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Tyagi S, Ghovanloo MR, Alsaloum M, Effraim P, Higerd-Rusli GP, Dib-Hajj F, Zhao P, Liu S, Waxman SG, Dib-Hajj SD. Targeted ubiquitination of Na V 1.8 reduces sensory neuronal excitability. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.04.636451. [PMID: 39975312 PMCID: PMC11838569 DOI: 10.1101/2025.02.04.636451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Chronic pain and addiction are a significant global health challenge. Voltage-gated sodium channel Na V 1.8, a pivotal driver of pain signaling, is a clinically validated target for the development of novel, non-addictive pain therapeutics. Small molecule inhibitors against Na V 1.8 have shown promise in acute pain indications, but large clinical effect sizes have not yet been demonstrated and efficacy in chronic pain indications are lacking. An alternative strategy to target Na V 1.8 channels for analgesia is to reduce the number of channels that are present on nociceptor membranes. We generated a therapeutic heterobifunctional protein, named UbiquiNa V , that contains a Na V 1.8-selective binding module and the catalytic subunit of the NEDD4 E3 Ubiquitin ligase. We show that UbiquiNav significantly reduces channel expression in the plasma membrane and reduces Na V 1.8 currents in rodent sensory neurons. We demonstrate that UbiquiNa V is selective for Na V 1.8 over other Na V isoforms and other components of the sensory neuronal electrogenisome. We then show that UbiquiNa V normalizes the distribution of Na V 1.8 protein to distal axons, and that UbiquiNa V normalizes the neuronal hyperexcitability in in vitro models of inflammatory and chemotherapy-induced neuropathic pain. Our results serve as a blueprint for the design of therapeutics that leverage the selective ubiquitination of Na V 1.8 channels for analgesia.
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Alexander SN, Green AR, Debner EK, Ramos Freitas LE, Abdelhadi HMK, Szabo-Pardi TA, Burton MD. The influence of sex on neuroimmune communication, pain, and physiology. Biol Sex Differ 2024; 15:82. [PMID: 39439003 PMCID: PMC11494817 DOI: 10.1186/s13293-024-00660-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 10/02/2024] [Indexed: 10/25/2024] Open
Abstract
With the National Institutes of Health's mandate to consider sex as a biological variable (SABV), there has been a significant increase of studies utilizing both sexes. Historically, we have known that biological sex and hormones influence immunological processes and now studies focusing on interactions between the immune, endocrine, and nervous systems are revealing sex differences that influence pain behavior and various molecular and biochemical processes. Neuroendocrine-immune interactions represent a key integrative discipline that will reveal critical processes in each field as it pertains to novel mechanisms in sex differences and necessary therapeutics. Here we appraise preclinical and clinical literature to discuss these interactions and key pathways that drive cell- and sex-specific differences in immunity, pain, and physiology.
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Affiliation(s)
- Shevon N Alexander
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Audrey R Green
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Emily K Debner
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Lindsey E Ramos Freitas
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Hanna M K Abdelhadi
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Thomas A Szabo-Pardi
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Michael D Burton
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA.
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Dong Yang M, Ming Jie W, Hui Zhou L, Zhao L, Xin L, Xiu Li W, Shuang Z. Spinal microglial M1 polarization contributes paclitaxel-induced neuropathic pain by triggering cells necroptosis. J Biochem Mol Toxicol 2024; 38:e23669. [PMID: 38459698 DOI: 10.1002/jbt.23669] [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: 08/25/2023] [Revised: 01/29/2024] [Accepted: 02/23/2024] [Indexed: 03/10/2024]
Abstract
Paclitaxel (PTX) is a chemotherapeutic agent that is widely used for the treatment of several types of tumors. However, PTX-induced peripheral neuropathy (PIPN) is an adverse effect generally induced by long-term PTX use that significantly impairs the quality of life. Necroptosis has been implicated in various neurodegenerative disorders. Necroptosis of dorsal root ganglion neurons triggers the pathogenesis of PIPN. Therefore, the present study aims to investigate the role of spinal neuronal necroptosis in PIPN. It also explores the potential role of microglial polarization in necroptosis. We established rat models of PIPN via quartic PTX administration on alternate days (accumulated dose: 8 mg/kg). PTX induced obvious neuronal necroptosis and upregulated the expression of receptor-interacting protein kinase (RIP3) and mixed lineage kinase domain-like protein (MLKL) in the spinal dorsal horn. These effects were inhibited with a necroptosis pathway inhibitor, necrostatin-1 (Nec-1). The effect of microglial polarization on the regulation of spinal necroptosis was elucidated by administering minocycline to inhibit PTX-induced M1 polarization of spinal microglia caused by PTX. We observed a significant inhibitory effect of minocycline on PTX-induced necroptosis in spinal cord cells, based on the downregulation of RIP3 and MLKL expression, and suppression of tumor necrosis factor-α and IL-β synthesis. Additionally, minocycline improved hyperalgesia symptoms in PIPN rats. Overall, this study suggests that PTX-induced polarization of spinal microglia leads to RIP3/MLKL-regulated necroptosis, resulting in PIPN. These findings suggest a potential target for the prevention and treatment of neuropathic pain.
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Affiliation(s)
- Ma Dong Yang
- Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Wang Ming Jie
- Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Li Hui Zhou
- Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Li Zhao
- Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Liu Xin
- Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Wang Xiu Li
- Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhao Shuang
- Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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Tyagi S, Higerd-Rusli GP, Ghovanloo MR, Dib-Hajj F, Zhao P, Liu S, Kim DH, Shim JS, Park KS, Waxman SG, Choi JS, Dib-Hajj SD. Compartment-specific regulation of Na V1.7 in sensory neurons after acute exposure to TNF-α. Cell Rep 2024; 43:113685. [PMID: 38261513 PMCID: PMC10947185 DOI: 10.1016/j.celrep.2024.113685] [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: 08/08/2023] [Revised: 11/09/2023] [Accepted: 01/02/2024] [Indexed: 01/25/2024] Open
Abstract
Tumor necrosis factor α (TNF-α) is a major pro-inflammatory cytokine, important in many diseases, that sensitizes nociceptors through its action on a variety of ion channels, including voltage-gated sodium (NaV) channels. We show here that TNF-α acutely upregulates sensory neuron excitability and current density of threshold channel NaV1.7. Using electrophysiological recordings and live imaging, we demonstrate that this effect on NaV1.7 is mediated by p38 MAPK and identify serine 110 in the channel's N terminus as the phospho-acceptor site, which triggers NaV1.7 channel insertion into the somatic membrane. We also show that the N terminus of NaV1.7 is sufficient to mediate this effect. Although acute TNF-α treatment increases NaV1.7-carrying vesicle accumulation at axonal endings, we did not observe increased channel insertion into the axonal membrane. These results identify molecular determinants of TNF-α-mediated regulation of NaV1.7 in sensory neurons and demonstrate compartment-specific effects of TNF-α on channel insertion in the neuronal plasma membrane.
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Affiliation(s)
- Sidharth Tyagi
- Medical Scientist Training Program, Yale School of Medicine, New Haven, CT 06511, USA; Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA.
| | - Grant P Higerd-Rusli
- Medical Scientist Training Program, Yale School of Medicine, New Haven, CT 06511, USA; Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA
| | - Mohammad-Reza Ghovanloo
- Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA
| | - Fadia Dib-Hajj
- Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA
| | - Peng Zhao
- Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA
| | - Shujun Liu
- Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA
| | - Dong-Hyun Kim
- Integrated Research Institute of Pharmaceutical Science, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, South Korea; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea
| | - Ji Seon Shim
- Department of Physiology, Kyung Hee University School of Medicine, Seoul 02447, South Korea
| | - Kang-Sik Park
- Department of Physiology, Kyung Hee University School of Medicine, Seoul 02447, South Korea
| | - Stephen G Waxman
- Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA.
| | - Jin-Sung Choi
- Integrated Research Institute of Pharmaceutical Science, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, South Korea.
| | - Sulayman D Dib-Hajj
- Center for Neuroscience and Regeneration Research, West Haven, CT 06516, USA; Department of Neurology, Yale School of Medicine, New Haven, CT 06516, USA; Center for Restoration of Nervous System Function, VA Connecticut Healthcare System, West Haven, CT 06516, USA.
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Piotti P, Pierantoni L, Albertini M, Pirrone F. Inflammation and Behavior Changes in Dogs and Cats. Vet Clin North Am Small Anim Pract 2024; 54:1-16. [PMID: 37722946 DOI: 10.1016/j.cvsm.2023.08.006] [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] [Indexed: 09/20/2023]
Abstract
Sickness is a normal response to infections or stress triggered by proinflammatory cytokines that drive local and systemic inflammatory responses. Proinflammatory cytokines act on the brain causing the so called "sickness behavior,"which is thought to improve recovery but can become maladaptive in the long term. Chronic inflammation characterizes many diseases and there is some evidence that dogs and cats experience age-associated increases in inflammation, a condition named "inflammaging." A complex and multifactorial relationship exists between these inflammatory mechanisms, pain, and psychological illness that may complicate veterinary diagnosis and affect the outcome.
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Affiliation(s)
- Patrizia Piotti
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell'Università, 6, Lodi 26900, Italy
| | - Ludovica Pierantoni
- Veterinary Behaviour & Consulting Services at CAN Training Centre, Via Camaldolilli, 79, Naples 80128, Italy
| | - Mariangela Albertini
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell'Università, 6, Lodi 26900, Italy.
| | - Federica Pirrone
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell'Università, 6, Lodi 26900, Italy
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Starinets A, Ponomarenko A, Tyrtyshnaia A, Manzhulo I. Synaptamide modulates glial and neurotransmitter activity in the spinal cord during neuropathic pain. J Chem Neuroanat 2023; 134:102361. [PMID: 37935251 DOI: 10.1016/j.jchemneu.2023.102361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/03/2023] [Accepted: 11/03/2023] [Indexed: 11/09/2023]
Abstract
N-docosahexaenoylethanolamine, or synaptamide, is an endogenous metabolite of docosahexaenoic acid that is known for synaptogenic and neurogenic effects. In our previous studies we have shown that synaptamide attenuates neuropathic pain, facilitates remyelination, and reduces neuroinflammation after the chronic constriction injury (CCI) of the sciatic nerve in rats. In the current study, we show that daily synaptamide administration (4 mg/kg/day) within 14 days post-surgery: (1) decreases micro- and astroglia activity in the dorsal and ventral horns of the lumbar spinal cord; (2) modulates pro-inflammatory (IL1β, IL6) and anti-inflammatory (IL4, IL10) cytokine level in the serum and spinal cord; (3) leads to a rise in synaptamide and anandamide concentration in the spinal cord; (4) enhances IL10, CD206 and N-acylethanolamine-hydrolyzing acid amidase synthesis in macrophage cell culture following LPS-induced inflammation. Thus, the ability of synaptamide to modulate glial and cytokine activity indicates its potential for implementation in the treatment peripheral nerve injury.
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Affiliation(s)
- Anna Starinets
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Vladivostok 690041, Russia
| | - Arina Ponomarenko
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Vladivostok 690041, Russia
| | - Anna Tyrtyshnaia
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Vladivostok 690041, Russia
| | - Igor Manzhulo
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Vladivostok 690041, Russia.
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Gauthier MM, Hayoz S, Banek CT. Neuroimmune interplay in kidney health and disease: Role of renal nerves. Auton Neurosci 2023; 250:103133. [PMID: 38061177 PMCID: PMC10748436 DOI: 10.1016/j.autneu.2023.103133] [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: 10/02/2023] [Revised: 11/15/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023]
Abstract
Renal nerves and their role in physiology and disease have been a topic of increasing interest in the past few decades. Renal inflammation contributes to many cardiorenal disease conditions, including hypertension, chronic kidney disease, and polycystic kidney disease. Much is known about the role of renal sympathetic nerves in physiology - they contribute to the regulation of sodium reabsorption, renin release, and renal vascular resistance. In contrast, far less is known about afferent, or "sensory," renal nerves, which convey signals from the kidney to the brain. While much remains unknown about these nerves in the context of normal physiology, even less is known about their contribution to disease states. Furthermore, it has become apparent that the crosstalk between renal nerves and the immune system may augment or modulate disease. Research from other fields, especially pain research, has provided critical insight into neuroimmune crosstalk. Sympathetic renal nerve activity may increase immune cell recruitment, but far less work has been done investigating the interplay between afferent renal nerves and the immune system. Evidence from other fields suggests that inflammation may augment afferent renal nerve activity. Furthermore, these nerves may exacerbate renal inflammation through the release of afferent-specific neurotransmitters.
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Affiliation(s)
- Madeline M Gauthier
- Department of Physiology, University of Arizona Health Sciences Center, Tucson, AZ, USA
| | - Sebastien Hayoz
- Department of Physiology, University of Arizona Health Sciences Center, Tucson, AZ, USA
| | - Christopher T Banek
- Department of Physiology, University of Arizona Health Sciences Center, Tucson, AZ, USA.
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8
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Sanchez JE, Noor S, Sun MS, Zimmerly J, Pasmay A, Sanchez JJ, Vanderwall AG, Haynes MK, Sklar LA, Escalona PR, Milligan ED. The FDA-approved compound, pramipexole and the clinical-stage investigational drug, dexpramipexole, reverse chronic allodynia from sciatic nerve damage in mice, and alter IL-1β and IL-10 expression from immune cell culture. Neurosci Lett 2023; 814:137419. [PMID: 37558176 PMCID: PMC10552878 DOI: 10.1016/j.neulet.2023.137419] [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: 04/23/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/11/2023]
Abstract
During the onset of neuropathic pain from a variety of etiologies, nociceptors become hypersensitized, releasing neurotransmitters and other factors from centrally-projecting nerve terminals within the dorsal spinal cord. Consequently, glial cells (astrocytes and microglia) in the spinal cord are activated and mediate the release of proinflammatory cytokines that act to enhance pain transmission and sensitize mechanical non-nociceptive fibers which ultimately results in light touch hypersensitivity, clinically observed as allodynia. Pramipexole, a D2/D3 preferring agonist, is FDA-approved for the treatment of Parkinson's disease and demonstrates efficacy in animal models of inflammatory pain. The clinical-stage investigational drug, R(+) enantiomer of pramipexole, dexpramipexole, is virtually devoid of D2/D3 agonist actions and is efficacious in animal models of inflammatory and neuropathic pain. The current experiments focus on the application of a mouse model of sciatic nerve neuropathy, chronic constriction injury (CCI), that leads to allodynia and is previously characterized to generate spinal glial activation with consequent release IL-1β. We hypothesized that both pramipexole and dexpramipexole reverse CCI-induced chronic neuropathy in mice, and in human monocyte cell culture studies (THP-1 cells), pramipexole prevents IL-1β production. Additionally, we hypothesized that in rat primary splenocyte culture, dexpramixole increases mRNA for the anti-inflammatory and pleiotropic cytokine, interleukin-10 (IL-10). Results show that following intravenous pramipexole or dexpramipexole, a profound decrease in allodynia was observed by 1 hr, with allodynia returning 24 hr post-injection. Pramipexole significantly blunted IL-1β protein production from stimulated human monocytes and dexpramipexole induced elevated IL-10 mRNA expression from rat splenocytes. The data support that clinically-approved compounds like pramipexole and dexpramipexole support their application as anti-inflammatory agents to mitigate chronic neuropathy, and provide a blueprint for future, multifaceted approaches for opioid-independent neuropathic pain treatment.
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Affiliation(s)
- J E Sanchez
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - S Noor
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - M S Sun
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - J Zimmerly
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - A Pasmay
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - J J Sanchez
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - A G Vanderwall
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - M K Haynes
- Center for Molecular Discovery (CMD) Innovation, Discovery and Training Complex (IDTC), University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - L A Sklar
- Center for Molecular Discovery (CMD) Innovation, Discovery and Training Complex (IDTC), University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - P R Escalona
- Department of Psychiatry, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; New Mexico VA Health Care System, Albuquerque NM 87108, USA
| | - E D Milligan
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
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Proinflammatory cytokines and their receptors as druggable targets to alleviate pathological pain. Pain 2022; 163:S79-S98. [DOI: 10.1097/j.pain.0000000000002737] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/14/2022] [Indexed: 02/07/2023]
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10
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Valdez-Morales EE, Sánchez-Navarro CA, Reyes-Pavón D, Barrios-Garcia T, Ochoa-Cortes F, Barajas-Espinosa A, Barragán-Iglesias P, Guerrero-Alba R. TNF-α enhances sensory DRG neuron excitability through modulation of P2X3 receptors in an acute colitis model. Front Immunol 2022; 13:872760. [PMID: 36032155 PMCID: PMC9416886 DOI: 10.3389/fimmu.2022.872760] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 07/18/2022] [Indexed: 11/15/2022] Open
Abstract
Previous studies have demonstrated that acute colonic inflammation leads to an increase in dorsal root ganglia (DRG) neuronal excitability. However, the signaling elements implicated in this hyperexcitability have yet to be fully unraveled. Extracellular adenosine 5’-triphosphate (ATP) is a well-recognized sensory signaling molecule that enhances the nociceptive response after inflammation through activation of P2X3 receptors, which are expressed mainly by peripheral sensory neurons. The aim of this study is to continue investigating how P2X3 affects neuronal hypersensitivity in an acute colitis animal model. To achieve this, DNBS (Dinitrobenzene sulfonic acid; 200 mg/kg) was intrarectally administered to C57BL/6 mice, and inflammation severity was assessed according to the following parameters: weight loss, macroscopic and microscopic scores. Perforated patch clamp technique was used to evaluate neuronal excitability via measuring changes in rheobase and action potential firing in T8-L1 DRG neurons. A-317491, a well-established potent and selective P2X3 receptor antagonist, served to dissect their contribution to recorded responses. Protein expression of P2X3 receptors in DRG was evaluated by western blotting and immunofluorescence. Four days post-DNBS administration, colons were processed for histological analyses of ulceration, crypt morphology, goblet cell density, and immune cell infiltration. DRG neurons from DNBS-treated mice were significantly more excitable compared with controls; these changes correlated with increased P2X3 receptor expression. Furthermore, TNF-α mRNA expression was also significantly higher in inflamed colons compared to controls. Incubation of control DRG neurons with TNF-α resulted in similar cell hyperexcitability as measured in DNBS-derived neurons. The selective P2X3 receptor antagonist, A-317491, blocked the TNF-α-induced effect. These results support the hypothesis that TNF-α enhances colon-innervating DRG neuron excitability via modulation of P2X3 receptor activity.
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Affiliation(s)
| | - Carlos A. Sánchez-Navarro
- Departamento de Medicina, Centro de Ciencias de la Salud , Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Diana Reyes-Pavón
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Tonatiuh Barrios-Garcia
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Fernando Ochoa-Cortes
- Licenciatura en Enfermería, Escuela Superior de Huejutla, Universidad Autónoma del Estado de Hidalgo, Hidalgo, Mexico
| | - Alma Barajas-Espinosa
- Licenciatura en Enfermería, Escuela Superior de Huejutla, Universidad Autónoma del Estado de Hidalgo, Hidalgo, Mexico
| | - Paulino Barragán-Iglesias
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Raquel Guerrero-Alba
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
- *Correspondence: Raquel Guerrero-Alba,
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Ye F, Lyu F, Wang H, Zheng Z. The involvement of immune system in intervertebral disc herniation and degeneration. JOR Spine 2022; 5:e1196. [PMID: 35386754 PMCID: PMC8966871 DOI: 10.1002/jsp2.1196] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 02/06/2022] [Accepted: 02/25/2022] [Indexed: 02/06/2023] Open
Abstract
Intervertebral disc (IVD) herniation and degeneration contributes significantly to low back pain (LBP), of which the molecular pathogenesis is not fully understood. Disc herniation may cause LBP and radicular pain, but not all LBP patients have disc herniation. Degenerated discs could be the source of pain, but not all degenerated discs are symptomatic. We previously found that disc degeneration and herniation accompanied by inflammation. We further found that anti-inflammatory molecules blocked immune responses, alleviated IVD degeneration and pain. Based on our recent findings and the work of others, we hypothesize that immune system may play a prominent role in the production of disc herniation or disc degeneration associated pain. While the nucleus pulposus (NP) is an immune-privileged organ, the damage of the physical barrier between NP and systemic circulation, or the innervation and vascularization of the degenerated NP, on one hand exposes NP as a foreign antigen to immune system, and on the other hand presents compression on the nerve root or dorsal root ganglion (DRG), which both elicit immune responses induced by immune cells and their mediators. The inflammation can remain for a long time at remote distance, with various types of cytokines and immune cells involved in this pain-inducing process. In this review, we aim to revisit the autoimmunity of the NP, immune cell infiltration after break of physical barrier, the inflammatory activities in the DRG and the generation of pain. We also summarize the involvement of immune system, including immune cells and cytokines, in degenerated or herniated IVDs and affected DRG.
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Affiliation(s)
- Fubiao Ye
- Department of Spine Surgery, The First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
- Department of Orthopaedics, Fujian Provincial HospitalProvincial Clinical Medical College of Fujian Medical UniversityFuzhouFujianChina
| | - Feng‐Juan Lyu
- Joint Center for Regenerative Medicine Research of South China University of Technology and The University of Western Australia, School of MedicineSouth China University of TechnologyGuangzhouChina
| | - Hua Wang
- Department of Spine Surgery, The First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Zhaomin Zheng
- Department of Spine Surgery, The First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
- Pain Research CenterSun Yat‐sen UniversityGuangzhouChina
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The Contribution of TSLP Activation to Hyperalgesia in Dorsal Root Ganglia Neurons of a Rat. Int J Mol Sci 2022; 23:ijms23042012. [PMID: 35216130 PMCID: PMC8875239 DOI: 10.3390/ijms23042012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 01/31/2022] [Accepted: 02/08/2022] [Indexed: 12/30/2022] Open
Abstract
Peripheral nerve injury involves divergent alterations within dorsal root ganglia (DRG) neurons sensitized by persistent inflammation. Thymic stromal lymphopoietin (TSLP) production is crucial in the development of chronic inflammatory responses. Herein, we investigate the changes of TSLP expression in rats’ DRG neurons between injured and uninjured sides in the same rat. Linalyl acetate (LA) was served as a TSLP inhibitor and given intraperitoneally. Rats were assigned to be group of chronic constriction injury (CCI) of the sciatic nerve and the group of CCI of the sciatic nerve administrated with LA. Over 14 days, the rats were measured for paw withdrawal thresholds. DRGs were collected to assess morphological changes via immunofluorescence study. After receiving CCI, the rats rapidly developed mechanical hyperalgesia. TSLP expression at DRG, on the ipsilateral injured side, was consistent with changes in pain behaviors. TSLP appeared in nerve fibers with both small diameters and large diameters. Additionally, TSLP was expressed mostly in transient receptor potential vanilloid-1 (TRPV1)-positive nociceptive neurons. Administration with LA can attenuate the pain behaviors and expression of TSLP in DRG neurons, and in apoptotic neurons at the injured side, but not in the contra-lateral uninjured side. Overall, these results imply that altered expressions of TSLP in nociceptive DRG neurons contributed to mechanical hyperalgesia in a CCI rat model.
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Maecker HT, Siebert JC, Rosenberg-Hasson Y, Koran LM, Ramalho M, Semelka RC. Dynamic Serial Cytokine Measurements During Intravenous Ca-DTPA Chelation in Gadolinium Deposition Disease and Gadolinium Storage Condition: A Pilot Study. Invest Radiol 2022; 57:71-76. [PMID: 34120127 PMCID: PMC8664920 DOI: 10.1097/rli.0000000000000803] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PURPOSE The aim of this study was to investigate the feasibility of measuring early changes in serum cytokine levels after intravenous diethylenetriaminepentaacetic acid (Ca-DTPA) chelation in patients manifesting either gadolinium deposition disease (GDD) or gadolinium storage condition (GSC) and the possible usefulness of this method in further research. METHODS Four patients with recent-onset GDD (≤1 year) and 2 patients with long-standing GSC (4 and 9 years) underwent chelation with intravenous bolus administration of Ca-DTPA. Multiple blood draws were performed to measure serum cytokines: at T = 0 (before Ca-DTPA injection) and 1, 5, 10, 30, 60 minutes, and 24 hours after Ca-DTPA injection. Patients rated the severity of GDD symptom flare at 24 hours. The 24-hour urine Gd amounts were measured prechelation and for the 24 hours after chelation. Serum samples were analyzed blind to whether patients had GDD or GSC but with knowledge of the time points characterizing each sample. RESULTS Urine samples for both GDD and GSC patients showed increases in Gd postchelation. All GDD patients experienced flare reactions postchelation; the 2 GSC patients did not. Two cytokines, EGF and sCD40L, peaked at 30 minutes postchelation in at least 4 of the 6 participants. Three cytokines, ENA78/CXCL5, EOTAXIN/CCL11, and LEPTIN, peaked at 24 hours in at least 4 of the 6 participants. Two participants were high outliers for a large number of cytokines across time points. No clear distinction between GDD and GSC was apparent from the cytokine patterns, although differences were present. CONCLUSIONS This pilot study describes precise temporal resolution (in the range of minutes) after a cytokine-inciting event. Select cytokines exhibited peak values at different time points. At this preliminary stage of investigation, peak cytokine release seems to reflect the amount of Gd mobilized rather than the severity of the patient symptomatic reaction. Too few subjects were studied to support statistical analysis between GDD and GSC groups, although differences were observed through visual data analysis.
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Affiliation(s)
- Holden T Maecker
- From the Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA
| | | | - Yael Rosenberg-Hasson
- From the Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA
| | - Lorrin M Koran
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA
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Wistrom E, Chase R, Smith PR, Campbell ZT. A compendium of validated pain genes. WIREs Mech Dis 2022; 14:e1570. [PMID: 35760453 PMCID: PMC9787016 DOI: 10.1002/wsbm.1570] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/28/2022] [Accepted: 06/06/2022] [Indexed: 12/30/2022]
Abstract
The development of novel pain therapeutics hinges on the identification and rigorous validation of potential targets. Model organisms provide a means to test the involvement of specific genes and regulatory elements in pain. Here we provide a list of genes linked to pain-associated behaviors. We capitalize on results spanning over three decades to identify a set of 242 genes. They support a remarkable diversity of functions spanning action potential propagation, immune response, GPCR signaling, enzymatic catalysis, nucleic acid regulation, and intercellular signaling. Making use of existing tissue and single-cell high-throughput RNA sequencing datasets, we examine their patterns of expression. For each gene class, we discuss archetypal members, with an emphasis on opportunities for additional experimentation. Finally, we discuss how powerful and increasingly ubiquitous forward genetic screening approaches could be used to improve our ability to identify pain genes. This article is categorized under: Neurological Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
- Eric Wistrom
- Department of Biological SciencesUniversity of Texas at DallasRichardsonTexasUSA
| | - Rebecca Chase
- Department of Biological SciencesUniversity of Texas at DallasRichardsonTexasUSA
| | - Patrick R. Smith
- Department of Biological SciencesUniversity of Texas at DallasRichardsonTexasUSA
| | - Zachary T. Campbell
- Department of Biological SciencesUniversity of Texas at DallasRichardsonTexasUSA,Center for Advanced Pain StudiesUniversity of Texas at DallasRichardsonTexasUSA
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Liu Y, Zhang J, Liu X, Zhou W, Stalin A, Fu C, Wu J, Cheng G, Guo S, Jia S, Li B, Wang H, Li J, Lu S. Investigation on the mechanisms of guiqi huoxue capsule for treating cervical spondylosis based on network pharmacology and molecular docking. Medicine (Baltimore) 2021; 100:e26643. [PMID: 34664825 PMCID: PMC8447999 DOI: 10.1097/md.0000000000026643] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 06/24/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Guiqi huoxue capsule (GQHXC) is a patented Chinese medicine used for treating a liver and kidney deficiency and blood stasis syndrome due to qi deficiency. It is caused by cervical spondylosis (cervical spondylotic radiculopathy (CSR), mixed cervical spondylosis mainly composed of nerve root type). Its underlying mechanisms need, however, to be further clarified. METHODS In this study, collecting compounds, predicting therapeutic targets, constructing networks, and analyzing biological functions and pathways were based on network pharmacology analysis. In addition, molecular docking verification was engaged to assess the binding potential of selected target-compound pairs. RESULTS We established 5 networks: compound-putative target network of GQHXC, protein-protein interaction (PPI) network related to CSR, compound-CSR target network, potential therapeutic targets PPI network, and herb-compound-target-pathway network. Network analysis indicated that 7 targets (tumor necrosis factor [TNF], interleukin 6 [IL6], nitric oxide synthase 3 [NOS3], Interleukin-8 [CXCL8], prostaglandin-endoperoxide synthase 2 [PTGS2], vascular endothelial growth factor A [VEGFA], and AP-1 transcription factor subunit [JUN]) might be the therapeutic targets of GQHXC in CSR. Moreover, molecular docking verification showed that TNF, IL6, NOS3, CXCL8, PTGS2, VEGFA, and JUN had a good is interaction with the corresponding compounds. Furthermore, enrichment analysis indicated that GQHXC might exert a curative role in CSR by regulating some important pathways, such as TNF signaling pathway, NF-kappa B signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and so on. CONCLUSION Our study preliminarily explained the underlying mechanisms of GQHXC for treating CSR, and molecular docking verification was adopted as an additional verification. These findings laid a valuable foundation for experimental research and further application of GQHXC in the clinical treatment of CSR.
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Affiliation(s)
- Yingying Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Wei Zhou
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Antony Stalin
- State Key Laboratory of Subtropical Silviculture, Department of Traditional Chinese Medicine, Zhejiang A&F University, Hangzhou, China
| | - Changgeng Fu
- Xiyuan Hospital of China Academy of Chinese Medical Sciences, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Guoliang Cheng
- State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Linyi, China
| | - Siyu Guo
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shanshan Jia
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Bingbing Li
- Xiyuan Hospital of China Academy of Chinese Medical Sciences, China
| | - Haojia Wang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jialin Li
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shan Lu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Boakye PA, Tang SJ, Smith PA. Mediators of Neuropathic Pain; Focus on Spinal Microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt Ligands, and Interleukin 1β. FRONTIERS IN PAIN RESEARCH 2021; 2:698157. [PMID: 35295524 PMCID: PMC8915739 DOI: 10.3389/fpain.2021.698157] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/14/2021] [Indexed: 01/04/2023] Open
Abstract
Intractable neuropathic pain is a frequent consequence of nerve injury or disease. When peripheral nerves are injured, damaged axons undergo Wallerian degeneration. Schwann cells, mast cells, fibroblasts, keratinocytes and epithelial cells are activated leading to the generation of an "inflammatory soup" containing cytokines, chemokines and growth factors. These primary mediators sensitize sensory nerve endings, attract macrophages, neutrophils and lymphocytes, alter gene expression, promote post-translational modification of proteins, and alter ion channel function in primary afferent neurons. This leads to increased excitability and spontaneous activity and the generation of secondary mediators including colony stimulating factor 1 (CSF-1), chemokine C-C motif ligand 21 (CCL-21), Wnt3a, and Wnt5a. Release of these mediators from primary afferent neurons alters the properties of spinal microglial cells causing them to release tertiary mediators, in many situations via ATP-dependent mechanisms. Tertiary mediators such as BDNF, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and other Wnt ligands facilitate the generation and transmission of nociceptive information by increasing excitatory glutamatergic transmission and attenuating inhibitory GABA and glycinergic transmission in the spinal dorsal horn. This review focusses on activation of microglia by secondary mediators, release of tertiary mediators from microglia and a description of their actions in the spinal dorsal horn. Attention is drawn to the substantial differences in the precise roles of various mediators in males compared to females. At least 25 different mediators have been identified but the similarity of their actions at sensory nerve endings, in the dorsal root ganglia and in the spinal cord means there is considerable redundancy in the available mechanisms. Despite this, behavioral studies show that interruption of the actions of any single mediator can relieve signs of pain in experimental animals. We draw attention this paradox. It is difficult to explain how inactivation of one mediator can relieve pain when so many parallel pathways are available.
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Affiliation(s)
- Paul A. Boakye
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, United States
| | - Shao-Jun Tang
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, United States
| | - Peter A. Smith
- Neuroscience and Mental Health Institute and Department of Pharmacology, University of Alberta, Edmonton, AB, Canada
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Chandan G, Kumar C, Chibber P, Kumar A, Singh G, Satti NK, Gulilat H, Saini AK, Bishayee A, Saini RV. Evaluation of analgesic and anti-inflammatory activities and molecular docking analysis of steroidal lactones from Datura stramonium L. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 89:153621. [PMID: 34252723 DOI: 10.1016/j.phymed.2021.153621] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 05/13/2021] [Accepted: 05/30/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Datura stramonium L. is widely used across the world for its therapeutic potential to treat inflammatory disorders. The current work was designed to isolate and identify steroidal lactones from D. stramonium leaves and evaluate their anti-inflammatory and analgesic properties. METHODS Several compounds were isolated from D. stramonium leaves and characterized by nuclear magnetic resonance and high-resonance electron spray ionization mass spectrometry techniques. Further, anti-inflammatory properties of these compounds were evaluated by in vitro assays, such as release of NO and pro-inflammatory cytokines by lipopolysaccharide (LPS)-activated J774A.1 macrophages. Using in vivo models, anti-inflammatory and analgesic effects were examined by mouse tail-flick, carrageenan-induced inflammation in rat paw model, vascular permeability in rats, and acetic acid-induced writhing in mice. The docking studies were performed for assessing the binding efficiency of the test compounds with cyclooxygenase-1 (COX-1) and COX-2, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), inducible nitric oxide synthases (iNOS) and nuclear factor-κB (NF-κB). RESULTS Three lactones were isolated and confirmed as daturalactone (D1), 12-deoxywithastramonolide (D23), and daturilin (D27). Further, the isolated compounds showed nitric oxide inhibition and pro-inflammatory cytokines released by LPS-activated J774A.1 macrophages. The in vivo results suggest that D1, D23 and D27 (20 mg/kg) were able to reduce the pain and inflammation in various animal models. The docking analysis showed that these three compounds actively bind with COX-1, COX-2, LOX-1, NF-κB, and iNOS, validating the anti-inflammatory effects of the lactones. CONCLUSION These findings demonstrate substantial anti-inflammatory and analgesic properties of D. stramonium-derived lactones and their potential as anti-inflammatory agents to treat chronic inflammatory ailments.
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Affiliation(s)
- Gourav Chandan
- School of Biotechnology, Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan 173 229, Himachal Pradesh, India; Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133 203, Haryana, India
| | - Chetan Kumar
- Division of Natural Products Chemistry, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu 180 001, Jammu and Kashmir, India
| | - Pankaj Chibber
- Pharmacokinetics-Pharmacodynamics, Toxicology and Formulation Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu 180 001, Jammu and Kashmir, India
| | - Ashwani Kumar
- Department of Bioinformatics, Jaypee University of Information Technology, Waknaghat 173234, Himachal Pradesh, India
| | - Gurdarshan Singh
- Lake Erie College of Osteopathic Medicine, Bradenton 34211, FL, USA
| | - Naresh K Satti
- Division of Natural Products Chemistry, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu 180 001, Jammu and Kashmir, India
| | - Henok Gulilat
- School of Biotechnology, Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan 173 229, Himachal Pradesh, India
| | - Adesh K Saini
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133 203, Haryana, India
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton 34211, FL, USA.
| | - Reena V Saini
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133 203, Haryana, India.
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Increased Expression of Thymic Stromal Lymphopoietin in Chronic Constriction Injury of Rat Nerve. Int J Mol Sci 2021; 22:ijms22137105. [PMID: 34281158 PMCID: PMC8268825 DOI: 10.3390/ijms22137105] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/27/2021] [Accepted: 06/28/2021] [Indexed: 12/11/2022] Open
Abstract
Thymic stromal lymphopoietin (TSLP) is a well-known cytokine for T helper 2 inflammatory responses. A nerve injury activates the neuroinflammation cascade and neuron-glia interaction in dorsal root ganglions (DRG)s, leading to neuropathic pain. Therefore, this study was to investigate the role of TSLP after nerve injury. Male Sprague-Dawley rats were divided as an experimental group with chronic constriction injury (CCI) to the sciatic nerve and a control group. The mechanical pain threshold response was determined by calibration forceps. After assessment of mechanical allodynia, the ipsilateral spinal cord, DRG, sciatic nerve and skin were harvested. Immunofluorescence staining was performed to identify cell types with various markers. Western blot analyses were performed to evaluate protein expressions. Mechanical allodynia developed after CCI and persisted for the next 14 days. Astrocyte reactions occurred and continued until day 14, too. After CCI, DRG and the sciatic nerve also had significantly increased expressions of TSLP/TSLP-R/STAT5. The TSLPR was localized to sensory neuronal endings innervating the skin. This study is the first to demonstrate that the TSLP complex and the STAT5 pathway in nerve are potential therapeutic targets because of their roles in pain regulation after nerve injury.
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Do Markers of Inflammation and/or Muscle Regeneration in Lumbar Multifidus Muscle and Fat Differ Between Individuals with Good or Poor Outcome Following Microdiscectomy for Lumbar Disc Herniation? Spine (Phila Pa 1976) 2021; 46:678-686. [PMID: 33290379 DOI: 10.1097/brs.0000000000003863] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Observational study. OBJECTIVE The aim of this study was to evaluate whether inflammatory and/or muscle regeneration markers in paraspinal tissues (multifidus muscle/fat) during microdiscectomy surgery in patients with lumbar disc herniation (LDH) with radiculopathy, differ between individuals with good or poor outcome. SUMMARY OF BACKGROUND DATA Structural back muscle changes, including fat infiltration, muscle atrophy, and fiber changes, are ubiquitous with LBP and are thought to be regulated by inflammatory and regeneration processes. Muscle changes might be relevant for recovery after microdiscectomy, but a link between expression of inflammatory and muscle regeneration genes in paraspinal tissues and clinical outcome has not been tested. METHOD Paraspinal tissues from deep multifidus muscles and fat (intramuscular, sub-cutaneous, epidural) were harvested from twenty-one patients with LDH undergoing microdiscectomy surgery. Quantitative polymerase chain reaction (qPCR) measured expression of 10 genes. Outcome was defined as good (visual analogue scale (VAS) low back pain (LBP)+) or poor (VAS LBP-) by an improvement of >33% or ≤33% on the pain VAS, respectively. Good functional improvement was defined as 25% improvement on the physical functioning scale (PFS). RESULTS Brain-derived neurotrophic factor expression in deep multifidus was 91% lower (P = 0.014) in the VAS LBP- than VAS LBP+ group. Expression of interleukin-1β in subcutaneous fat was 48% higher (P = 0.026) in the VAS LBP- than VAS LBP+ group. No markers differed based on PFS. CONCLUSION Results show a relationship between impaired muscle regeneration profile in multifidus muscle and poor outcome following microdiscectomy for LDH. Inflammatory dysregulation in subcutaneous fat overlying the back region might predict poor surgical outcome.Level of Evidence: 4.
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Behavioral Symptom Clusters, Inflammation, and Quality of Life in Chronic Low Back Pain. Pain Manag Nurs 2021; 22:361-368. [PMID: 33478899 DOI: 10.1016/j.pmn.2020.11.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/22/2020] [Accepted: 11/29/2020] [Indexed: 11/23/2022]
Abstract
BACKGROUND Chronic low back pain is a prevalent condition, often involving an inflammatory process. Behavioral symptoms, including depressed mood, fatigue, and sleep disturbance, intensifies pain and reduces quality of life. AIMS The objectives of this pilot study were to identify behavioral symptom clusters (depressive mood, fatigue, poor sleep) in individuals with chronic low back pain, and to determine whether there are differences in pain, quality of life and inflammation (plasma IL-6) based on cluster membership. DESIGN AND SETTINGS A cross-sectional study was conducted in a pain clinic. PARTICIPANTS/ SUBJECTS Participants between ages 21 to 70 years (N=69) were enrolled if they had chronic low back pain for at least six months. METHODS Participants completed instruments measuring, pain, depressive mood, fatigue, sleep, and demographic form. Blood (10ml) was obtained. Latent class analysis was used to identify clusters. RESULTS AND CONCLUSIONS Findings revealed a two-class model, with Class 1 characterized by more depressive mood, fatigue, and sleep disturbance compared to Class 2. Class 1 participants reported worse quality of life than those in Class 2. Pain severity and pain interference were not significantly different between the classes. Levels of IL-6 were significantly greater in Class 1 participants compared to Class 2 with higher levels of IL-6 correlating with greater pain severity and sleep disturbances. Logistic regression revealed higher levels of IL-6 predicted Class 1 membership. Behavioral symptoms cluster exist in chronic low back pain patients and impact quality of life. Inflammation may contribute to relationship between behavioral symptoms and pain severity.
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21
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Singh L, Kaur A, Garg S, Bhatti R. Skimmetin/osthole mitigates pain-depression dyad via inhibiting inflammatory and oxidative stress-mediated neurotransmitter dysregulation. Metab Brain Dis 2021; 36:111-121. [PMID: 32870425 DOI: 10.1007/s11011-020-00604-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 07/20/2020] [Indexed: 12/14/2022]
Abstract
Pain and depression are often co-existing pathological states that promote mutual severity resulting in limited efficacy of current treatment strategies. Thus, there is a need to develop an efficacious alternate treatment regimen for pain-depression dyad. Skimmetin and osthole are molecules of natural origin that have been explored for an anti-hyperglycemic, anti-bacterial, anti-fungal, and anti-diabetic activities in preclinical studies. in animal models. The current study has been designed to explore the beneficial effect of skimmetin/osthole in reserpine-induced pain-depression dyad in mice. Female Swiss albino mice (n = 6) were challenged with reserpine (0.5 mg/kg s.c.) for the first 3 days to induce a pain-depression dyad-like state. Skimmetin (10 mg/kg i.p.) and osthole (10 mg/kg i.p.) were administered for 5 days consecutively, starting from the first day of study. Reserpine treatment significantly reduced the pain threshold in the pressure application measurement (PAM) and electronic von frey (eVF) test. In forced swim test (FST) and Morris water maze (MWM) test mice displayed an increased immobility time and latency to reach platform respectively. Biochemical results showed an increased level of TNF-α, IL-1β, TBARS, glutamate, and reduced level of GSH, norepinephrine, and serotonin in the reserpine treated group. Reserpine treatment also increased brain MAO-A activity. Skimmetin/osthole treatment was found to attenuate the behavioral and biochemical alterations induced by reserpine. The results of the current investigation delineated that skimmetin/osthole may exert anti-nociceptive, anti-depressant, and improved cognition via inhibiting inflammatory and oxidative stress-mediated neurotransmitter dysregulation.
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Affiliation(s)
- Lovedeep Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
| | - Anudeep Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
| | - Saweta Garg
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
| | - Rajbir Bhatti
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India.
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Zhang S, Hu B, Liu W, Wang P, Lv X, Chen S, Shao Z. The role of structure and function changes of sensory nervous system in intervertebral disc-related low back pain. Osteoarthritis Cartilage 2021; 29:17-27. [PMID: 33007412 DOI: 10.1016/j.joca.2020.09.002] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/18/2020] [Accepted: 09/21/2020] [Indexed: 02/06/2023]
Abstract
Low back pain (LBP) is a common musculoskeletal symptom, which can be developed in multiple clinical diseases. It is widely recognized that intervertebral disc (IVD) degeneration (IVDD) is one of the leading causes of LBP. However, the pathogenesis of IVD-related LBP is still controversial, and the treatment means are also insufficient to date. In recent decades, the role of structure and function changes of sensory nervous system in the induction and the maintenance of LBP is drawing more and more attention. With the progress of IVDD, IVD cell exhaustion and extracellular matrix degradation result in IVD structural damage, while neovascularization, innervation and inflammatory activation further deteriorate the microenvironment of IVD. New nerve ingrowth into degenerated IVD amplifies the impacts of IVD-derived nociceptive molecules on sensory endings. Moreover, IVDD is usually accompanied with disc herniation, which could injure and inflame affected nerves. Under mechanical and pro-inflammatory stimulation, the pain-transmitting pathway exhibits a sensitized function state and ultimately leads to LBP. Hence, relevant pathogenic factors, such as neurotrophins, ion channels, inflammatory factors, etc., are supposed to serve as promising therapeutic targets for LBP. The purpose of this review is to comprehensively summarize the current evidence on 1) the pathological changes of sensory nervous system during IVDD and their association with LBP, and 2) potential therapeutic strategies for LBP targeting relevant pathogenic factors.
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Affiliation(s)
- S Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - B Hu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - W Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - P Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - X Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - S Chen
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Z Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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23
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Djouhri L, Zeidan A, Alzoghaibi M, Al Otaibi MF, Abd El-Aleem SA. L5 Spinal Nerve Axotomy Induces Distinct Electrophysiological Changes in Axotomized L5- and Adjacent L4-Dorsal Root Ganglion Neurons in Rats In Vivo. J Neurotrauma 2020; 38:330-341. [PMID: 32993425 DOI: 10.1089/neu.2020.7264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Peripheral neuropathic pain (PNP) is a major health problem for which effective drug treatment is lacking. Its underlying neuronal mechanisms are still illusive, but pre-clinical studies using animal models of PNP including the L5-spinal nerve axotomy (L5-SNA) model, suggest that it is partly caused by excitability changes in dorsal root ganglion (DRG) neurons. L5-SNA results in two DRG neuronal groups: (1) axotomized/damaged neurons in L5- plus some in L4-DRGs, and (2) ipsilateral L4-neurons with intact/uninjured fibers intermingling with degenerating L5-fibers. The axotomized neurons are deprived of peripherally derived trophic factors and degenerate causing neuroinflammation, whereas the uninjured L4-neuorns are subject to increased trophic factors and neuroinflammation associated with Wallerian degeneration of axotomized L5-nerve fibers. Whether these two groups of DRG neurons exhibit similar or distinct electrophysiological changes after L5-SNA remains unresolved. Conflicting evidence for this may result from some studies assuming that all L4-fibers are undamaged. Here, we recorded somatic action potentials (APs) intracellularly from C- and A-fiber L4/L5 DRG neurons in vivo, to examine our hypothesis that L5-SNA would induce distinct electrophysiological changes in the two populations of DRG neurons. Consistent with this hypothesis, we found (7 days post-SNA), in SNA rats with established pain hypersensitivity, slower AP kinetics in axotomized L5-neurons and faster AP kinetics in L4-nociceptive neurons including decreased rise time in Aδ-and Aβ-fiber nociceptors, and after-hyperpolarization duration in Aβ-fiber nociceptors. We also found several changes in axotomized L5-neurons but not in L4-nociceptive neurons, and some changes in L4-nociceptive but not L5-neurons. The faster AP kinetics (decreased refractory period) in L4-nociceptive neurons that are consistent with their reported hyperexcitability may lead to repetitive firing and thus provide enhanced afferent input necessary for initiating and/or maintaining PNP development. The changes in axotomized L5-neurons may contribute to the central mechanisms of PNP via enhanced neurotransmitter release in the central nervous system (CNS).
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Affiliation(s)
- Laiche Djouhri
- Department of Basic Medical Sciences, College of Medicine (QU Health), Qatar University, Doha, Qatar
| | - Asad Zeidan
- Department of Basic Medical Sciences, College of Medicine (QU Health), Qatar University, Doha, Qatar
| | - Mohammad Alzoghaibi
- Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohammad F Al Otaibi
- Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Seham A Abd El-Aleem
- Department of Histology and Cell Biology, University of Manchester, Manchester, United Kingdom.,Department of Pathology, Faculty of Medicine, Minia University, Minia, Egypt
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24
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Maecker HT, Wang W, Rosenberg-Hasson Y, Semelka RC, Hickey J, Koran LM. An initial investigation of serum cytokine levels in patients with gadolinium retention. Radiol Bras 2020; 53:306-313. [PMID: 33071374 PMCID: PMC7545733 DOI: 10.1590/0100-3984.2019.0075] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Objective To determine whether individuals with proposed gadolinium deposition disease (GDD) have elevated serum levels of pro-inflammatory and pro-fibrotic cytokines, and whether specific cytokines are correlated with certain symptoms. Materials and Methods Twenty-four participants recruited between May 2016 and June 2017 met GDD diagnostic criteria. The 64 control subjects provided serum samples before prophylactic flu vaccination. Serum cytokine levels were obtained with Luminex serum cytokine assay using eBiosciences/Affymetrix human 62-plex kits. Wilcoxon rank-sum tests were performed to assess the difference between the median fluorescence intensity values for the participants and the control group. Generalized linear models were built to evaluate the association between each cytokine of interest and selected participant symptoms. Results Serum levels of 14 cytokines, including nine pro-inflammatory cytokines, were statistically significantly elevated compared to controls (p ≤ 0.05). Hypotheses regarding pro-fibrotic cytokines and cytokine links to specific symptoms' intensity were not confirmed. Conclusion The statistically significantly elevated cytokines may be markers of susceptibility to GDD or agents of symptom induction. These findings suggest that individuals developing symptoms characteristic of GDD after a contrast-assisted magnetic resonance imaging should be studied to investigate whether gadolinium retention and elevated cytokines may be related to their symptoms.
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Affiliation(s)
| | - Weiqi Wang
- Stanford University Medical Center, Stanford, CA, USA
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25
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Pettersson N, Kragsbjerg F, Hamrin A, Bergman S, Forsblad-d'Elia H, Karling P. Increased chronic pain in patients with ulcerative colitis is mostly associated to increased disease activity. A cross-sectional case-control study. Scand J Gastroenterol 2020; 55:1193-1199. [PMID: 32946699 DOI: 10.1080/00365521.2020.1820567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUNDS/AIMS Musculoskeletal symptoms are common in patients with ulcerative colitis (UC), but no study has compared the prevalence of chronic pain to controls from a general population. METHODS Patients with UC (n = 1164) and controls (n = 3867) were sent questionnaires comprising demography, history of pain, pain localization and UC patients' Patient-Simple Clinical Colitis Activity Index. Chronic regional pain (ChRP) and chronic widespread pain (ChWP) were defined as having pain for at least 3 months. RESULTS The response rate for the patients with UC was 49.0% and for the control persons 61.7% (p < .001). The reported prevalence of ChRP and ChWP was higher in patients with UC versus controls (33.1% vs. 24.2%; p < .001 and 19.8% vs. 12.5%; p < .001). The patients with UC reported significantly more pain in the regions 'lower back', 'hip/upper leg' and 'lower leg/foot' compared to controls. The patients with P-SCCAI ≥ 5 (n = 121) reported more ChWP than patients with P-SCCAI <5 (n = 426) (46.3% vs. 12.7%; p < .001) and controls (n = 2425) (46.3 vs. 12.5%; p < .001) in all body regions. No significant difference in ChWP was found between patients with P-SCCAI <5 and controls (12.7% vs. 12.5%; p = .917). CONCLUSIONS Patients with UC reported more chronic pain than controls from the general population, especially from the lower back and hip region. Higher UC disease activity was associated with more pain in all body regions.
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Affiliation(s)
- Nina Pettersson
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Fredrik Kragsbjerg
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Arvid Hamrin
- Department of Medicine, Sundsvall-Härnösand Hospital, Sundsvall, Sweden
| | - Stefan Bergman
- Primary Health Care Unit, Department of Public Health and Community Medicine, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,FoU Spenshult, Halmstad, Sweden
| | | | - Pontus Karling
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
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26
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Granulocyte-Macrophage Colony Stimulating Factor As an Indirect Mediator of Nociceptor Activation and Pain. J Neurosci 2020; 40:2189-2199. [PMID: 32019828 DOI: 10.1523/jneurosci.2268-19.2020] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 01/07/2020] [Accepted: 01/14/2020] [Indexed: 12/11/2022] Open
Abstract
The interaction between the immune system and the nervous system has been at the center of multiple research studies in recent years. Whereas the role played by cytokines as neuronal mediators is no longer contested, the mechanisms by which cytokines modulate pain processing remain to be elucidated. In this study, we have analyzed the involvement of granulocyte-macrophage colony stimulating factor (GM-CSF) in nociceptor activation in male and female mice. Previous studies have suggested GM-CSF might directly activate neurons. However, here we established the absence of a functional GM-CSF receptor in murine nociceptors, and suggest an indirect mechanism of action, via immune cells. We report that GM-CSF applied directly to magnetically purified nociceptors does not induce any transcriptional changes in nociceptive genes. In contrast, conditioned medium from GM-CSF-treated murine macrophages was able to drive nociceptor transcription. We also found that conditioned medium from nociceptors treated with the well established pain mediator, nerve growth factor, could also modify macrophage gene transcription, providing further evidence for a bidirectional crosstalk.SIGNIFICANCE STATEMENT The interaction of the immune system and the nervous system is known to play an important role in the development and maintenance of chronic pain disorders. Elucidating the mechanisms of these interactions is an important step toward understanding, and therefore treating, chronic pain disorders. This study provides evidence for a two-way crosstalk between macrophages and nociceptors in the peripheral nervous system, which may contribute to the sensitization of nociceptors by cytokines in pain development.
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27
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Angst DBM, Pinheiro RO, Vieira JSDS, Cobas RA, Hacker MDAVB, Pitta IJR, Giesel LM, Sarno EN, Jardim MR. Cytokine Levels in Neural Pain in Leprosy. Front Immunol 2020; 11:23. [PMID: 32038662 PMCID: PMC6992577 DOI: 10.3389/fimmu.2020.00023] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 01/07/2020] [Indexed: 12/20/2022] Open
Abstract
Pain is a frequent symptom in leprosy patients. It may be predominantly nociceptive, as in neuritis, or neuropathic, due to injury or nerve dysfunction. The differential diagnosis of these two forms of pain is a challenge in clinical practice, especially because it is quite common for a patient to suffer from both types of pain. A better understanding of cytokine profile may serve as a tool in assessing patients and also help to comprehend pathophysiology of leprosy pain. Patients with leprosy and neural pain (n = 22), neuropathic pain (n = 18), neuritis (nociceptive pain) (n = 4), or no pain (n = 17), further to those with diabetic neuropathy and neuropathic pain (n = 17) were recruited at Souza Araujo Out-Patient Unit (Fiocruz, Rio de Janeiro, RJ, Brazil). Serum levels of IL1β, IL-6, IL-10, IL-17, TNF, CCL-2/MCP-1, IFN-γ, CXCL-10/IP-10, and TGF-β were evaluated in the different Groups. Impairment in thermal or pain sensitivity was the most frequent clinical finding (95.5%) in leprosy neuropathy patients with and without pain, but less frequent in Diabetic Group (88.2%). Previous reactional episodes have occurred in patients in the leprosy and Pain Group (p = 0.027) more often. Analysis of cytokine levels have demonstrated that the concentrations of IL-1β, TNF, TGF-β, and IL-17 in serum samples of patients having leprosy neuropathy in combination with neuropathic or nociceptive pain were higher when compared to the samples of leprosy neuropathy patients without pain. In addition, these cytokine levels were significantly augmented in leprosy patients with neuropathic pain in relation to those with neuropathic pain due to diabetes. IL-1β levels are an independent variable associated with both types of pain in patients with leprosy neuropathy. IL-6 concentration was increased in both groups with pain. Moreover, CCL-2/MCP-1 and CXCL-10/IP-10 levels were higher in patients with diabetic neuropathy over those with leprosy neuropathy. In brief, IL-1β is an independent variable related to neuropathic and nociceptive pain in patients with leprosy, and could be an important biomarker for patient follow-up. IL-6 was higher in both groups with pain (leprosy and diabetic patients), and could be a therapeutic target in pain control.
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Affiliation(s)
- Débora Bartzen Moraes Angst
- Leprosy Laboratory, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
- Postgraduate Program in Neurology of Federal University of Rio de Janeiro State (UNIRIO), Rio de Janeiro, Brazil
| | | | | | - Roberta Arnoldi Cobas
- Endocrinology Discipline of the Faculty of Medical Sciences, State University of Rio de Janeiro (UERJ), Rio de Janeiro, Brazil
| | | | - Izabela Jardim Rodrigues Pitta
- Leprosy Laboratory, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
- Postgraduate Program in Neurology of Federal University of Rio de Janeiro State (UNIRIO), Rio de Janeiro, Brazil
| | - Louise Mara Giesel
- Leprosy Laboratory, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
| | - Euzenir Nunes Sarno
- Leprosy Laboratory, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
| | - Márcia Rodrigues Jardim
- Leprosy Laboratory, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
- Postgraduate Program in Neurology of Federal University of Rio de Janeiro State (UNIRIO), Rio de Janeiro, Brazil
- Neurology Discipline of the Faculty of Medical Sciences, State University of Rio de Janeiro (UERJ), Rio de Janeiro, Brazil
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28
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Kuffler DP. Injury-Induced Effectors of Neuropathic Pain. Mol Neurobiol 2019; 57:51-66. [PMID: 31701439 DOI: 10.1007/s12035-019-01756-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 08/29/2019] [Indexed: 02/07/2023]
Abstract
Injuries typically result in the development of neuropathic pain, which decreases in parallel with wound healing. However, the pain may remain after the injury appears to have healed, which is generally associated with an ongoing underlying pro-inflammatory state. Injury induces many cells to release factors that contribute to the development of a pro-inflammatory state, which is considered an essential first step towards wound healing. However, pain elimination requires a transition of the injury site from pro- to anti-inflammatory. Therefore, developing techniques that eliminate chronic pain require an understanding of the cells resident at and recruited to injury sites, the factors they release, that promote a pro-inflammatory state, and promote the subsequent transition of that site to be anti-inflammatory. Although a relatively large number of cells, factors, and gene expression changes are involved in these processes, it may be possible to control a relatively small number of them leading to the reduction and elimination of chronic neuropathic pain. This first of two papers examines the roles of the most salient cells and mediators associated with the development and maintenance of chronic neuropathic pain. The following paper examines the cells and mediators involved in reducing and eliminating chronic neuropathic pain.
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Affiliation(s)
- Damien P Kuffler
- Institute of Neurobiology, Medical Sciences Campus, University of Puerto Rico, 201 Blvd. del Valle, San Juan, PR, 00901, USA.
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29
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Leptin and Associated Mediators of Immunometabolic Signaling: Novel Molecular Outcome Measures for Neurostimulation to Treat Chronic Pain. Int J Mol Sci 2019; 20:ijms20194737. [PMID: 31554241 PMCID: PMC6802360 DOI: 10.3390/ijms20194737] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/15/2019] [Accepted: 09/19/2019] [Indexed: 12/13/2022] Open
Abstract
Chronic pain is a devastating condition affecting the physical, psychological, and socioeconomic status of the patient. Inflammation and immunometabolism play roles in the pathophysiology of chronic pain disorders. Electrical neuromodulation approaches have shown a meaningful success in otherwise drug-resistant chronic pain conditions, including failed back surgery, neuropathic pain, and migraine. A literature review (PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles) was performed using the following search terms: chronic pain disorders, systemic inflammation, immunometabolism, prediction, biomarkers, metabolic disorders, and neuromodulation for chronic pain. Experimental studies indicate a relationship between the development and maintenance of chronic pain conditions and a deteriorated immunometabolic state mediated by circulating cytokines, chemokines, and cellular components. A few uncontrolled in-human studies found increased levels of pro-inflammatory cytokines known to drive metabolic disorders in chronic pain patients undergoing neurostimulation therapies. In this narrative review, we summarize the current knowledge and possible relationships of available neurostimulation therapies for chronic pain with mediators of central and peripheral neuroinflammation and immunometabolism on a molecular level. However, to address the needs for predictive factors and biomarkers, large-scale databank driven clinical trials are needed to determine the clinical value of molecular profiling.
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30
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Sugimoto K, Nakamura T, Tokunaga T, Uehara Y, Okada T, Taniwaki T, Fujimoto T, Oike Y, Nakamura E. Angiopoietin-Like Protein 2 Induces Synovial Inflammation in the Facet Joint Leading to Degenerative Changes via Interleukin-6 Secretion. Asian Spine J 2019; 13:368-376. [PMID: 30685956 PMCID: PMC6547404 DOI: 10.31616/asj.2018.0178] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 09/11/2018] [Indexed: 11/23/2022] Open
Abstract
Study Design Experimental human study. Purpose To determine whether angiopoietin-like protein 2 (ANGPTL2) is highly expressed in the hyperplastic facet joint (FJ) synovium and whether it activates interleukin-6 (IL-6) secretion in FJ synoviocytes. Overview of Literature Mechanical stress-induced synovitis is partially, but significantly, responsible for degenerative and subsequently osteoarthritic changes in the FJ tissues in patients with lumbar spinal stenosis (LSS). However, the underlying molecular mechanism remains unclear. IL-6 is highly expressed in degenerative FJ synovial tissue and is responsible for local chronic inflammation. ANGPTL2, an inflammatory and mechanically induced mediator, promotes the expression of IL-6 in many cells. Methods FJ tissues were harvested from five patients who had undergone lumbar surgery. Immunohistochemistry for ANGPTL2, IL-6, and cell markers was performed in the FJ tissue samples. After cultured synoviocytes from the FJ tissues were subjected to mechanical stress, ANGPTL2 expression and secretion were measured quantitatively using real-time quantitative reverse-transcription–polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA), respectively. Following ANGPTL2 administration in the FJ synoviocytes, anti-nuclear factor-κB (NF-κB) activation was investigated using immunocytochemistry, and IL-6 expression and secretion were assayed quantitatively with or without NF-κB inhibitor. Moreover, we assessed whether ANGPTL2-induced IL-6 modulates leucocyte recruitment in the degenerative process by focusing on the monocyte chemoattractant protein-1 (MCP-1) expression. Results ANGPTL2 and IL-6 were highly expressed in the hyperplastic FJ synovium samples. ANGPTL2 was co-expressed in both, fibroblast-like and macrophage-like synoviocytes. Further, the expression and secretion of ANGPTL2 in the FJ synoviocytes increased in response to stimulation by mechanical stretching. ANGPTL2 protein promoted the nuclear translocation of NF-κB and induced IL-6 expression and secretion in the FJ synoviocytes. This effect was reversed following treatment with NF-κB inhibitor. Furthermore, ANGPTL2-induced IL-6 upregulated the MCP-1 expression in the FJ synoviocytes. Conclusions Mechanical stress-induced ANGPTL2 promotes chronic inflammation in the FJ synovium by activating IL-6 secretion, leading to FJ degeneration and subsequent LSS.
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Affiliation(s)
- Kazuki Sugimoto
- Department of Orthopaedics, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Takayuki Nakamura
- Department of Orthopaedics, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Takuya Tokunaga
- Department of Orthopaedics, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Yusuke Uehara
- Department of Orthopaedics, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Tatsuya Okada
- Department of Orthopaedics, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Takuya Taniwaki
- Department of Orthopaedics, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Toru Fujimoto
- Department of Orthopaedics, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Yuichi Oike
- Department of Molecular Genetics, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Eiichi Nakamura
- Department of Orthopaedics, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
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31
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Guha D, Shamji MF. The Dorsal Root Ganglion in the Pathogenesis of Chronic Neuropathic Pain. Neurosurgery 2018; 63 Suppl 1:118-126. [PMID: 27399376 DOI: 10.1227/neu.0000000000001255] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Affiliation(s)
| | - Mohammed F Shamji
- Department of Surgery and.,Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.,Division of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada
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32
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Krupkova O, Sadowska A, Kameda T, Hitzl W, Hausmann ON, Klasen J, Wuertz-Kozak K. p38 MAPK Facilitates Crosstalk Between Endoplasmic Reticulum Stress and IL-6 Release in the Intervertebral Disc. Front Immunol 2018; 9:1706. [PMID: 30174670 PMCID: PMC6107791 DOI: 10.3389/fimmu.2018.01706] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 07/10/2018] [Indexed: 11/24/2022] Open
Abstract
Degenerative disc disease is associated with increased expression of pro-inflammatory cytokines in the intervertebral disc (IVD). However, it is not completely clear how inflammation arises in the IVD and which cellular compartments are involved in this process. Recently, the endoplasmic reticulum (ER) has emerged as a possible modulator of inflammation in age-related disorders. In addition, ER stress has been associated with the microenvironment of degenerated IVDs. Therefore, the aim of this study was to analyze the effects of ER stress on inflammatory responses in degenerated human IVDs and associated molecular mechanisms. Gene expression of ER stress marker GRP78 and pro-inflammatory cytokines IL-6, IL-8, IL-1β, and TNF-α was analyzed in human surgical IVD samples (n = 51, Pfirrmann grade 2-5). The expression of GRP78 positively correlated with the degeneration grade in lumbar IVDs and IL-6, but not with IL-1β and TNF-α. Another set of human surgical IVD samples (n = 25) was used to prepare primary cell cultures. ER stress inducer thapsigargin (Tg, 100 and 500 nM) activated gene and protein expression of IL-6 and induced phosphorylation of p38 MAPK. Both inhibition of p38 MAPK by SB203580 (10 µM) and knockdown of ER stress effector CCAAT-enhancer-binding protein homologous protein (CHOP) reduced gene and protein expression of IL-6 in Tg-treated cells. Furthermore, the effects of an inflammatory microenvironment on ER stress were tested. TNF-α (5 and 10 ng/mL) did not activate ER stress, while IL-1β (5 and 10 ng/mL) activated gene and protein expression of GRP78, but did not influence [Ca2+]i flux and expression of CHOP, indicating that pro-inflammatory cytokines alone may not induce ER stress in vivo. This study showed that IL-6 release in the IVD can be initiated following ER stress and that ER stress mediates IL-6 release through p38 MAPK and CHOP. Therapeutic targeting of ER stress response may reduce the consequences of the harsh microenvironment in degenerated IVD.
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Affiliation(s)
- Olga Krupkova
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | | | - Takuya Kameda
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
- Fukushima Medical University, Fukushima, Japan
| | - Wolfgang Hitzl
- Biostatistics, Research Office, Paracelsus Medical University, Salzburg, Austria
- Department of Ophthalmology and Optometry, Paracelsus Medical University, Salzburg, Austria
| | | | | | - Karin Wuertz-Kozak
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
- Academic Teaching Hospital, Spine Research Institute, Paracelsus Medical University, Salzburg, Austria
- Spine Center, Schön Klinic Munich Harlaching, Munich, Germany
- Department of Health Sciences, University of Potsdam, Potsdam, Germany
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33
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Evashwick-Rogler TW, Lai A, Watanabe H, Salandra JM, Winkelstein BA, Cho SK, Hecht AC, Iatridis JC. Inhibiting tumor necrosis factor-alpha at time of induced intervertebral disc injury limits long-term pain and degeneration in a rat model. JOR Spine 2018; 1. [PMID: 29963655 PMCID: PMC6022768 DOI: 10.1002/jsp2.1014] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background Painful intervertebral disc (IVD) degeneration has tremendous societal costs and few effective therapies. Intradiscal tumor necrosis factor‐alpha (TNFα) is commonly associated with low back pain, but the direct relationship remains unclear. Purpose Treatment strategies for low back pain require improved understanding of the complex relationships between pain, intradiscal pro‐inflammatory cytokines, and structural IVD degeneration. A rat in vivo lumbar IVD puncture model was used to 1) determine the role of TNFα in initiating painful IVD degeneration, and 2) identify statistical relationships between painful behavior, IVD degeneration, and intradiscal pro‐inflammatory cytokine expression. Methods Lumbar IVDs were punctured anteriorly and injected with TNFα, anti‐TNFα, or saline and compared with sham and naive controls. Hindpaw mechanical hyperalgesia was assayed weekly to determine pain over time. 6‐weeks post‐surgery, animals were sacrificed, and IVD degeneration, IVD height, and intradiscal TNFα and interleukin‐1 beta (IL‐1β) expressions were assayed. Results Intradiscal TNFα injection increased pain and IVD degeneration whereas anti‐TNFα alleviated pain to sham level. Multivariate step‐wise linear regression identified pain threshold was predicted by IVD degeneration and intradiscal TNFα expression. Pain threshold was also linearly associated with IVD height loss and IL‐1β. Discussion The significant associations between IVD degeneration, height loss, inflammation, and painful behavior highlight the multifactorial nature of painful IVD degeneration and the challenges to diagnose and treat a specific underlying factor. We concluded that TNFα is an initiator of painful IVD degeneration and its early inhibition can mitigate pain and degeneration. Intradiscal TNFα inhibition following IVD injury may warrant investigation for its potential to alter downstream painful IVD degeneration processes.
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Affiliation(s)
- Thomas W Evashwick-Rogler
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Alon Lai
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Hironobu Watanabe
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York.,Keiyu Spine Center, Keiyu Orthopedic Hospital, Tatebayashi, Japan
| | - Jonathan M Salandra
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Beth A Winkelstein
- Departments of Bioengineering and Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Samuel K Cho
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Andrew C Hecht
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - James C Iatridis
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
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Ma J, Kavelaars A, Dougherty PM, Heijnen CJ. Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: Targeting the source. Cancer 2018; 124:2289-2298. [PMID: 29461625 DOI: 10.1002/cncr.31248] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 12/21/2017] [Accepted: 12/29/2017] [Indexed: 12/23/2022]
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of many chemotherapeutic agents, affecting >60% of patients with cancer. Moreover, CIPN persists long into survivorship in approximately 20% to 30% of these patients. To the authors' knowledge, no drugs have been approved to date by the US Food and Drug Administration to effectively manage chemotherapy-induced neuropathic pain. The majority of the drugs tested for the management of CIPN aim at symptom relief, including pain and paresthesia, yet are not very efficacious. The authors propose that there is a need to acquire a more thorough understanding of the etiology of CIPN so that effective, mechanism-based, disease-modifying interventions can be developed. It is important to note that such interventions should not interfere with the antitumor effects of chemotherapy. Mitochondria are rod-shaped cellular organelles that represent the powerhouses of the cell, in that they convert oxygen and nutrients into the cellular energy "currency" adenosine triphosphate. In addition, mitochondria regulate cell death. Neuronal mitochondrial dysfunction and the associated nitro-oxidative stress represent crucial final common pathways of CIPN. Herein, the authors discuss the potential to prevent or reverse CIPN by protecting mitochondria and/or inhibiting nitro-oxidative stress with novel potential drugs, including the mitochondrial protectant pifithrin-μ, histone deacetylase 6 inhibitors, metformin, antioxidants, peroxynitrite decomposition catalysts, and anti-inflammatory mediators including interleukin 10. This review hopefully will contribute toward bridging the gap between preclinical research and the development of realistic novel therapeutic strategies to prevent or reverse the devastating neurotoxic effects of chemotherapy on the (peripheral) nervous system. Cancer 2018;124:2289-98. © 2018 American Cancer Society.
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Affiliation(s)
- Jiacheng Ma
- Neuroimmunology Laboratory, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Annemieke Kavelaars
- Neuroimmunology Laboratory, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Patrick M Dougherty
- Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cobi J Heijnen
- Neuroimmunology Laboratory, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Duncan SA, Baganizi DR, Sahu R, Singh SR, Dennis VA. SOCS Proteins as Regulators of Inflammatory Responses Induced by Bacterial Infections: A Review. Front Microbiol 2017; 8:2431. [PMID: 29312162 PMCID: PMC5733031 DOI: 10.3389/fmicb.2017.02431] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 11/23/2017] [Indexed: 12/31/2022] Open
Abstract
Severe bacterial infections can lead to both acute and chronic inflammatory conditions. Innate immunity is the first defense mechanism employed against invading bacterial pathogens through the recognition of conserved molecular patterns on bacteria by pattern recognition receptors (PRRs), especially the toll-like receptors (TLRs). TLRs recognize distinct pathogen-associated molecular patterns (PAMPs) that play a critical role in innate immune responses by inducing the expression of several inflammatory genes. Thus, activation of immune cells is regulated by cytokines that use the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway and microbial recognition by TLRs. This system is tightly controlled by various endogenous molecules to allow for an appropriately regulated and safe host immune response to infections. Suppressor of cytokine signaling (SOCS) family of proteins is one of the central regulators of microbial pathogen-induced signaling of cytokines, principally through the inhibition of the activation of JAK/STAT signaling cascades. This review provides recent knowledge regarding the role of SOCS proteins during bacterial infections, with an emphasis on the mechanisms involved in their induction and regulation of antibacterial immune responses. Furthermore, the implication of SOCS proteins in diverse processes of bacteria to escape host defenses and in the outcome of bacterial infections are discussed, as well as the possibilities offered by these proteins for future targeted antimicrobial therapies.
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Affiliation(s)
- Skyla A Duncan
- Center for NanoBiotechnology Research, Alabama State University, Montgomery, AL, United States
| | - Dieudonné R Baganizi
- Center for NanoBiotechnology Research, Alabama State University, Montgomery, AL, United States
| | - Rajnish Sahu
- Center for NanoBiotechnology Research, Alabama State University, Montgomery, AL, United States
| | - Shree R Singh
- Center for NanoBiotechnology Research, Alabama State University, Montgomery, AL, United States
| | - Vida A Dennis
- Center for NanoBiotechnology Research, Alabama State University, Montgomery, AL, United States
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Kwok CH, Trang T. Pain: From genes and proteins to cells in the living organism. J Neurosci Res 2017; 95:1239-1241. [DOI: 10.1002/jnr.24046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Revised: 02/08/2017] [Accepted: 02/08/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Charlie H.T. Kwok
- Hotchkiss Brain Institute; University of Calgary; Calgary Alberta Canada
| | - Tuan Trang
- Hotchkiss Brain Institute; University of Calgary; Calgary Alberta Canada
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Fukuyama T, Ganchingco JR, Bäumer W. Demonstration of rebound phenomenon following abrupt withdrawal of the JAK1 inhibitor oclacitinib. Eur J Pharmacol 2017; 794:20-26. [DOI: 10.1016/j.ejphar.2016.11.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 11/09/2016] [Accepted: 11/11/2016] [Indexed: 11/26/2022]
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Discrete hypo/de-pigmented spots as an early, prodromal, objective sign of somatic origin pain. Pain Rep 2016; 1:e581. [PMID: 29392199 PMCID: PMC5770169 DOI: 10.1097/pr9.0000000000000581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Affiliation(s)
- Seetharaman Hariharan
- Department of Clinical Surgical Sciences, The University of the West Indies, St Augustine, Trinidad & Tobago
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Janum S, Nielsen ST, Werner MU, Mehlsen J, Kehlet H, Møller K. Pain perception in healthy volunteers: effect of repeated exposure to experimental systemic inflammation. Innate Immun 2016; 22:546-56. [PMID: 27554053 DOI: 10.1177/1753425916663638] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 07/08/2016] [Indexed: 11/15/2022] Open
Abstract
We aimed to study the relationship between pain perception and cytokine release during systemic inflammation. We present a randomized crossover trial in healthy volunteers (n = 17) in 37 individual trials. Systemic inflammation was induced by an i.v. bolus of Escherichia coli LPS (2 ng/kg) on two separate trial days, with or without a nicotine patch applied 10 h previously. Pain perception at baseline, and 2 and 6 h after LPS was assessed by pressure algometry and tonic heat stimulation at an increasing temperature (45-48℃) during both trials. Compared with baseline, pain pressure threshold was reduced 2 and 6 h after LPS, while heat pain perception was accentuated at all testing temperatures after 2 but not 6 h. The magnitude of changes in pain perception did not correlate to cytokine release. No effect of transdermal nicotine or training status was observed. In conclusion, LPS administration in healthy human volunteers leads to reduction in pain pressure threshold and an increase in pain perception to heat stimuli, supporting a relationship between acute systemic inflammation and pain perception.
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Affiliation(s)
- Susanne Janum
- Center of Inflammation and Metabolism, CIM 7641, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Department of Anesthesiology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Signe T Nielsen
- Center of Inflammation and Metabolism, CIM 7641, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Mads U Werner
- Multidisciplinary Pain Center, Department of Neuroanesthesiology, Rigshospitalet, Copenhagen, Denmark
| | - Jesper Mehlsen
- Coordinating Research Centre, Frederiksberg Hospital, Frederiksberg, Denmark
| | - Henrik Kehlet
- Institute of Surgical Pathophysiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Kirsten Møller
- Department of Neuroanesthesiology, Rigshospitalet, University of Copenhagen, Denmark
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Hansen BB, Hansen P, Carrino JA, Fournier G, Rasti Z, Boesen M. Imaging in mechanical back pain: Anything new? Best Pract Res Clin Rheumatol 2016; 30:766-785. [DOI: 10.1016/j.berh.2016.08.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 06/21/2016] [Accepted: 08/04/2016] [Indexed: 12/13/2022]
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Zhang S, Zhang J, Wang X. Comparison of tumor curettage and resection for treatment of giant cell tumor of the bone around the knee joint. Pak J Med Sci 2016; 32:662-6. [PMID: 27375710 PMCID: PMC4928419 DOI: 10.12669/pjms.323.9654] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Objective: To analyze the efficacies of tumor curettage and resection for treatment of giant cell tumor of the bone (GCTB) around the knee joint (KJ). Methods: A total of 126 KJ-GCTB cases were treated at our department from August 2011 to February 2015. These cases were divided into two groups (A and B) according to treatment methods. Group A underwent tumor curettage, while group B underwent tumor resection. Results: The relapse rates did not differ significantly between the groups (P>0.05), while the complication rate in group A was significantly lower than that in group B (P<0.05). In addition, the Enneking score for group A was significantly higher than that for group B (P<0.05); in addition, postoperative local recurrence, histopathological grading according to Jaffe, and radiographic imaging-based Campanacci’s staging positively correlated (P<0.05). Conclusion: Tumor curettage was the preferred surgical approach for patients with KJ-GCTB.
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Affiliation(s)
- Sheng Zhang
- Sheng Zhang, Department of Orthopedics, Yan'an People's Hospital, Yan'an 716000, Shanxi Province, China
| | - Jianhua Zhang
- Jianhua Zhang, Department of Orthopedics, the Affiliated Hospital of Yan'an University, Yan'an 716000, Shanxi Province, China
| | - Xin Wang
- Xin Wang, Department of Orthopedics, Yan'an People's Hospital, Yan'an 716000, Shanxi Province, China
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Altun I. Cytokine profile in degenerated painful intervertebral disc: variability with respect to duration of symptoms and type of disease. Spine J 2016; 16:857-61. [PMID: 26975459 DOI: 10.1016/j.spinee.2016.03.019] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 02/09/2016] [Accepted: 03/02/2016] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Neuroinflammation is supposed to play a crucial role in the generation of chronic pain. Numerous trials have documented the contribution of proinflammatory cytokines in the pathophysiology of pain associated with peripheral and central nociception. Local and systemic expressions of proinflammatory cytokines have been implicated as mediators of pain. Among these cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) are especially notable because of their hyperalgesic impacts after nerve damage. PURPOSE The aim of the present study was to evaluate and compare the tissue levels of IL-1β, IL-6, interleukin-10 (IL-10), and TNF-α in subligamentous and free fragment types of degenerated intervertebral disc in acute and chronic periods. STUDY DESIGN This was a cross-sectional study. PATIENT SAMPLE A cross-sectional study was implemented on a total of 49 patients (24 women, 25 men) with an average age of 38.2±4.9 treated surgically by means of microdiscectomy. OUTCOME MEASURES Of these cases, 19 had complaints for less than 6 months, whereas 30 patients had been suffering from low back pain and leg pain for more than 6 months. Thirty-eight patients have been diagnosed with subligamentous type and 11 patients had free fragment type of disc degeneration. METHODS The levels of IL-1β, IL-6, IL-10, and TNF-α were assessed in tissue samples prepared from nucleus pulposus tissue obtained during microdiscectomy. Results were compared in patients with acute and chronic duration of complaints, as well as subligamentous and free fragment types of intervertebral disc degeneration. RESULTS The levels of IL-1β (p<.001), IL-6 (p<.001), IL-10 (p<.001), and TNF-α (p<.001) were significantly higher in patients with acute duration of complaints. Similarly, free fragment type of intervertebral disc degeneration displayed remarkably higher levels of IL-1β (p=.009), IL-6 (p<.001), IL-10 (p=.024), and TNF-α (p=.017) compared with the subligamentous type. CONCLUSIONS Inflammatory cytokines seem to have a more apparent role in intervertebral disc degeneration especially in acute period and in free fragment type. Further trials should be performed for elucidation of pathophysiology at the molecular level and the development of more effective diagnostic and therapeutic measures.
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Affiliation(s)
- Idiris Altun
- Department of Neurosurgery, Medical Faculty, Kahramanmaras Sutcu Imam University, Kahramanmaras 46100, Turkey.
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Cioato SG, Medeiros LF, Marques Filho PR, Vercelino R, de Souza A, Scarabelot VL, de Oliveira C, Adachi LNS, Fregni F, Caumo W, Torres IL. Long-Lasting Effect of Transcranial Direct Current Stimulation in the Reversal of Hyperalgesia and Cytokine Alterations Induced by the Neuropathic Pain Model. Brain Stimul 2016; 9:209-17. [DOI: 10.1016/j.brs.2015.12.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 11/05/2015] [Accepted: 12/06/2015] [Indexed: 12/27/2022] Open
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Huili J, Xue Y, Xiujun R, Ya T. Electroacupuncture alters pain-related behaviors and expression of spinal prostaglandin E 2 in a rat model of neuropathic pain. J TRADIT CHIN MED 2016; 36:85-91. [DOI: 10.1016/s0254-6272(16)30013-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Stress-Induced Microglia Activation and Monocyte Trafficking to the Brain Underlie the Development of Anxiety and Depression. Curr Top Behav Neurosci 2016; 31:155-172. [PMID: 27352390 DOI: 10.1007/7854_2016_25] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Psychosocial stress is capable of causing immune dysregulation and increased neuroinflammatory signaling by repeated activation of the neuroendocrine and autonomic systems that may contribute to the development of anxiety and depression. The stress model of repeated social defeat (RSD) recapitulates many of the stress-driven alterations in the neuroimmune system seen in humans experiencing repeated forms of stress and associated affective disorders. For example, RSD-induced neuronal and microglia activation corresponds with sympathetic outflow to the peripheral immune system and increased ability of bone marrow derived myeloid progenitor cells (MPC) to redistribute throughout the body, including to the central nervous system (CNS), reinforcing stress-associated behaviors. An overview of the neuroendocrine, immunological, and behavioral stress-induced responses will be reviewed in this chapter using RSD to illustrate the mechanisms leading to stress-related alterations in inflammation in both the periphery and CNS, and stress-related changes in behavioral responses.
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Dynamic weight bearing is an efficient and predictable method for evaluation of arthritic nociception and its pathophysiological mechanisms in mice. Sci Rep 2015; 5:14648. [PMID: 26511791 PMCID: PMC4625149 DOI: 10.1038/srep14648] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 09/02/2015] [Indexed: 12/20/2022] Open
Abstract
The assessment of articular nociception in experimental animals is a challenge because available methods are limited and subject to investigator influence. In an attempt to solve this problem, the purpose of this study was to establish the use of dynamic weight bearing (DWB) as a new device for evaluating joint nociception in an experimental model of antigen-induced arthritis (AIA) in mice. AIA was induced in Balb/c and C57BL/6 mice, and joint nociception was evaluated by DWB. Western Blotting and real-time PCR were used to determine protein and mRNA expression, respectively. DWB detected a dose- and time-dependent increase in joint nociception during AIA and was able to detect the dose-response effects of different classes of analgesics. Using DWB, it was possible to evaluate the participation of spinal glial cells (microglia and astrocytes) and cytokines (IL-1β and TNFα) for the genesis of joint nociception during AIA. In conclusion, the present results indicated that DWB is an effective, objective and predictable test to study both the pathophysiological mechanisms involved in arthritic nociception in mice and for evaluating novel analgesic drugs against arthritis.
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Dagistan Y, Cukur S, Dagistan E, Gezici AR. Importance of IL-6, MMP-1, IGF-1, and BAX Levels in Lumbar Herniated Disks and Posterior Longitudinal Ligament in Patients with Sciatic Pain. World Neurosurg 2015. [PMID: 26211852 DOI: 10.1016/j.wneu.2015.07.039] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The aim of this study was to evaluate prognostic importance of interleukin-6 (IL-6), matrix metalloproteinase (MMP)-1, insulin-like growth factor (IGF)-1, and Bcl-2-associated X protein (BAX) levels in biopsy specimens taken from the intervertebral disk specimens and the posterior longitudinal ligaments of patients with sciatic pain. METHODS The specimens of the intervertebral disk and the posterior longitudinal ligament were obtained from 52 patients undergoing herniectomy and diskectomy at the Neurosurgery Department of the Abant Izzet Baysal University Izzet Baysal Training and Research Hospital between April 2012 and February 2014. The immunohistochemical expressions of IL-6, MMP-1, IGF-1, and BAX were evaluated in three categories: mild, moderate, and intense. RESULTS The IL-6 expression in the intervertebral disk specimens was intense in the sequestration group when compared with that of the "protrusion" and "extrusion" groups. The intervertebral disk specimens in "extrusion" and "sequestration" groups were stained intensely for MMP-1. The IGF-1 expression was stained intensely in the intervertebral disk tissue of the extrude group patients. For the "extrusion" and "sequestration" groups, the intervertebral disk specimens were stained intensely for BAX compared with the protrude group. The IL-6 expression in the posterior longitudinal ligament specimens was more intense in the "sequestration" and "extrusion" groups when compared with that of the protrude group. The MMP-1 expressions were milder in the sequestration group when compared with that of the "extrusion" and "protrusion" groups. CONCLUSIONS Our findings suggest that the cytokines, enzymes, growth factors, and proapoptotic proteins, such as IL-6, MMP-1, IGF-1, and BAX, may be critical factors in the pathophysiology of the degeneration of the intervertebral disks in patients with symptomatic degenerative disk disease.
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Affiliation(s)
- Yasar Dagistan
- Department of Neurosurgery, Abant Izzet Baysal University Medical School, Izzet Baysal Training and Research Hospital, Bolu, Turkey.
| | - Selma Cukur
- Department of Pathology, Abant Izzet Baysal University Medical School, Izzet Baysal Training and Research Hospital, Bolu, Turkey
| | - Emine Dagistan
- Department of Radiology, Abant Izzet Baysal University Medical School, Izzet Baysal Training and Research Hospital, Bolu, Turkey
| | - Ali Riza Gezici
- Department of Neurosurgery, Abant Izzet Baysal University Medical School, Izzet Baysal Training and Research Hospital, Bolu, Turkey
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Ramirez K, Shea DT, McKim DB, B.F. R, Sheridan JF. Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav Immun 2015; 46:212-20. [PMID: 25701613 PMCID: PMC4414808 DOI: 10.1016/j.bbi.2015.01.016] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Revised: 01/29/2015] [Accepted: 01/31/2015] [Indexed: 12/18/2022] Open
Abstract
Psychosocial stress is associated with altered immunity, anxiety and depression. Previously we showed that repeated social defeat (RSD) promoted microglia activation and social avoidance behavior that persisted for 24days after cessation of RSD. The aim of the present study was to determine if imipramine (a tricyclic antidepressant) would reverse RSD-inducedsocial avoidance and ameliorate neuroinflammatory responses. To test this, C57BL/6 mice were divided into treatment groups. One group from RSD and controls received daily injections of imipramine for 24days, following 6 cycles of RSD. Two other groups were treated with saline. RSD mice spent significantly less time in the interaction zone when an aggressor was present in the cage. Administration of imipramine reversed social avoidance behavior, significantly increasing the interaction time, so that it was similar to that of control mice. Moreover, 24days of imipramine treatment in RSD mice significantly decreased stress-induced mRNA levels for IL-6 in brain microglia. Following ex vivo LPS stimulation, microglia from mice exposed to RSD, had higher mRNA expression of IL-6, TNF-α, and IL-1β, and this was reversed by imipramine treatment. In a second experiment, imipramine was added to drinking water confirming the reversal of social avoidant behavior and decrease in mRNA expression of IL-6 in microglia. These data suggest that the antidepressant imipramine may exert its effect, in part, by down-regulating microglial activation.
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Affiliation(s)
- Karol Ramirez
- Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH 43210, USA; Facultad de Odontología, Universidad de Costa Rica, San Pedro, San José 11501-2060, Costa Rica.
| | - Daniel T. Shea
- Institute for Behavioral Medicine Research, The Ohio State University Medical Center, Columbus, OH 43210, USA
| | - Daniel B. McKim
- Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH 43210, USA,Institute for Behavioral Medicine Research, The Ohio State University Medical Center, Columbus, OH 43210, USA
| | - Reader B.F.
- Institute for Behavioral Medicine Research, The Ohio State University Medical Center, Columbus, OH 43210, USA
| | - John F. Sheridan
- Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH 43210, USA,Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, Columbus, OH 43210, USA,Institute for Behavioral Medicine Research, The Ohio State University Medical Center, Columbus, OH 43210, USA,Corresponding author at: College of Dentistry, Division of Biosciences, PO BOX 182357, Columbus, OH 43218-2357, USA, Tel.: +1 614 688 4629, fax: +1 614 292 6087
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