strategy for the Treatment of Alzheimer's Disease Complicated With Osteoporosis. Front Pharmacol 2022; 13:842101. [PMID: 35721142 PMCID: PMC9198449 DOI: 10.3389/fphar.2022.842101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/21/2022] [Indexed: 11/13/2022] Open
Abstract
Alzheimer’s disease (AD) and osteoporosis (OP) are progressive degenerative diseases caused by multiple factors, placing a huge burden on the world. Much evidence indicates that OP is a common complication in AD patients. In addition, there is also evidence to show that patients with OP have a higher risk of AD than those without OP. This suggests that the association between the two diseases may be due to a pathophysiological link rather than one disease causing the other. Several in vitro and in vivo studies have also proved their common pathogenesis. Based on the theory of traditional Chinese medicine, some classic and specific natural Chinese medicines are widely used to effectively treat AD and OP. Current evidence also shows that these treatments can ameliorate both brain damage and bone metabolism disorder and further alleviate AD complicated with OP. These valuable therapies might provide effective and safe alternatives to major pharmacological strategies.
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Affiliation(s)
- Weifan Xu
- Department of Pharmacognosy, School of Pharmacy, Naval Medical University, Shanghai, China.,Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Yiping Jiang
- Department of Pharmacognosy, School of Pharmacy, Naval Medical University, Shanghai, China
| | - Nani Wang
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China
| | - Huanhuan Bai
- Department of Pharmacognosy, School of Pharmacy, Naval Medical University, Shanghai, China
| | - Shengyan Xu
- Department of Pharmacognosy, School of Pharmacy, Naval Medical University, Shanghai, China
| | - Tianshuang Xia
- Department of Pharmacognosy, School of Pharmacy, Naval Medical University, Shanghai, China
| | - Hailiang Xin
- Department of Pharmacognosy, School of Pharmacy, Naval Medical University, Shanghai, China
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Braun S, Zaucke F, Brenneis M, Rapp AE, Pollinger P, Sohn R, Jenei-Lanzl Z, Meurer A. The Corpus Adiposum Infrapatellare (Hoffa's Fat Pad)-The Role of the Infrapatellar Fat Pad in Osteoarthritis Pathogenesis. Biomedicines 2022; 10:1071. [PMID: 35625808 PMCID: PMC9138316 DOI: 10.3390/biomedicines10051071] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 04/28/2022] [Accepted: 05/03/2022] [Indexed: 02/01/2023] Open
Abstract
In recent years, the infrapatellar fat pad (IFP) has gained increasing research interest. The contribution of the IFP to the development and progression of knee osteoarthritis (OA) through extensive interactions with the synovium, articular cartilage, and subchondral bone is being considered. As part of the initiation process of OA, IFP secretes abundant pro-inflammatory mediators among many other factors. Today, the IFP is (partially) resected in most total knee arthroplasties (TKA) allowing better visualization during surgical procedures. Currently, there is no clear guideline providing evidence in favor of or against IFP resection. With increasing numbers of TKAs, there is a focus on preventing adverse postoperative outcomes. Therefore, anatomic features, role in the development of knee OA, and consequences of resecting versus preserving the IFP during TKA are reviewed in the following article.
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Affiliation(s)
- Sebastian Braun
- Department of Orthopedics (Friedrichsheim), University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany; (M.B.); (A.M.)
| | - Frank Zaucke
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Department of Orthopedics (Friedrichsheim), University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany; (F.Z.); (A.E.R.); (P.P.); (R.S.); (Z.J.-L.)
| | - Marco Brenneis
- Department of Orthopedics (Friedrichsheim), University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany; (M.B.); (A.M.)
| | - Anna E. Rapp
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Department of Orthopedics (Friedrichsheim), University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany; (F.Z.); (A.E.R.); (P.P.); (R.S.); (Z.J.-L.)
| | - Patrizia Pollinger
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Department of Orthopedics (Friedrichsheim), University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany; (F.Z.); (A.E.R.); (P.P.); (R.S.); (Z.J.-L.)
| | - Rebecca Sohn
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Department of Orthopedics (Friedrichsheim), University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany; (F.Z.); (A.E.R.); (P.P.); (R.S.); (Z.J.-L.)
| | - Zsuzsa Jenei-Lanzl
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Department of Orthopedics (Friedrichsheim), University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany; (F.Z.); (A.E.R.); (P.P.); (R.S.); (Z.J.-L.)
| | - Andrea Meurer
- Department of Orthopedics (Friedrichsheim), University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany; (M.B.); (A.M.)
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Diterbutyl phthalate attenuates osteoarthritis in ACLT mice via suppressing ERK/c-fos/NFATc1 pathway, and subsequently inhibiting subchondral osteoclast fusion. Acta Pharmacol Sin 2022; 43:1299-1310. [PMID: 34381182 PMCID: PMC9061820 DOI: 10.1038/s41401-021-00747-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 07/17/2021] [Indexed: 12/11/2022]
Abstract
Osteoarthritis (OA) is the most common arthritis with a rapidly increasing prevalence. Disease progression is irreversible, and there is no curative therapy available. During OA onset, abnormal mechanical loading leads to excessive osteoclastogenesis and bone resorption in subchondral bone, causing a rapid subchondral bone turnover, cyst formation, sclerosis, and finally, articular cartilage degeneration. Moreover, osteoclast-mediated angiogenesis and sensory innervation in subchondral bone result in abnormal vascularization and OA pain. The traditional Chinese medicine Panax notoginseng (PN; Sanqi) has long been used in treatment of bone diseases including osteoporosis, bone fracture, and OA. In this study we established two-dimensional/bone marrow mononuclear cell/cell membrane chromatography/time of flight mass spectrometry (2D/BMMC/CMC/TOFMS) technique and discovered that diterbutyl phthalate (DP) was the active constituent in PN inhibiting osteoclastogenesis. Then we explored the therapeutic effect of DP in an OA mouse model with anterior cruciate ligament transaction (ACLT). After ACLT was conducted, the mice received DP (5 mg·kg-1·d-1, ip) for 8 weeks. Whole knee joint tissues of the right limb were harvested at weeks 2, 4, and 8 for analysis. We showed that DP administration impeded overactivated osteoclastogenesis in subchondral bone and ameliorated articular cartilage deterioration. DP administration blunted aberrant H-type vessel formation in subchondral bone marrow and alleviated OA pain assessed in Von Frey test and thermal plantar test. In RANKL-induced RAW264.7 cells in vitro, DP (20 μM) retarded osteoclastogenesis by suppressing osteoclast fusion through inhibition of the ERK/c-fos/NFATc1 pathway. DP treatment also downregulated the expression of dendritic cell-specific transmembrane protein (DC-STAMP) and d2 isoform of the vacuolar (H+) ATPase V0 domain (Atp6v0d2) in the cells. In conclusion, we demonstrate that DP prevents OA progression by inhibiting abnormal osteoclastogenesis and associated angiogenesis and neurogenesis in subchondral bone.
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Abstract
Joint pain is the hallmark symptom of osteoarthritis (OA) and the main reason for patients to seek medical assistance. OA pain greatly contributes to functional limitations of joints and reduced quality of life. Although several pain-relieving medications are available for OA treatment, the current intervention strategy for OA pain cannot provide satisfactory pain relief, and the chronic use of the drugs for pain management is often associated with significant side effects and toxicities. These observations suggest that the mechanisms of OA-related pain remain undefined. The current review mainly focuses on the characteristics and mechanisms of OA pain. We evaluate pathways associated with OA pain, such as nerve growth factor (NGF)/tropomyosin receptor kinase A (TrkA), calcitonin gene-related peptide (CGRP), C–C motif chemokine ligands 2 (CCL2)/chemokine receptor 2 (CCR2) and tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, and the Wnt/β-catenin signaling pathway. In addition, animal models currently used for OA pain studies and emerging preclinical studies are discussed. Understanding the multifactorial components contributing to OA pain could provide novel insights into the development of more specific and effective drugs for OA pain management.
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32
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Gonçalves S, Gowler PR, Woodhams SG, Turnbull J, Hathway G, Chapman V. The challenges of treating osteoarthritis pain and opportunities for novel peripherally directed therapeutic strategies. Neuropharmacology 2022; 213:109075. [DOI: 10.1016/j.neuropharm.2022.109075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 03/07/2022] [Accepted: 04/21/2022] [Indexed: 12/22/2022]
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Nolan MW, Uzan OC, Green NA, Lana SE, Lascelles BDX. Intensity of perioperative analgesia but not pre-treatment pain is predictive of survival in dogs undergoing amputation plus chemotherapy for extremity osteosarcoma. Vet Comp Oncol 2022; 20:568-576. [PMID: 35257492 PMCID: PMC9544272 DOI: 10.1111/vco.12808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 02/10/2022] [Accepted: 02/25/2022] [Indexed: 11/28/2022]
Abstract
The purpose of this bi‐institutional retrospective study was to determine whether, in dogs treated with limb amputation and adjunctive chemotherapy for osteosarcoma, oncologic outcomes are impacted by either: (1) baseline cancer pain severity, or (2) the approaches used for perioperative pain management. Data were extracted from the medical records of 284 dogs that underwent both limb amputation and chemotherapy (carboplatin and/or doxorubicin) between 1997 and 2017 for localized (non‐metastatic) osteosarcoma of the appendicular skeleton. Kaplan–Meier survival curves and Cox proportional hazard (PH) models were used to determine the impact that retrospectively scored baseline pain levels (high vs. low) and various analgesic and local anaesthetic treatments had on both metastasis‐free survival and all‐cause mortality. For the entire population, the median disease free interval and median overall survival times were 253 and 284 days, respectively. Baseline pain was rated as “low” in 84 dogs, and “high” in 190 dogs; pain severity had no detectable effect on either metastasis‐free survival or all‐cause mortality. When accounting for the potential influences of known prognostic factors, dogs treated with what was characterized as a high‐intensity perioperative analgesic plan (including both a non‐steroidal anti‐inflammatory drug [NSAID] and a bupivacaine‐eluting soaker catheter placed at the amputation site) had a higher probability of survival than dogs treated with a low‐intensity perioperative analgesic plan (neither an NSAID, nor a soaker catheter); the median overall survival times were 252 and 378 days, respectively (hazard ratio: 2.922; p = .020).
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Affiliation(s)
- Michael W Nolan
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.,Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA.,Comparative Pain Research and Education Center, North Carolina State University, Raleigh, NC, USA
| | - Olivia C Uzan
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.,Flint Animal Cancer Center, Colorado State University, Fort Collins, CO, USA
| | - Noah A Green
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
| | - Susan E Lana
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.,Flint Animal Cancer Center, Colorado State University, Fort Collins, CO, USA
| | - B Duncan X Lascelles
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.,Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA.,Comparative Pain Research and Education Center, North Carolina State University, Raleigh, NC, USA.,Translational Research in Pain Program, Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.,Thurston Arthritis Center, UNC School of Medicine, Chapel Hill, NC, USA.,Center for Translational Pain Research, Department of Anesthesiology, Duke University, Durham, NC, USA
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34
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CGRP Regulates Nucleus Pulposus Cell Apoptosis and Inflammation via the MAPK/NF- κB Signaling Pathways during Intervertebral Disc Degeneration. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2021:2958584. [PMID: 34987701 PMCID: PMC8720589 DOI: 10.1155/2021/2958584] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 12/03/2021] [Indexed: 12/22/2022]
Abstract
Chronic low back pain (CLBP) has been proved to be the dominating cause of disability in patients with lumbar degenerative diseases. Of the various etiological factors, intervertebral disc degeneration (IVDD) has been the dominating cause. In the past few decades, the role and changes of nerve systems, especially the peripheral sensory fibers and their neurotransmitters, in the induction and progression of IVDD have attracted growing concerns. The expression of many neuropeptides, such as SP, NPY, and CGRP, in the nociceptive pathways is increased during the progression of IVDD and responsible for the discogenic pain. Here, the role of CGRP in the progression of IVDD was firstly investigated both in vitro and in vivo. Firstly, we confirmed that human degenerated intervertebral disc tissue exhibited elevated expression of CGRP and its receptor. Secondly, in vitro experiments suggested that CGRP could inhibit the proliferation and induce apoptosis in human nucleus pulposus (NP) cells, as well as promote inflammation and degenerated phenotypes through activating NF-κB and MAPK signaling pathways. Thirdly, CGRP receptor antagonist, Rimegepant, can ameliorate the adverse effects of CGRP imposed on NP cells, which were confirmed in vitro and in vivo. Our results will bring about a brand-new insight into the roles of neuromodulation in IVDD and related therapeutic attempts.
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Li X, Ye Y, Zhou W, Shi Q, Wang L, Li T. Anti-Inflammatory Effects of BoNT/A Against Complete Freund's Adjuvant-Induced Arthritis Pain in Rats: Transcriptome Analysis. Front Pharmacol 2021; 12:735075. [PMID: 34803684 PMCID: PMC8602683 DOI: 10.3389/fphar.2021.735075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 10/11/2021] [Indexed: 01/01/2023] Open
Abstract
Arthritis is the most common cause to lead to chronic pain. Botulinum toxin type A (BoNT/A) has been widely used to treat chronic pain. In our previous study, we confirmed the anti-inflammatory and antinociceptive effects of BoNT/A in the Complete Freund’s Adjuvant (CFA)-induced arthritis model, but the underlying anti-inflammatory mechanism was not fully elucidated. The purpose of this study was to investigate the anti-inflammatory effects and mechanisms of BoNT/A on arthritis using transcriptomic analysis. The BoNT/A was injected into the rat ankle joint on day 21 after CFA injection. The von Frey and hot plate tests were applied to assess the pain-related behaviors at different time points. Five days after BoNT/A treatment, gene expression profiling in dorsal root ganglion (DRG) was performed using RNA sequencing (RNA-seq). The differentially expressed genes (DEGs) were analyzed by various tools. The mechanical allodynia and thermal hyperalgesia were significantly reversed after BoNT/A injection. RNA-seq revealed 97 DEGs between the CFA group and Sham group; these DEGs were enriched inflammatory response, IL-17 signaling pathway, etc. There are 71 DEGs between the CFA+BoNT/A group and the CFA group; these DEGs related to response to peptide, PI3K-Akt signaling pathway, ECM–receptor interactions, etc. Three key genes were significantly decreased after CFA-induced arthritis pain, while BoNT/A increased the expression of these genes. The identification of S100A9, S100A8, and MMP8 genes can provide new therapeutic targets for arthritis pain and affect the signaling pathway to play an anti-inflammatory role after the treatment of BoNT/A.
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Affiliation(s)
- Xinhe Li
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yinshuang Ye
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenwen Zhou
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qilin Shi
- Department of Rehabilitation Medicine, Qingdao West Coast New District People's Hospital, Qingdao, China
| | - Lin Wang
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tieshan Li
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
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Noor-Mohammadi E, Ligon CO, Mackenzie K, Stratton J, Shnider S, Greenwood-Van Meerveld B. A Monoclonal Anti-Calcitonin Gene-Related Peptide Antibody Decreases Stress-Induced Colonic Hypersensitivity. J Pharmacol Exp Ther 2021; 379:270-279. [PMID: 34620725 DOI: 10.1124/jpet.121.000731] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 09/24/2021] [Indexed: 12/20/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a brain-gut disorder characterized by abdominal pain and altered bowel habits. Although the etiology of IBS remains unclear, stress in adulthood or in early life has been shown to be a significant factor in the development of IBS symptomatology. Evidence suggests that aberrant calcitonin gene-related peptide (CGRP) signaling may be involved in afferent sensitization and visceral organ hypersensitivity. Here, we used a monoclonal anti-CGRP divalent antigen-binding fragment [F(ab')2] antibody to test the hypothesis that inhibition of peripheral CGRP signaling reverses colonic hypersensitivity induced by either chronic adult stress or early life stress. A cohort of adult male rats was exposed to repeated water avoidance stress. Additionally, a second cohort consisting of female rats was exposed to a female-specific neonatal odor-attachment learning paradigm of unpredictable early life stress. Colonic sensitivity was then assessed in adult animals via behavioral responses to colorectal distension (CRD). To analyze spinal nociceptive signaling in response to CRD, dorsal horn extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was measured via immunohistochemistry. Repeated psychologic stress in adulthood or unpredictable stress in early life induced colonic hypersensitivity and enhanced evoked ERK1/2 phosphorylation in the spinal cord after CRD in rats. These phenotypes were reversed by administration of a monoclonal anti-CGRP F(ab')2 fragment antibody. Stress-induced changes in visceral sensitivity and spinal nociceptive signaling were reversed by inhibition of peripheral CGRP signaling, which suggests a prominent role for CGRP in central sensitization and the development of stress-induced visceral hypersensitivity. SIGNIFICANCE STATEMENT: Targeting peripheral calcitonin gene-related peptide (CGRP) with a monoclonal anti-CGRP divalent antigen-binding fragment antibody reduced central sensitization and attenuated colonic hypersensitivity induced by either chronic adult stress or early life stress. CGRP-targeting antibodies are approved for migraine prevention, and the results of this study suggest that targeting CGRP may provide a novel treatment strategy for irritable bowel syndrome-related, stress-induced visceral pain.
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Affiliation(s)
- Ehsan Noor-Mohammadi
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma (E.N.-M., C.O.L., B.G.-V.M); and Teva Pharmaceutical Industries, Ltd., Redwood City, California (K.M., J.S., S.S.)
| | - Casey Owen Ligon
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma (E.N.-M., C.O.L., B.G.-V.M); and Teva Pharmaceutical Industries, Ltd., Redwood City, California (K.M., J.S., S.S.)
| | - Kimberly Mackenzie
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma (E.N.-M., C.O.L., B.G.-V.M); and Teva Pharmaceutical Industries, Ltd., Redwood City, California (K.M., J.S., S.S.)
| | - Jennifer Stratton
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma (E.N.-M., C.O.L., B.G.-V.M); and Teva Pharmaceutical Industries, Ltd., Redwood City, California (K.M., J.S., S.S.)
| | - Sara Shnider
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma (E.N.-M., C.O.L., B.G.-V.M); and Teva Pharmaceutical Industries, Ltd., Redwood City, California (K.M., J.S., S.S.)
| | - Beverley Greenwood-Van Meerveld
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma (E.N.-M., C.O.L., B.G.-V.M); and Teva Pharmaceutical Industries, Ltd., Redwood City, California (K.M., J.S., S.S.)
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Cheng YC, Chiu YM, Dai ZK, Wu BN. Loganin Ameliorates Painful Diabetic Neuropathy by Modulating Oxidative Stress, Inflammation and Insulin Sensitivity in Streptozotocin-Nicotinamide-Induced Diabetic Rats. Cells 2021; 10:2688. [PMID: 34685668 PMCID: PMC8534751 DOI: 10.3390/cells10102688] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/22/2021] [Accepted: 10/07/2021] [Indexed: 12/27/2022] Open
Abstract
Loganin is an iridoid glycoside with antioxidant, anti-inflammatory, glucose-lowering activities which may address the pathological mechanisms of painful diabetic neuropathy (PDN) related to inflammation, oxidative stress, and hyperglycemia. This study investigated the underlying mechanisms of action of loganin on PDN. The in vivo model of PDN was established by streptozotocin-nicotinamide (STZ-NA) induction in Sprague Dawley (SD) rats. Subsequently, loganin (5 mg/kg) was administered by daily intraperitoneal injection. High-glucose stimulated human SH-SY5Y cells co-incubated with loganin were used to mimic the in vitro model of PDN. Loganin improved PDN rats' associated pain behaviors (allodynia and hyperalgesia), insulin resistance index (HOMA-IR), and serum levels of superoxide dismutase (SOD), catalase and glutathione. Loganin also reduced pain-associated channel protein CaV3.2 and calcitonin gene-related peptide (CGRP) in the surficial spinal dorsal horn of PDN rats. Loganin inhibited oxidative stress and NF-κB activation and decreased the levels of mRNA and protein of proinflammatory factors IL-1β and TNF-α. Moreover, loganin attenuated insulin resistance by modulating the JNK-IRS-1 (insulin receptor substrate-1)-Akt-GSK3β signaling pathway in PDN rats. These results suggested that loganin improved PDN-mediated pain behaviors by inhibiting oxidative stress-provoked inflammation in the spinal cord, resulting in improved neuropathic pain.
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Affiliation(s)
- Yu-Chi Cheng
- Drug Development and Value Creation Research Center, Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (Y.-C.C.); (Y.-M.C.)
| | - Yu-Min Chiu
- Drug Development and Value Creation Research Center, Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (Y.-C.C.); (Y.-M.C.)
| | - Zen-Kong Dai
- Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Pediatrics, Division of Pediatric Cardiology and Pulmonology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Bin-Nan Wu
- Drug Development and Value Creation Research Center, Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (Y.-C.C.); (Y.-M.C.)
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
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Stöckl S, Eitner A, Bauer RJ, König M, Johnstone B, Grässel S. Substance P and Alpha-Calcitonin Gene-Related Peptide Differentially Affect Human Osteoarthritic and Healthy Chondrocytes. Front Immunol 2021; 12:722884. [PMID: 34512650 PMCID: PMC8430215 DOI: 10.3389/fimmu.2021.722884] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/09/2021] [Indexed: 12/13/2022] Open
Abstract
Osteoarthritis (OA) is a degenerative joint disease that not only causes cartilage loss but also structural damage in all joint tissues. Joints are innervated by alpha-calcitonin gene-related peptide (αCGRP) and substance P (SP)-positive sensory nerve fibers. Alteration of sensory joint innervation could be partly responsible for degenerative changes in joints that contribute to the development of OA. Therefore, our aim was to analyze and compare the molecular effects of SP and αCGRP on the metabolism of articular chondrocytes from OA patients and non-OA cartilage donors. We treated the cells with SP or αCGRP and analysed the influence of these neuropeptides on chondrocyte metabolism and modulation of signaling pathways. In chondrocytes from healthy cartilage, SP had minimal effects compared with its effects on OA chondrocytes, where it induced inflammatory mediators, inhibited chondrogenic markers and promoted apoptosis and senescence. Treatment with αCGRP also increased apoptosis and senescence and reduced chondrogenic marker expression in OA chondrocytes, but stimulated an anabolic and protective response in healthy chondrocytes. The catabolic influence of SP and αCGRP might be due to activation of ERK signaling that could be counteracted by an increased cAMP response. We suggest that a switch between the G-subunits of the corresponding receptors after binding their ligands SP or αCGRP plays a central role in mediating the observed effects of sensory neuropeptides on chondrocytes.
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Affiliation(s)
- Sabine Stöckl
- Department of Orthopaedic Surgery, Experimental Orthopaedics, Center for Medical Biotechnology, University of Regensburg, Regensburg, Germany
| | - Annett Eitner
- Department of Trauma, Hand and Reconstructive Surgery, Experimental Trauma Surgery, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.,Department of Physiology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
| | - Richard J Bauer
- Department of Oral and Maxillofacial Surgery, Center for Medical Biotechnology, University Hospital Regensburg, Regensburg, Germany
| | - Matthias König
- Department of Orthopedics, University Medical Center Regensburg, Asklepios Klinikum Bad Abbach, Bad Abbach, Germany
| | - Brian Johnstone
- Department of Orthopaedics and Rehabilitation, Oregon Health & Science University, Portland, OR, United States
| | - Susanne Grässel
- Department of Orthopaedic Surgery, Experimental Orthopaedics, Center for Medical Biotechnology, University of Regensburg, Regensburg, Germany
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Maleitzke T, Hildebrandt A, Weber J, Dietrich T, Appelt J, Jahn D, Zocholl D, Baranowsky A, Duda GN, Tsitsilonis S, Keller J. Proinflammatory and bone protective role of calcitonin gene-related peptide alpha in collagen antibody-induced arthritis. Rheumatology (Oxford) 2021; 60:1996-2009. [PMID: 33221885 DOI: 10.1093/rheumatology/keaa711] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 09/22/2020] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Calcitonin gene-related peptide alpha (αCGRP) represents an immunomodulatory neuropeptide implicated in pain perception. αCGRP also functions as a critical regulator of bone formation and is overexpressed in patients with rheumatoid arthritis (RA). In the present study, we investigated the role of αCGRP in experimental RA regarding joint inflammation and bone remodelling. METHODS Collagen II-antibody-induced arthritis (CAIA) was induced in wild type (WT) and αCGRP-deficient (αCGRP-/-) mice. Animals were monitored over 10 and 48 days with daily assessments of the semiquantitative arthritis score and grip strength test. Joint inflammation, cartilage degradation and bone erosions were assessed by histology, gene expression analysis and µCT. RESULTS CAIA was accompanied by an overexpression of αCGRP in WT joints. αCGRP-/- mice displayed reduced arthritic inflammation and cartilage degradation. Congruently, the expression of TNF-α, IL-1β, CD80 and MMP13 was induced in WT, but not αCGRP-/- animals. WT mice displayed an increased bone turnover during the acute inflammatory phase, which was not the case in αCGRP-/- mice. Interestingly, WT mice displayed a full recovery from the inflammatory bone disease, whereas αCGRP-/- mice exhibited substantial bone loss over time. CONCLUSION This study demonstrates a proinflammatory and bone protective role of αCGRP in CAIA. Our data indicate that αCGRP not only enhances joint inflammation, but also controls bone remodelling as part of arthritis resolution. As novel αCGRP inhibitors are currently introduced clinically for the treatment of migraine, their potential impact on RA progression warrants further clinical investigation.
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Affiliation(s)
- Tazio Maleitzke
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Alexander Hildebrandt
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Jérôme Weber
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Tamara Dietrich
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Jessika Appelt
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Denise Jahn
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Dario Zocholl
- Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Anke Baranowsky
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Georg N Duda
- Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Serafeim Tsitsilonis
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Johannes Keller
- Berlin Institute of Health (BIH), Berlin, Germany.,Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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40
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Aggarwal S, Ranjha R, Paul J. Neuroimmunomodulation by gut bacteria: Focus on inflammatory bowel diseases. World J Gastrointest Pathophysiol 2021; 12:25-39. [PMID: 34084590 PMCID: PMC8160600 DOI: 10.4291/wjgp.v12.i3.25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/01/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Microbes colonize the gastrointestinal tract are considered as highest complex ecosystem because of having diverse bacterial species and 150 times more genes as compared to the human genome. Imbalance or dysbiosis in gut bacteria can cause dysregulation in gut homeostasis that subsequently activates the immune system, which leads to the development of inflammatory bowel disease (IBD). Neuromediators, including both neurotransmitters and neuropeptides, may contribute to the development of aberrant immune response. They are emerging as a regulator of inflammatory processes and play a key role in various autoimmune and inflammatory diseases. Neuromediators may influence immune cell’s function via the receptors present on these cells. The cytokines secreted by the immune cells, in turn, regulate the neuronal functions by binding with their receptors present on sensory neurons. This bidirectional communication of the enteric nervous system and the enteric immune system is involved in regulating the magnitude of inflammatory pathways. Alterations in gut bacteria influence the level of neuromediators in the colon, which may affect the gastrointestinal inflammation in a disease condition. Changed neuromediators concentration via dysbiosis in gut microbiota is one of the novel approaches to understand the pathogenesis of IBD. In this article, we reviewed the existing knowledge on the role of neuromediators governing the pathogenesis of IBD, focusing on the reciprocal relationship among the gut microbiota, neuromediators, and host immunity. Understanding the neuromediators and host-microbiota interactions would give a better insight in to the disease pathophysiology and help in developing the new therapeutic approaches for the disease.
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Affiliation(s)
- Surbhi Aggarwal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi 110016, India
- School of Life Sciences, Jawaharlal Nehru University, Delhi 110067, India
| | - Raju Ranjha
- School of Life Sciences, Jawaharlal Nehru University, Delhi 110067, India
- Field Unit Raipur, ICMR-National Institute of Malaria Research, Raipur 492015, Chhattisgarh, India
| | - Jaishree Paul
- School of Life Sciences, Jawaharlal Nehru University, Delhi 110067, India
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41
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Moattari CR, Granstein RD. Neuropeptides and neurohormones in immune, inflammatory and cellular responses to ultraviolet radiation. Acta Physiol (Oxf) 2021; 232:e13644. [PMID: 33724698 DOI: 10.1111/apha.13644] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 12/16/2022]
Abstract
Humans are exposed to varying amounts of ultraviolet radiation (UVR) through sunlight. UVR penetrates into human skin leading to release of neuropeptides, neurotransmitters and neuroendocrine hormones. These messengers released from local sensory nerves, keratinocytes, Langerhans cells (LCs), mast cells, melanocytes and endothelial cells (ECs) modulate local and systemic immune responses, mediate inflammation and promote differing cell biologic effects. In this review, we will focus on both animal and human studies that elucidate the roles of calcitonin gene-related peptide (CGRP), substance P (SP), nerve growth factor (NGF), nitric oxide and proopiomelanocortin (POMC) derivatives in mediating immune and inflammatory effects of exposure to UVR as well as other cell biologic effects of UVR exposure.
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La Hausse De Lalouviere L, Morice O, Fitzgerald M. Altered sensory innervation and pain hypersensitivity in a model of young painful arthritic joints: short- and long-term effects. Inflamm Res 2021; 70:483-493. [PMID: 33715021 PMCID: PMC8012329 DOI: 10.1007/s00011-021-01450-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 02/24/2021] [Accepted: 03/04/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Early life experience can cause long-term alterations in the nociceptive processes underlying chronic pain, but the consequences of early life arthritic joint inflammation upon the sensory innervation of the joint is not known. Here, we measure pain sensitivity and sensory innervation in a young, juvenile and adult rodent model of arthritic joints and test the consequences of joint inflammation in young animals upon adult arthritic pain and joint innervation. METHODS Unilateral ankle joint injections of complete Freund's adjuvant (CFA) (6-20 µl) were performed in young, postnatal day (P)8, adolescent (P21) and adult (P40) rats. A separate cohort of animals were injected at P8, and again at P40. Hindpaw mechanical sensitivity was assessed using von Frey monofilaments (vF) for 10 days. Nerve fibres were counted in sections through the ankle joint immunostained for calcitonin gene-related peptide (CGRP) and neurofilament 200 kDa (NF200). RESULTS Ankle joint CFA injection increased capsular width at all ages. Significant mechanical pain hypersensitivity and increased number of joint CGRP + ve sensory fibres occurred in adolescent and adult, but not young, rats. Despite the lack of acute reaction, joint inflammation at a young age resulted in significantly increased pain hypersensitivity and CGRP+ fibre counts when the rats were re-inflamed as adults. CONCLUSIONS Joint inflammation increases the sensory nociceptive innervation and induces acute pain hypersensitivity in juvenile and adult, but not in young rats. However, early life joint inflammation 'primes' the joint such that adult inflammatory pain behaviour and nociceptive nerve endings in the joint are significantly increased. Early life joint inflammation may be an important factor in the generation and maintenance of chronic arthritic pain.
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Affiliation(s)
- Luke La Hausse De Lalouviere
- Department of Neuroscience, Physiology and Pharmacology, University College London, Medawar Building, Gower Street, London, WC1E 6BT, UK
| | - Oscar Morice
- Department of Neuroscience, Physiology and Pharmacology, University College London, Medawar Building, Gower Street, London, WC1E 6BT, UK
| | - Maria Fitzgerald
- Department of Neuroscience, Physiology and Pharmacology, University College London, Medawar Building, Gower Street, London, WC1E 6BT, UK.
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Ma Z, Huang Z, Zhang L, Li X, Xu B, Xiao Y, Shi X, Zhang H, Liao T, Wang P. Vanillic Acid Reduces Pain-Related Behavior in Knee Osteoarthritis Rats Through the Inhibition of NLRP3 Inflammasome-Related Synovitis. Front Pharmacol 2021; 11:599022. [PMID: 33658936 PMCID: PMC7917290 DOI: 10.3389/fphar.2020.599022] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 12/23/2020] [Indexed: 12/13/2022] Open
Abstract
Objectives: Synovitis plays an important role in knee osteoarthritis (KOA) pain. The activation of the NOD-like receptor protein 3 (NLRP3) inflammasome in fibroblast-like synoviocytes (FLSs) promotes KOA development. In this study, we aimed to investigate whether vanillic acid (VA), a monomer derived from Chinese herbal medicines, could target NLRP3 inflammasome-related synovitis to reduce pain. Methods: Rats in the KOA and KOA + VA groups were injected with monosodium iodoacetate (MIA) in the knee to induce KOA. From day 14, the KOA + VA group was given VA at 30 mg/kg every day via gastric intubation. FLSs were collected from the synovial tissues. We examined both the protein and gene expression of caspase-1, apoptosis-associated speck-like protein with a caspase recruitment domain (ASC), NLRP3, components of the NLRP3 inflammasome, and interleukin-1β (IL-1β) and IL-18 in vivo and in vitro. Results: The upregulation of caspase-1, ASC, and NLRP3 in the KOA model were reduced by VA. VA also lowered the level of IL-1β and IL-18 in the KOA model. In addition, VA relieved pain-related behavior of KOA model rats and downregulated the pain mediators CGRP, NGF, and TrkA in FLSs. Interestingly, we also observed reduced synovial fibrosis in the animal experiments. Conclusion: Our research showed that VA reduces synovitis and pain-related behaviors in a rat model of KOA, which provides the basis for further investigations into the potential therapeutic impact of VA in KOA.
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Affiliation(s)
- Zhenyuan Ma
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Province Hospital of Chinese Medicine, Nanjing, China.,Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhengquan Huang
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Li Zhang
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Province Hospital of Chinese Medicine, Nanjing, China.,Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaochen Li
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Province Hospital of Chinese Medicine, Nanjing, China.,Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Bo Xu
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Province Hospital of Chinese Medicine, Nanjing, China.,Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yancheng Xiao
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Province Hospital of Chinese Medicine, Nanjing, China.,Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaoqing Shi
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Haosheng Zhang
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Province Hospital of Chinese Medicine, Nanjing, China.,Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Taiyang Liao
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Province Hospital of Chinese Medicine, Nanjing, China.,Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Peimin Wang
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
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Xu J, Wang J, Chen X, Li Y, Mi J, Qin L. The Effects of Calcitonin Gene-Related Peptide on Bone Homeostasis and Regeneration. Curr Osteoporos Rep 2020; 18:621-632. [PMID: 33030684 DOI: 10.1007/s11914-020-00624-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/29/2020] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW The goals of this review are two folds: (1) to describe the recent understandings on the roles of calcitonin gene-related peptide-α (CGRP) in bone homeostasis and the underlying mechanisms of related neuronal regulation and (2) to propose innovative CGRP-modulated approaches for enhancing bone regeneration in challenging bone disorders. RECENT FINDINGS CGRP is predominantly produced by the densely distributed sensory neuronal fibers in bone, declining with age. Under mechanical and biochemical stimulations, CGRP releases and exerts either physiological or pathophysiological roles. CGRP at physiological level orchestrates the communications of bone cells with cells of other lineages, affecting not only osteogenesis, osteoclastogenesis, and adipogenesis but also angiogenesis, demonstrating with pronounced anabolic effect, thus is essential for maintaining bone homeostasis, with tuned nerve-vessel-bone network. In addition, its effects on immunity and cell recruitment are also crucial for bone fracture healing. Binding to the G protein-coupled receptor composited by calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1) on cellular surface, CGRP triggers various intracellular signaling cascades involving cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB). Peaking at early stage post-fracture, CGRP promotes bone formation, displaying with larger callus. Then CGRP gradually decreases over time, allowing normal or physiological bone remodeling. By elevating CGRP at early stage, low-intensity pulsed ultrasound (LIPUS), electrical stimulation, and magnesium-based bio-mineral products may promisingly accelerate bone regeneration experimentally in medical conditions like osteoporosis, osteoporotic fracture, and spine fusion. Excess CGRP expression is commonly observed in pathological conditions including cancer metastatic lesions in bone and fracture delayed- or non-healing, resulting in persistent chronic pain. To date, these discoveries have largely been limited to animal models. Clinical applications are highly desirable. Compelling evidence show the anabolic effects of CGRP on bone in animals. However, further validation on the role of CGRP and the underlying mechanisms in human skeletons is required. It remains unclear if it is type H vessel connecting neuronal CGRP to osteogenesis, and if there is only specific rather than all osteoprogenitors responsible to CGRP. Clear priority should be put to eliminate these knowledge gaps by integrating with high-resolution 3D imaging of transparent bulk bone and single-cell RNA-sequencing. Last but not the least, given that small molecule antagonists such as BIBN4096BS can block the beneficial effects of CGRP on bone, concerns on the potential side effects of humanized CGRP-neutralizing antibodies when systemically administrated to treat migraine in clinics are arising.
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Affiliation(s)
- Jiankun Xu
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.
- Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Health and Science Institute, The Chinese University of Hong Kong, Hong Kong, China.
- Joint Laboratory of Chinese Academic of Science and Hong Kong for Biomaterials, The Chinese University of Hong Kong, Hong Kong, China.
| | - Jiali Wang
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, China
| | - Xiaodan Chen
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China
| | - Ye Li
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China
| | - Jie Mi
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China
| | - Ling Qin
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.
- Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Health and Science Institute, The Chinese University of Hong Kong, Hong Kong, China.
- Joint Laboratory of Chinese Academic of Science and Hong Kong for Biomaterials, The Chinese University of Hong Kong, Hong Kong, China.
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Shakouri SK, Dolatkhah N, Omidbakhsh S, Pishgahi A, Hashemian M. Serum inflammatory and oxidative stress biomarkers levels are associated with pain intensity, pressure pain threshold and quality of life in myofascial pain syndrome. BMC Res Notes 2020; 13:510. [PMID: 33160410 PMCID: PMC7648320 DOI: 10.1186/s13104-020-05352-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/23/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES We aimed to determine the serum concentrations of some inflammatory and oxidative stress biomarkers in relation with pain intensity and quality of life in patients with myofascial pain syndrome (MPS) compared to healthy controls. This study is a case-control study. The participants were selected from MPS patients who referred to rehabilitation outpatient clinics of the Tabriz University of Medical Sciences, Iran. RESULTS Serum hs-CRP (4.68 ± 4.36 vs. 2.92 ± 4.55 g/mlµ respectively, p = 0.011), phospholipase A2 (PLA2) (6.81 ± 2.22 vs. 4.73 ± 2.97 pg/ml respectively, p < 0.001) and malondialdehyde (MDA) (2.63 ± 0.71 vs. 1.98 ± 0.90 nmol/ml respectively, p < 0.001) levels were significantly higher and serum total antioxidant capacity (TAC) (2.46 ± 0.49 vs. 2.83 ± 0.82 mmol/L respectively, p = 0.011) and superoxide dismutase (SOD) (78.89 ± 37.93 vs. 154.25 ± 115.93 U/ml respectively, p < 0.001) levels were significantly lower in the MPS patients compared to healthy controls. Serum high-sensitivity C-reactive protein (hs-CRP) level was significantly and positively associated with resting (r = 0.349, p = 0.019), activity (r = 0.295, p = 0.049) and night pain (r = 0.304, p = 0.043) intensities, pressure pain threshold (PPT) (r = 0.210, p = 0.047) and pain duration (r = 0.283, p = 0.007). Serum TAC level was significantly and negatively associated with resting pain intensity (r = -0.312, p = 0.037). Some scales and subscales of quality of life were positively correlated with serum TAC level and negatively associated with serum hs-CRP and PLA2 levels.
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Affiliation(s)
- Seyed Kazem Shakouri
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Dolatkhah
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Physical Medicine and Rehabilitation Research Center, Emam Reza Hospital, Golgasht, Azadi Ave, Tabriz, Iran
| | - Sepideh Omidbakhsh
- Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Pishgahi
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Hashemian
- Department of Biology, School of Art and Science, Utica College, Utica, NY USA
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Leroux A, Paiva Dos Santos B, Leng J, Oliveira H, Amédée J. Sensory neurons from dorsal root ganglia regulate endothelial cell function in extracellular matrix remodelling. Cell Commun Signal 2020; 18:162. [PMID: 33076927 PMCID: PMC7574530 DOI: 10.1186/s12964-020-00656-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 09/06/2020] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Recent physiological and experimental data highlight the role of the sensory nervous system in bone repair, but its precise role on angiogenesis in a bone regeneration context is still unknown. Our previous work demonstrated that sensory neurons (SNs) induce the osteoblastic differentiation of mesenchymal stem cells, but the influence of SNs on endothelial cells (ECs) was not studied. METHODS Here, in order to study in vitro the interplay between SNs and ECs, we used microfluidic devices as an indirect co-culture model. Gene expression analysis of angiogenic markers, as well as measurements of metalloproteinases protein levels and enzymatic activity, were performed. RESULTS We were able to demonstrate that two sensory neuropeptides, calcitonin gene-related peptide (CGRP) and substance P (SP), were involved in the transcriptional upregulation of angiogenic markers (vascular endothelial growth factor, angiopoietin 1, type 4 collagen, matrix metalloproteinase 2) in ECs. Co-cultures of ECs with SNs also increased the protein level and enzymatic activity of matrix metalloproteinases 2 and 9 (MMP2/MMP9) in ECs. CONCLUSIONS Our results suggest a role of sensory neurons, and more specifically of CGRP and SP, in the remodelling of endothelial cells extracellular matrix, thus supporting and enhancing the angiogenesis process. Video abstract.
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Affiliation(s)
- Alice Leroux
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000, Bordeaux, France.
| | | | - Jacques Leng
- Univ. Bordeaux, CNRS, Solvay, LOF, UMR 5258, F-33006, Pessac, France
| | - Hugo Oliveira
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000, Bordeaux, France
| | - Joëlle Amédée
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000, Bordeaux, France
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Rodionova K, Veelken R, Hilgers KF, Paulus EM, Linz P, Fischer MJM, Schenker M, Reeh P, Tiegs G, Ott C, Schmieder R, Schiffer M, Amann K, Ditting T. Afferent renal innervation in anti-Thy1.1 nephritis in rats. Am J Physiol Renal Physiol 2020; 319:F822-F832. [PMID: 33017188 DOI: 10.1152/ajprenal.00063.2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Afferent renal nerves exhibit a dual function controlling central sympathetic outflow via afferent electrical activity and influencing intrarenal immunological processes by releasing peptides such as calcitonin gene-related peptide (CGRP). We tested the hypothesis that increased afferent and efferent renal nerve activity occur with augmented release of CGRP in anti-Thy1.1 nephritis, in which enhanced CGRP release exacerbates inflammation. Nephritis was induced in Sprague-Dawley rats by intravenous injection of OX-7 antibody (1.75 mg/kg), and animals were investigated neurophysiologically, electrophysiologically, and pathomorphologically 6 days later. Nephritic rats exhibited proteinuria (169.3 ± 10.2 mg/24 h) with increased efferent renal nerve activity (14.7 ± 0.9 bursts/s vs. control 11.5 ± 0.9 bursts/s, n = 11, P < 0.05). However, afferent renal nerve activity (in spikes/s) decreased in nephritis (8.0 ± 1.8 Hz vs. control 27.4 ± 4.1 Hz, n = 11, P < 0.05). In patch-clamp recordings, neurons with renal afferents from nephritic rats showed a lower frequency of high activity following electrical stimulation (43.4% vs. 66.4% in controls, P < 0.05). In vitro assays showed that renal tissue from nephritic rats exhibited increased CGRP release via spontaneous (14 ± 3 pg/mL vs. 6.8 ± 2.8 pg/ml in controls, n = 7, P < 0.05) and stimulated mechanisms. In nephritic animals, marked infiltration of macrophages in the interstitium (26 ± 4 cells/mm2) and glomeruli (3.7 ± 0.6 cells/glomerular cross-section) occurred. Pretreatment with the CGRP receptor antagonist CGRP8-37 reduced proteinuria, infiltration, and proliferation. In nephritic rats, it can be speculated that afferent renal nerves lose their ability to properly control efferent sympathetic nerve activity while influencing renal inflammation through increased CGRP release.
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Affiliation(s)
- Kristina Rodionova
- Department of Internal Medicine 4 (Nephrology und Hypertension), University of Erlangen, Erlangen, Germany
| | - Roland Veelken
- Department of Internal Medicine 4 (Nephrology und Hypertension), University of Erlangen, Erlangen, Germany.,Department of Internal Medicine 4 (Nephrology und Hypertension), Paracelsus Private Medical School, Klinikum Nuremberg, Nuremberg, Germany
| | - Karl F Hilgers
- Department of Internal Medicine 4 (Nephrology und Hypertension), University of Erlangen, Erlangen, Germany
| | - Eva-Maria Paulus
- Department of Internal Medicine 4 (Nephrology und Hypertension), University of Erlangen, Erlangen, Germany
| | - Peter Linz
- Department of Radiology, University of Erlangen, Erlangen, Germany
| | - Michael J M Fischer
- Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Martina Schenker
- Department of Internal Medicine 4 (Nephrology und Hypertension), University of Erlangen, Erlangen, Germany.,Department of Physiology and Pathophysiology, University Erlangen, Erlangen, Germany
| | - Peter Reeh
- Department of Physiology and Pathophysiology, University Erlangen, Erlangen, Germany
| | - Gisa Tiegs
- Center of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Ott
- Department of Internal Medicine 4 (Nephrology und Hypertension), University of Erlangen, Erlangen, Germany.,Department of Internal Medicine 4 (Nephrology und Hypertension), Paracelsus Private Medical School, Klinikum Nuremberg, Nuremberg, Germany
| | - Roland Schmieder
- Department of Internal Medicine 4 (Nephrology und Hypertension), University of Erlangen, Erlangen, Germany
| | - Mario Schiffer
- Department of Internal Medicine 4 (Nephrology und Hypertension), University of Erlangen, Erlangen, Germany
| | - Kerstin Amann
- Department of Nephropathology, University of Erlangen, Erlangen, Germany
| | - Tilmann Ditting
- Department of Internal Medicine 4 (Nephrology und Hypertension), University of Erlangen, Erlangen, Germany.,Department of Internal Medicine 4 (Nephrology und Hypertension), Paracelsus Private Medical School, Klinikum Nuremberg, Nuremberg, Germany
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Alves CJ, Couto M, Sousa DM, Magalhães A, Neto E, Leitão L, Conceição F, Monteiro AC, Ribeiro-da-Silva M, Lamghari M. Nociceptive mechanisms driving pain in a post-traumatic osteoarthritis mouse model. Sci Rep 2020; 10:15271. [PMID: 32943744 PMCID: PMC7499425 DOI: 10.1038/s41598-020-72227-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 08/20/2020] [Indexed: 11/29/2022] Open
Abstract
In osteoarthritis (OA), pain is the dominant clinical symptom, yet the therapeutic approaches remain inadequate. The knowledge of the nociceptive mechanisms in OA, which will allow to develop effective therapies for OA pain, is of utmost need. In this study, we investigated the nociceptive mechanisms involved in post-traumatic OA pain, using the destabilization of the medial meniscus (DMM) mouse model. Our results revealed the development of peripheral pain sensitization, reflected by augmented mechanical allodynia. Along with the development of pain behaviour, we observed an increase in the expression of calcitonin gene-related peptide (CGRP) in both the sensory nerve fibers of the periosteum and the dorsal root ganglia. Interestingly, we also observed that other nociceptive mechanisms commonly described in non-traumatic OA phenotypes, such as infiltration of the synovium by immune cells, neuropathic mechanisms and also central sensitization were not present. Overall, our results suggest that CGRP in the sensory nervous system is underlying the peripheral sensitization observed after traumatic knee injury in the DMM model, highlighting the CGRP as a putative therapeutic target to treat pain in post-traumatic OA. Moreover, our findings suggest that the nociceptive mechanisms involved in driving pain in post-traumatic OA are considerably different from those in non-traumatic OA.
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Affiliation(s)
- C J Alves
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal. .,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.
| | - M Couto
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - D M Sousa
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - A Magalhães
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal
| | - E Neto
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - L Leitão
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Instituto Ciências Biomédicas Abel Salazar (ICBAS), Universidade de Porto, Porto, Portugal
| | - F Conceição
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Instituto Ciências Biomédicas Abel Salazar (ICBAS), Universidade de Porto, Porto, Portugal
| | - A C Monteiro
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - M Ribeiro-da-Silva
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Faculdade de Medicina, Universidade do Porto (FMUP), Porto, Portugal.,Serviço de Ortopedia e Traumatologia, Centro Hospitalar São João, Porto, Portugal
| | - M Lamghari
- Neuro-Skeletal Circuits Group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Instituto Ciências Biomédicas Abel Salazar (ICBAS), Universidade de Porto, Porto, Portugal
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Zhou S, Han M, Ren Y, Yang X, Duan L, Zeng Y, Li J. Dibutyl phthalate aggravated asthma-like symptoms through oxidative stress and increasing calcitonin gene-related peptide release. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 199:110740. [PMID: 32446102 DOI: 10.1016/j.ecoenv.2020.110740] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/02/2020] [Accepted: 05/05/2020] [Indexed: 06/11/2023]
Abstract
Dibutyl phthalate (DBP) is one of the most ubiquitous phthalate esters found in everyday products, and is receiving increased attention as an immunologic adjuvant. However, information regarding DBP-aggravated allergic asthma is still limited. This study used a mouse model sensitized with ovalbumin (OVA) to determine any adverse effects of DBP on allergic asthma. Our results reveal that allergic asthmatic mice exposed to DBP for an extended period had a significant increase in inflammatory cell infiltration; a significant increase in levels of serum immunoglobulin and T helper 2 cell (Th2) and T helper 17 cell (Th17) cytokines in lung tissue; and significant changes in lung histology and AHR, all of which are typical asthmatic symptoms. The levels of oxidative stress and levels of the neuropeptide, calcitonin gene related peptide (CGRP), were also elevated after DBP exposure. Interestingly, blocking oxidative stress by administering melatonin (MT) not only reduced oxidative stress and CGRP levels, but also ameliorated the asthmatic symptoms. Collectively, these results show that DBP exacerbates asthma-like pathologies by increasing the expression of CGRP mediated by oxidative stress.
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Affiliation(s)
- Sangyu Zhou
- Brain Science and Advanced Technology Institute, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430081, China
| | - Man Han
- Brain Science and Advanced Technology Institute, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430081, China
| | - Yaolin Ren
- Brain Science and Advanced Technology Institute, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430081, China
| | - Xu Yang
- Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, 430079, China
| | - Liju Duan
- School of Public Health, Huazhong University of Science and Technology, Wuhan, 430030, 430079, China
| | - Yan Zeng
- Brain Science and Advanced Technology Institute, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430081, China
| | - Jinquan Li
- Brain Science and Advanced Technology Institute, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430081, China; Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China.
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50
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Kumar AJ, Martins DO, Arruda BP, Lee VY, Chacur M, Nogueira MI. Impairment of nociceptive responses after neonatal anoxia correlates with somatosensory thalamic damage: A study in rats. Behav Brain Res 2020; 390:112690. [DOI: 10.1016/j.bbr.2020.112690] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 05/01/2020] [Accepted: 05/02/2020] [Indexed: 10/24/2022]
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