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Chiu AP, Lesnak J, Gabriel K, Price TJ, Arendt-Nielsen L, Bobos P, Curatolo M. Human molecular mechanisms of discogenic low back pain: A scoping review. THE JOURNAL OF PAIN 2025; 27:104693. [PMID: 39374801 PMCID: PMC11807758 DOI: 10.1016/j.jpain.2024.104693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 09/25/2024] [Accepted: 10/02/2024] [Indexed: 10/09/2024]
Abstract
The limited understanding of the mechanisms underlying human discogenic low back pain (DLBP) has hampered the development of effective treatments. While there is much research on disc degeneration, the association between degeneration and pain is weak. Therefore, there is an urgent need to identify pain-inducing molecular mechanism to facilitate the development of mechanism-specific therapeutics. This scoping review aims to determine the current knowledge of molecular mechanisms associated with human DLBP. A systematic search on CENTRAL, CINAHL, Citation searching, ClinicalTrials.gov, Embase, Google Scholar, MEDLINE, PsycINFO, PubMed, Scopus, Web of Science, and World Health Organization was performed. Studies with human DLBP as diagnosed by discography or imaging that analyzed human disc tissues and reported pain-related outcomes were included, and those on predominant radicular pain were excluded. The search returned 6012 studies. Most studies did not collect pain-related outcomes. Those that included pain assessment relied on self-report of pain intensity and disability. Six studies qualified for data extraction and synthesis. The main molecular mechanisms associated with DLBP were the expressions of nociceptive neuropeptides and cytokines, particularly TNF-αdue to its strong association with pain outcomes. Activation of NF-κB signaling pathway, alterations in adrenoceptor expressions, and increase in reactive oxygen species (ROS) were also associated with DLBP through regulation of pro-inflammatory factors and pain-related neuropeptides. Current evidence converges to TNF-α, NF-κB signaling, and ROS-induced pro-inflammation. Major weaknesses in the current literature are the focus on degeneration without pain phenotyping, and lack of association of molecular findings with pain outcomes. PERSPECTIVE: This scoping review identified TNF-α, NF-κB signaling, and ROS-induced pro-inflammation as relevant mechanisms of human discogenic low back pain. Major weaknesses in the current literature are the focus on degeneration without pain phenotyping, and lack of association of molecular findings with pain outcomes.
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Affiliation(s)
- Abby P Chiu
- Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA, USA; Clinical Learning, Evidence And Research (CLEAR) Center for Musculoskeletal Research, University of Washington, Seattle, WA, USA
| | - Joseph Lesnak
- Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, USA
| | - Katherin Gabriel
- Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, USA
| | - Theodor J Price
- Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, USA
| | - Lars Arendt-Nielsen
- Center for Neuroplasticity and Pain (CNAP), SMI, Medical School, Aalborg University, Denmark; Department of Gastroenterology & Hepatology, Mech-Sense, Clinical Institute, Aalborg University Hospital, Aalborg, Denmark; Steno Diabetes Center North Denmark, Clinical Institute, Aalborg University Hospital, Aalborg, Denmark
| | - Pavlos Bobos
- School of Physical Therapy, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
| | - Michele Curatolo
- Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA, USA; Clinical Learning, Evidence And Research (CLEAR) Center for Musculoskeletal Research, University of Washington, Seattle, WA, USA.
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Zhang X, Li S, Liu X, Ma Z, Zhang Q, Zhang Y, An J, Luo Z. The protective effect and experimental research progress of pleotropic statins in intervertebral disc degeneration. J Orthop Surg Res 2025; 20:122. [PMID: 39891158 PMCID: PMC11783947 DOI: 10.1186/s13018-025-05487-8] [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: 11/28/2024] [Accepted: 01/11/2025] [Indexed: 02/03/2025] Open
Abstract
Intervertebral disc degeneration (IVDD) is one of the primary causes of low back pain, significantly affecting the quality of life in the elderly population and imposing a substantial economic burden. Currently, clinical treatments for IVDD mainly focus on symptom management, with no available therapies capable of reversing or curing the disease. In recent years, statins, a class of drugs traditionally used in the treatment of cardiovascular diseases, have been shown to exert beneficial effects on IVDD through multiple mechanisms. With the advancement of research into the pleiotropic effects of statins, an increasing body of evidence suggests their potential as effective therapeutic agents for IVDD. This review summarizes the pleiotropic effects of statins and explores their potential mechanisms and actions in IVDD, with particular emphasis on changes in the expression of relevant molecular markers. Furthermore, recent advancements in the application of statins for IVDD treatment are discussed, along with the potential of combining statins with other drugs as part of multi-target therapeutic strategies. This review aims to provide a scientific reference for further investigations into the use of statins in the treatment of IVDD.
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Affiliation(s)
- Xianxu Zhang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, 730000, P.R. China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, 730000, China
| | - Shicheng Li
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, 730000, P.R. China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, 730000, China
| | - Xin Liu
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, 730000, P.R. China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, 730000, China
| | - Zhong Ma
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, 730000, P.R. China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, 730000, China
| | - Qiang Zhang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, 730000, P.R. China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, 730000, China
| | - Yuji Zhang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, 730000, P.R. China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, 730000, China
| | - Jiangdong An
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, 730000, P.R. China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, 730000, China
| | - Zhiqiang Luo
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, 730000, P.R. China.
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, 730000, China.
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Peng BG. Fundamentals of intervertebral disc degeneration and related discogenic pain. World J Orthop 2025; 16:102119. [PMID: 39850042 PMCID: PMC11752479 DOI: 10.5312/wjo.v16.i1.102119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/12/2024] [Accepted: 12/19/2024] [Indexed: 01/13/2025] Open
Abstract
Lumbar intervertebral disc degeneration is thought to be the main cause of low back pain, although the mechanisms by which it occurs and leads to pain remain unclear. In healthy adult discs, vessels and nerves are present only in the outer layer of the annulus fibrosus and in the bony endplate. Animal models, and histological and biomechanical studies have shown that annulus tear or endplate injury is the initiating factor for painful disc degeneration. Injury to the disc triggers a local inflammatory repair response that activates nociceptors and promotes the synthesis of neuropeptides such as substance P and calcitonin gene-related peptide, by dorsal root ganglion neurons. These neuropeptides are transported to injured discs and act as pro-inflammatory molecules, promoting the production of an "inflammatory soup" by inducing vasodilatation and plasma extravasation as well as by promoting the release of chemical mediators from disc cells and infiltrating immune cells, causing neurogenic inflammation that leads to progressive disc degeneration and discogenic pain.
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Affiliation(s)
- Bao-Gan Peng
- Department of Orthopedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
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Peng BG, Li YC, Yang L. Role of neurogenic inflammation in intervertebral disc degeneration. World J Orthop 2025; 16:102120. [PMID: 39850033 PMCID: PMC11752484 DOI: 10.5312/wjo.v16.i1.102120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/29/2024] [Accepted: 12/20/2024] [Indexed: 01/13/2025] Open
Abstract
In healthy intervertebral discs (IVDs), nerves and blood vessels are present only in the outer annulus fibrosus, while in degenerative IVDs, a large amount of nerve and blood vessel tissue grows inward. Evidence supports that neurogenic inflammation produced by neuropeptides such as substance P and calcitonin gene related peptide released by the nociceptive nerve fibers innervating the IVDs plays a crucial role in the process of IVD degeneration. Recently, non-neuronal cells, including IVD cells and infiltrating immune cells, have emerged as important players in neurogenic inflammation. IVD cells and infiltrating immune cells express functional receptors for neuropeptides through which they receive signals from the nervous system. In return, IVD cells and immune cells produce neuropeptides and nerve growth factor, which stimulate nerve fibers. This communication generates a positive bidirectional feedback loop that can enhance the inflammatory response of the IVD. Recently emerging transient receptor potential channels have been recognized as contributors to neurogenic inflammation in the degenerative IVDs. These findings suggest that neurogenic inflammation involves complex pathophysiological interactions between sensory nerves and multiple cell types in the degenerative IVDs. Clarifying the mechanism of neurogenic inflammation in IVD degeneration may provide in-depth understanding of the pathology of discogenic low back pain.
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Affiliation(s)
- Bao-Gan Peng
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
| | - Yong-Chao Li
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
| | - Liang Yang
- Department of Orthopeadics, Featured Medical Center of Chinese People’s Armed Police Forces, Tianjin 300000, China
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Yang H, Chen X, Chen J, Dong Y, Huang Y, Qin L, Tan J, Yi W. The pathogenesis and targeted therapies of intervertebral disc degeneration induced by cartilage endplate inflammation. Front Cell Dev Biol 2024; 12:1492870. [PMID: 39687521 PMCID: PMC11647014 DOI: 10.3389/fcell.2024.1492870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024] Open
Abstract
Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, where degeneration and death of nucleus pulposus cells within the intervertebral disc (IVD) can be obviously revealed. This degeneration can result in an imbalance in the extracellular matrix due to the loss of proteoglycans and water content, which can further lead to catabolic and anabolic dysfunction of the IVD. Recently, the dysfunction of cartilage endplate (CEP) during aging has drawn large attention due to its essential functions in contributing nutrient exchange and maintaining IVD homeostasis. Furthermore, the inflammation and disturbed homeostasis of CEP not only accelerate the degradation of nucleus pulposus extracellular matrix, but also exacerbate IVDD by causing nucleus pulposus cell death through other pathological factors. Here in this review, we summarized the possible pathological factors and the underlying mechanisms of the CEP inflammation-induced IVDD, including exosomes degeneration, CEP calcification, ferroptosis, mechanical changes, and cell senescence. Besides, changes of miRNAs, pain-related neural reflex arc and pathways associated with CEP inflammation-induced IVDD are also reviewed. In addition, new strategies specifically designed for CEP inflammation-induced IVDD are also discussed in the last section. We hope this paper can not only offer some new insights for advancing novel strategies for treating IVDD, but also serve as a valuable reference for researchers in this field.
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Affiliation(s)
- Hantao Yang
- Department of Spine Surgery and Innovative Laboratory of Orthopedics, Shenzhen Nanshan People’s Hospital, Shenzhen, Guangdong, China
| | - Xuandu Chen
- Department of Spine Surgery and Innovative Laboratory of Orthopedics, Shenzhen Nanshan People’s Hospital, Shenzhen, Guangdong, China
| | - Jun Chen
- Orthopedic Laboratory, Orthopedic Department and Hubei Sports Medicine Center, Wuhan Fourth Hospital, Wuhan, China
| | - Yansong Dong
- Department of Spine Surgery and Innovative Laboratory of Orthopedics, Shenzhen Nanshan People’s Hospital, Shenzhen, Guangdong, China
| | - Yafang Huang
- Department of Spine Surgery and Innovative Laboratory of Orthopedics, Shenzhen Nanshan People’s Hospital, Shenzhen, Guangdong, China
- Orthopedic Laboratory, Orthopedic Department and Hubei Sports Medicine Center, Wuhan Fourth Hospital, Wuhan, China
| | - Lei Qin
- Department of Spine Surgery and Innovative Laboratory of Orthopedics, Shenzhen Nanshan People’s Hospital, Shenzhen, Guangdong, China
| | - Jie Tan
- Department of Spine Surgery and Innovative Laboratory of Orthopedics, Shenzhen Nanshan People’s Hospital, Shenzhen, Guangdong, China
- Orthopedic Laboratory, Orthopedic Department and Hubei Sports Medicine Center, Wuhan Fourth Hospital, Wuhan, China
| | - Weihong Yi
- Department of Spine Surgery and Innovative Laboratory of Orthopedics, Shenzhen Nanshan People’s Hospital, Shenzhen, Guangdong, China
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Rodriguez P, López-Landa A, Romo-Parra H, Rubio-Osornio M, Rubio C. Unraveling the ozone impact and oxidative stress on the nervous system. Toxicology 2024; 509:153973. [PMID: 39423999 DOI: 10.1016/j.tox.2024.153973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/07/2024] [Accepted: 10/15/2024] [Indexed: 10/21/2024]
Abstract
Ozone (O₃), a potent oxidant, can penetrate the body through breathing, generating reactive oxygen species (ROS) and triggering inflammatory processes. Oxidative stress, an imbalance between the production of ROS and the body's antioxidant capacity, plays a crucial role in the pathophysiology of various neurodegenerative diseases. This phenomenon can negatively impact the Central Nervous System (CNS), inducing structural and functional alterations that contribute to the development of neurological pathologies. This review examines how O₃-induced oxidative stress affects the nervous system by analyzing existing literature on the involved molecular mechanisms and potential antioxidant systems to mitigate its effects. Through a comprehensive review of experimental studies, our objective is to shed light on the interaction between O₃ and the nervous system, as well as its signaling pathways and altered genes, providing a foundation for future research in this field. Several studies have demonstrated that prolonged exposure to O₃ leads to increased expression of reactive oxygen species, causing alterations in the blood-brain barrier and damage to astrocytes and microglia. These effects can lead to an increase in the production of proinflammatory cytokines, neurotoxins, and genes, exacerbating neuronal damage and accelerating the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and other neurological disorders. The results of this review suggest that exposure to O₃ may induce oxidative damage to the nervous system, which could have significant implications for public health.
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Affiliation(s)
- Paola Rodriguez
- Neurophysiology Department, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez", Mexico, Mexico
| | - Alejandro López-Landa
- Neurophysiology Department, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez", Mexico, Mexico; Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Héctor Romo-Parra
- Neurophysiology Department, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez", Mexico, Mexico; Psychology Department, Universidad Iberoamericana, Mexico, Mexico
| | - Moisés Rubio-Osornio
- Neurochemistry Department, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez", Mexico, Mexico
| | - Carmen Rubio
- Neurophysiology Department, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez", Mexico, Mexico.
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Li Y, Dai C, Wu B, Yang L, Yan X, Liu T, Chen J, Zheng Z, Peng B. Intervertebral disc injury triggers neurogenic inflammation of adjacent healthy discs. Spine J 2024; 24:1527-1537. [PMID: 38608821 DOI: 10.1016/j.spinee.2024.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 03/14/2024] [Accepted: 04/04/2024] [Indexed: 04/14/2024]
Abstract
BACKGROUND CONTEXT Intervertebral disc degeneration is common and may play an important role in low back pain, but it is not well-understood. Previous studies have shown that the outer layer of the annulus fibrosus of a healthy disc is innervated by nociceptive nerve fibers. In the process of disc degeneration, it can grow into the inner annulus fibrosus or nucleus pulposus and release neuropeptides. Disc degeneration is associated with inflammation that produces inflammatory factors and potentiates nociceptor sensitization. Subsequently neurogenic inflammation is induced by neuropeptide release from activated primary afferent terminals. Because the innervation of a lumbar disc comes from multisegmental dorsal root ganglion neurons, does neurogenic inflammation in a degenerative disc initiate neurogenic inflammation in neighboring healthy discs by antidromic activity? PURPOSE This study was based on animal experiments in Sprague-Dawley rats to investigate the role of neurogenic inflammation in adjacent healthy disc degeneration induced by disc injury. STUDY DESIGN This was an experimental study. METHODS Seventy-five 12-week-old, male Sprague-Dawley rats were allocated to 3 groups (sham group, disc injury group and disc injury+TrkA antagonist group). The disc injury group was punctured in the tail disc between the eighth and ninth coccygeal vertebrae (Co8-9) to establish an animal model of tail intervertebral disc degeneration. The sham group underwent only skin puncture and the disc injury+TrkA antagonist group was intraperitoneally injected with GW441756 two days before disc puncture. The outcome measure included quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS Disc injury induced an increase in aggrecan, NGF, TrkA, CGRP, SP, IL-1β, and IL-6 mRNA levels in the injured (Co8-9) and adjacent discs (Co7-8), which reached a peak on day 1, then gradually decreased, and returned to normal on day 14. After intraperitoneal injection of GW441756 prior to puncture, the mRNA levels of the above indicators were down-regulated in Co7-8 and Co8-9 intervertebral discs on the 1st and 7th days. The protein content of the above indicators in Co7-8 and Co8-9 intervertebral discs showed roughly the same trend as mRNA levels. CONCLUSIONS Degeneration of one disc can induce neurogenic inflammation of adjacent healthy discs in a rat model. CLINICAL SIGNIFICANCE This model supports a key role of neurogenic inflammation in disc degeneration, and may play a role in the experience of low back pain.
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Affiliation(s)
- Yongchao Li
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China
| | - Chen Dai
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China
| | - Bing Wu
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China
| | - Liang Yang
- Department of Orthopeadics, Featured Medical Center of Chinese People's Armed Police Forces, 220 Chenglin Road, Dongli District, Tianjin, P.R. China
| | - Xiujie Yan
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China
| | - Tanghua Liu
- Algology Institute of Sino-US Zhongguancun Precision Medicine Academy, 45 Beiwa Road, Haidian District, Beijing, P.R. China
| | - Jindong Chen
- Department of Orthopaedics, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, 21 South Silver Spring Road, Qingyuan, P.R. China
| | - Zhaomin Zheng
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan No. 2 Road, Guangzhou, P.R. China; Pain Research Center, Sun Yat-sen University, 135 Xingang West Road, Haizhu District, Guangzhou, P.R. China.
| | - Baogan Peng
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China.
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Satarker S, Gurram PC, Nassar A, Manandhar S, Vibhavari R, Yarlagadda DL, Mudgal J, Lewis S, Arora D, Nampoothiri M. Evaluating the Role of N-Acetyl-L-Tryptophan in the Aβ 1-42-Induced Neuroinflammation and Cognitive Decline in Alzheimer's Disease. Mol Neurobiol 2024; 61:4421-4440. [PMID: 38091207 PMCID: PMC11236887 DOI: 10.1007/s12035-023-03844-4] [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: 09/27/2023] [Accepted: 11/29/2023] [Indexed: 07/11/2024]
Abstract
Alzheimer's disease (AD), a neurodegenerative condition previously known to affect the older population, is also now seen in younger individuals. AD is often associated with cognitive decline and neuroinflammation elevation primarily due to amyloid β (Aβ) accumulation. Multiple pathological complications in AD call for therapies with a wide range of neuroprotection. Our study aims to evaluate the effect of N-acetyl-L-tryptophan (NAT) in ameliorating the cognitive decline and neuroinflammation induced by Aβ 1-42 oligomers and to determine the therapeutic concentration of NAT in the brain. We administered Aβ 1-42 oligomers in rats via intracerebroventricular (i.c.v.) injection to induce AD-like conditions. The NAT-treated animals lowered the cognitive decline in the Morris water maze characterized by shorter escape latency and increased path efficiency and platform entries. Interestingly, the hippocampus and frontal cortex showed downregulation of tumor necrosis factor, interleukin-6, and substance P levels. NAT treatment also reduced acetylcholinesterase activity and total and phosphorylated nuclear factor kappa B and Tau levels. Lastly, we observed upregulation of cAMP response element-binding protein 1 (CREB1) signaling. Surprisingly, our HPLC method was not sensitive enough to detect the therapeutic levels of NAT in the brain, possibly due to NAT concentrations being below the lowest limit of quantification of our validated method. To summarize, the administration of NAT significantly lowered cognitive decline, neuroinflammatory pathways, and Tau protein and triggered the upregulation of CREB1 signaling, suggesting its neuroprotective role in AD-like conditions.
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Affiliation(s)
- Sairaj Satarker
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Prasada Chowdari Gurram
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Ajmal Nassar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Suman Manandhar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Rja Vibhavari
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Dani Lakshman Yarlagadda
- Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Jayesh Mudgal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Shaila Lewis
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Devinder Arora
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
- School of Pharmacy and Medical Sciences, Griffith University, QLD, Gold Coast, 4222, Australia
| | - Madhavan Nampoothiri
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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Ozone in Chemotherapy-Induced Peripheral Neuropathy—Current State of Art, Possibilities, and Perspectives. Int J Mol Sci 2023; 24:ijms24065279. [PMID: 36982352 PMCID: PMC10049472 DOI: 10.3390/ijms24065279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/01/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most detrimental toxicity to a patient’s quality of life. Pathophysiological mechanisms involved in CIPN pathogenesis are complex, multifactorial, and only partially examined. They are suspected to be associated with oxidative stress (OS), mitochondrial dysfunction, ROS-induced apoptosis, myelin sheath and DNA damage, and immunological and inflammatory processes. Unfortunately, medications commonly used for the management of other neuropathic pain syndromes, including gabapentinoids, opioids, and tricyclic antidepressants (such as desipramine and nortriptyline), do not bring satisfactory results in CIPN. The aim of this review is to evaluate the existing literature on the potential use of medical ozone as a treatment for CIPN. This paper would explore the potential therapeutic benefits of medical ozone. The review would evaluate the existing literature on the use of medical ozone in other contexts, as well as its potential application in treating CIPN. The review would also suggest possible research methods, such as randomized controlled trials, to evaluate the efficacy of medical ozone as a treatment for CIPN. Medical ozone has been used to disinfect and treat diseases for over 150 years. The effectiveness of ozone in treating infections, wounds, and a variety of diseases has been well documented. Ozone therapy is also documented to inhibit the growth of human cancer cells and has antioxidative and anti-inflammatory effects. Due to its ability to modulate oxidative stress, inflammation, and ischemia/hypoxia, ozone may have a potentially valuable effect on CIPN.
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Aripaka SS, Bech-Azeddine R, Jørgensen LM, Mikkelsen JD. Transient receptor potential (TRP) channels mRNA transcripts in the lumbar intervertebral discs: biomarkers for inflammation, pain, disability, and clinical outcome. Mol Cell Biochem 2023; 478:121-130. [PMID: 35737198 DOI: 10.1007/s11010-022-04501-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 06/08/2022] [Indexed: 01/17/2023]
Abstract
Transient receptor potential (TRP) channels are widely expressed cation channels that play an essential role in mediating Ca2+ homeostasis and are considered potential regulators of inflammatory pain. This study investigates the expression of the TRP channel subtypes TRPV1, TRPV4, TRPC6, TRPM2, TRPM8 in lumbar intervertebral disc (IVD) biopsies from patients with chronic low back pain (LBP). We determined the expression of these TRP channel subtypes in the annulus fibrosus (AF) and the nucleus pulposus (NP) from 46 patients with LBP undergoing 1-2 level lumbar fusion surgery for degenerative disc disease. The mRNA transcripts were analyzed using quantitative real-time polymerase chain reaction (RT-qPCR), and the expression levels were compared against visual analog scale (VAS) and oswestry disability index (ODI) scores (0-100) for pain and disability. A significant positive correlation was demonstrated between VAS score and the mRNA expression of TRPV1, TRPC6, TRPM2, TRPM8 in the AF. We also found a significant positive correlation between ODI scores and expression of TRPV1 and TRPM8. Further, there is a significant positive correlation between TNF-α and TRPV1, TRPM2 and TRPM8 expression in the AF, and IL-6 to TRPV1 in the NP. Interestingly, when investigating treatment response via a 12-month postoperative follow-up ODI, we found a significant correlation between only TRPV1 expression at baseline and the follow-up ODI scores, which indicates this marker could predict the effectiveness of surgery. These results strongly suggest an association between pain, inflammatory mediators, and TRP channel expression in lumbar disc biopsies of patients with chronic LBP.
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Affiliation(s)
- Sanjay S Aripaka
- Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, 4-6, Inge Lehmanns vej, 2100, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rachid Bech-Azeddine
- Center for Rheumatology and Spine Diseases, Copenhagen Spine Research Unit, Rigshospitalet, Glostrup, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Louise M Jørgensen
- Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, 4-6, Inge Lehmanns vej, 2100, Copenhagen, Denmark.,Center for Rheumatology and Spine Diseases, Copenhagen Spine Research Unit, Rigshospitalet, Glostrup, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens D Mikkelsen
- Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, 4-6, Inge Lehmanns vej, 2100, Copenhagen, Denmark. .,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. .,Institute of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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11
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Novoa C, Salazar P, Cisternas P, Gherardelli C, Vera-Salazar R, Zolezzi JM, Inestrosa NC. Inflammation context in Alzheimer's disease, a relationship intricate to define. Biol Res 2022; 55:39. [PMID: 36550479 PMCID: PMC9784299 DOI: 10.1186/s40659-022-00404-3] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 11/15/2022] [Indexed: 12/24/2022] Open
Abstract
Alzheimer's disease (AD), the most common form of dementia, is characterized by the accumulation of amyloid β (Aβ) and hyperphosphorylated tau protein aggregates. Importantly, Aβ and tau species are able to activate astrocytes and microglia, which release several proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β), together with reactive oxygen (ROS) and nitrogen species (RNS), triggering neuroinflammation. However, this inflammatory response has a dual function: it can play a protective role by increasing Aβ degradation and clearance, but it can also contribute to Aβ and tau overproduction and induce neurodegeneration and synaptic loss. Due to the significant role of inflammation in the pathogenesis of AD, several inflammatory mediators have been proposed as AD markers, such as TNF-α, IL-1β, Iba-1, GFAP, NF-κB, TLR2, and MHCII. Importantly, the use of anti-inflammatory drugs such as NSAIDs has emerged as a potential treatment against AD. Moreover, diseases related to systemic or local inflammation, including infections, cerebrovascular accidents, and obesity, have been proposed as risk factors for the development of AD. In the following review, we focus on key inflammatory processes associated with AD pathogenesis.
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Affiliation(s)
- Catalina Novoa
- Centro de Envejecimiento y Regeneración (CARE-UC), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda Bernardo O'Higgins 340, P.O. Box 114-D, Santiago, Chile
| | - Paulina Salazar
- Centro de Envejecimiento y Regeneración (CARE-UC), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda Bernardo O'Higgins 340, P.O. Box 114-D, Santiago, Chile
| | - Pedro Cisternas
- Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua, Chile
| | - Camila Gherardelli
- Centro de Envejecimiento y Regeneración (CARE-UC), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda Bernardo O'Higgins 340, P.O. Box 114-D, Santiago, Chile
| | - Roberto Vera-Salazar
- Facultad de Ciencias Médicas, Escuela de Kinesiología, Universidad de Santiago de Chile, Santiago, Chile
| | - Juan M Zolezzi
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas, Chile
| | - Nibaldo C Inestrosa
- Centro de Envejecimiento y Regeneración (CARE-UC), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda Bernardo O'Higgins 340, P.O. Box 114-D, Santiago, Chile.
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas, Chile.
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12
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Sun K, Jiang J, Wang Y, Sun X, Zhu J, Xu X, Sun J, Shi J. The role of nerve fibers and their neurotransmitters in regulating intervertebral disc degeneration. Ageing Res Rev 2022; 81:101733. [PMID: 36113765 DOI: 10.1016/j.arr.2022.101733] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/11/2022] [Accepted: 09/11/2022] [Indexed: 01/31/2023]
Abstract
Intervertebral disc degeneration (IVDD) has been the major contributor to chronic lower back pain (LBP). Abnormal apoptosis, senescence, and pyroptosis of IVD cells, extracellular matrix (ECM) degradation, and infiltration of immune cells are the major molecular alternations during IVDD. Changes at tissue level frequently occur at advanced IVD tissue. Ectopic ingrowth of nerves within inner annulus fibrosus (AF) and nucleus pulposus (NP) tissue has been considered as the primary cause for LBP. Innervation at IVD tissue mainly included sensory and sympathetic nerves, and many markers for these two types of nerves have been detected since 1940. In fact, in osteoarthritis (OA), beyond pain transmission, the direct regulation of neuropeptides on functions of chondrocytes have attracted researchers' great attention recently. Many physical and pathological similarities between joint and IVD have shed us the light on the neurogenic mechanism involved in IVDD. Here, an overview of the advances in the nervous system within IVD tissue will be performed, with a discussion on in the role of nerve fibers and their neurotransmitters in regulating IVDD. We hope this review can attract more research interest to address neuromodulation and IVDD itself, which will enhance our understanding of the contribution of neuromodulation to the structural changes within IVD tissue and inflammatory responses and will help identify novel therapeutic targets and enable the effective treatment of IVDD disease.
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Affiliation(s)
- Kaiqiang Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China; Department of Orthopedics, Naval Medical Center of PLA, China
| | - Jialin Jiang
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Yuan Wang
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Xiaofei Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Jian Zhu
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Ximing Xu
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Jingchuan Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China.
| | - Jiangang Shi
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China.
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13
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Haghani M, Jafari M, Meftahi GH, Behzadnia MJ, Bahari Z, Salimi-Sabour E, Jangravi Z. Analgesic effects of Terminalia chebula extract are mediated by the suppression of the protein expression of nerve growth factor and nuclear factor-κB in the brain and oxidative markers following neuropathic pain in rats. Mol Biol Rep 2022; 49:10457-10467. [DOI: 10.1007/s11033-022-07870-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 08/15/2022] [Indexed: 11/24/2022]
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14
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Apoptosis and (in) Pain—Potential Clinical Implications. Biomedicines 2022; 10:biomedicines10061255. [PMID: 35740277 PMCID: PMC9219669 DOI: 10.3390/biomedicines10061255] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 05/14/2022] [Accepted: 05/15/2022] [Indexed: 02/06/2023] Open
Abstract
The deregulation of apoptosis is involved in the development of several pathologies, and recent evidence suggests that apoptosis may be involved in chronic pain, namely in neuropathic pain. Neuropathic pain is a chronic pain state caused by primary damage or dysfunction of the nervous system; however, the details of the molecular mechanisms have not yet been fully elucidated. Recently, it was found that nerve endings contain transient receptor potential (TRP) channels that sense and detect signals released by injured tissues and respond to these damage signals. TRP channels are similar to the voltage-gated potassium channels or nucleotide-gated channels that participate in calcium and magnesium homeostasis. TRP channels allowing calcium to penetrate into nerve terminals can activate apoptosis, leading to nerve terminal destruction. Further, some TRPs are activated by acid and reactive oxygen species (ROS). ROS are mainly produced in the mitochondrial respiratory chain, and an increase in ROS production and/or a decrease in the antioxidant network may induce oxidative stress (OS). Depending on the OS levels, they can promote cellular proliferation and/or cell degeneration or death. Previous studies have indicated that proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), play an important role in the peripheral mediation of neuropathic pain. This article aims to perform a review of the involvement of apoptosis in pain, particularly the role of OS and neuroinflammation, and the clinical relevance of this knowledge. The potential discovery of new biomarkers and therapeutic targets can result in the development of more effective and targeted drugs to treat chronic pain, namely neuropathic pain. Highlights: Oxidative stress and neuroinflammation can activate cell signaling pathways that can lead to nerve terminal destruction by apoptosis. These could constitute potential new pain biomarkers and targets for therapy in neuropathic pain.
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15
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The 7-Hydroxyflavone attenuates chemotherapy-induced neuropathic pain by targeting inflammatory pathway. Int Immunopharmacol 2022; 107:108674. [PMID: 35276461 DOI: 10.1016/j.intimp.2022.108674] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 02/19/2022] [Accepted: 02/28/2022] [Indexed: 12/19/2022]
Abstract
Vincristine and paclitaxel are widely used chemotherapeutic drugs for the treatment of brain tumors, breast cancer, leukemia, lymphomas, and malignant solid tumors. Though, these drugs are associated with some severe adverse effects including peripheral neuropathic pain. The anti-nociceptive and anti-inflammatory properties of the 7-Hydroxyflavone (7HF) were evaluated in the mice using thermally- and chemically-induced nociception, naloxone antagonistic test, and carrageenan-induced paw edema models. Initially, the in-vitro cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitory assays were carried out. Peripheral neuropathic pain was induced in the Sprague Dawley (SD) rats by administration of paclitaxel (4 mg/kg) and vincristine (200 µg/kg) on days 1, 3, 5, 7, and 9, respectively. The protective effect of 7HF was assessed against the chemotherapy-induced peripheral neuropathy in the rats. Moreover, the expression of the inflammatory mediators in the spinal cord was investigated through RT-PCR. In addition, a computational study was performed to find the potential therapeutic targets and the binding mechanism of 7HF. The 7HF caused concentration-dependent inhibition of COX-2 and 5-LOX, it attenuated the nociceptive pain, carrageenan-induced paw edema, and the development of mechanical and cold allodynia, and hyperalgesia dose-dependently without causing motor coordination deficit. Likewise, the 7HF decreased the vincristine-induced increased expression of different inflammatory mediators including COX-2, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and nuclear factor-kappa B (NF-κB). The computational study showed the effective interactions of 7HF with the binding sites of NF-κB, COX-2, and 5-LOX, exert its inhibitory activities. These findings reveal that the 7HF has anti-nociceptive, anti-inflammatory, and anti-neuropathic potentials.
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16
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Li Z, Zhou Y, Li Z. NFKB1 Signalling Activation Contributes to TRPV1 Over-expression via Repressing MiR-375 and MiR-455: a Study on Neuropathic Low Back Pain. Folia Biol (Praha) 2022; 68:105-111. [PMID: 36689317 DOI: 10.14712/fb2022068030105] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Transient receptor potential cation channel subfamily V member 1 (TRPV1) has been found over-expressed in low back pain (LBP) patients with neuropathic pain (NP), but the underlying mechanism is still unclear. In the present study, the up-regulation of the TRPV1 protein level in sinuvertebral nerve biopsies from patients with NP was verified by immunoblotting, but the TRPV1 mRNA level was not significantly changed. MiRNAs targeting TRPV1 mRNA were predicted by a bioinformatic tool, and the interactions between the miRNAs and TRPV1 were confirmed by dual luciferase assay. The correlation between NFKB1 signalling and TRPV1 expression was analysed and confirmed by using sNF96.2 cells after lipopolysaccharide stimulation. We found that five out of 18 miRNAs repressed TRPV1 expression, and the levels of miR-375 and miR-455 were negatively correlated with the protein level of TRPV1 in patients with NP. MiR-375 and miR-455 were identified to repress TRPV1 expression via targeting the 3'UTR of TRPV1 mRNA. NFKB1 signalling activation down-regulated the expression of miR-375 and miR-455, and thus up-regulated the TRPV1 protein level. In conclusion, we partially unveiled the mechanism of how TRPV1 is over-expressed in chronic LBP patients with NP and provided two potential candidate miRNAs for NP treatment.
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Affiliation(s)
- Z Li
- Department of Orthopaedics and Plastic Surgery, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan 430050, Hubei Province, China
| | - Y Zhou
- Department of Orthopaedics, Xiantao First People's Hospital Affiliated to Yangtzeu University, Xiantao 430050, Hubei Province, China
| | - Z Li
- Department of Orthopaedics, Taikang Tongji (Wuhan) Hospital, Wuhan 430050, Hubei Province, China
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17
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Herbal Prescription SH003 Alleviates Docetaxel-Induced Neuropathic Pain in C57BL/6 Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:4120334. [PMID: 34422067 PMCID: PMC8373497 DOI: 10.1155/2021/4120334] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 08/04/2021] [Indexed: 12/18/2022]
Abstract
Docetaxel-based therapy has been applied to kill cancers including lung and breast cancers but frequently causes peripheral neuropathy such as mechanical allodynia. Lack of effective drugs for chemotherapy-induced peripheral neuropathy (CIPN) treatment leads us to find novel drugs. Here, we investigated whether and how novel anticancer herbal prescription SH003 alleviates mechanical allodynia in mouse model of docetaxel-induced neuropathic pain. Docetaxel-induced mechanical allodynia was evaluated using von Frey filaments. Nerve damage and degeneration in paw skin of mice were investigated by immunofluorescence staining. Neuroinflammation markers in bloodstream, lumbar (L4-L6) spinal cord, and sciatic nerves were examined by ELISA or western blot analysis. Docetaxel (15.277 mg/kg) was intravenously injected into the tail vein of C57BL/6 mice, and mechanical allodynia was followed up. SH003 (557.569 mg/kg) was orally administered at least 60 min before the mechanical allodynia test, and von Frey test was performed twice. Docetaxel injection induced mechanical allodynia, and SH003 administration restored withdrawal threshold. Meanwhile, degeneration of intraepidermal nerve fibers (IENF) was observed in docetaxel-treated mice, but SH003 treatment suppressed it. Moreover, docetaxel injection increased levels of TNF-α and IL-6 in plasma and expressions of phospho-NF-κB and phospho-STAT3 in both of lumbar spinal cord and sciatic nerves, while SH003 treatment inhibited those changes. Taken together, it is worth noting that TNF-α and IL-6 in plasma and phospho-NF-κB and phospho-STAT3 in spinal cord and sciatic nerves are putative biomarkers of docetaxel-induced peripheral neuropathy (DIPN) in mouse models. In addition, we suggest that SH003 would be beneficial for alleviation of docetaxel-induced neuropathic pain.
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18
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Fan X, Zhou C, Huang C, Zhang J. Asperuloside ameliorates lipopolysaccharide-induced primary human periodontal ligament cell injury by decreasing TLR4 expression and NF-κB activation. Arch Oral Biol 2021; 129:105199. [PMID: 34174589 DOI: 10.1016/j.archoralbio.2021.105199] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 06/02/2021] [Accepted: 06/11/2021] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The mechanism underlying lipopolysaccharide (LPS)-induced primary human periodontal ligament (PDLC) cell injury is unclear. In this study, we focused on the therapeutic function of asperuloside (ASP) on LPS-induced cell injury. DESIGN The study enrolled 41 participants, including 18 healthy controls and 23 CP patients. Western blotting was used to measure the expression of Toll-like receptor 4 (TLR4), phosphorylated p65 (p-p65) and cyclin D1. Enzyme-linked immunosorbent assays (ELISAs) were utilized to evaluate the protein levels of proinflammatory factors interleukin (IL)-1β, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α). MTT assays and 5-ethynyl-2'-deoxyuridine (EdU) staining were performed to investigate cell proliferation. Immunohistochemistry was used to detect TLR4 and p65 expression in gingival tissues. RESULTS AND CONCLUSIONS Asperuloside ameliorates lipopolysaccharide-induced PDLC cell injury by decreasing TLR4 expression and NF-κB activation, while this protective effect of ASP was reversed by TLR4 overexpression.
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Affiliation(s)
- Xiaodan Fan
- Department of Stomatology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China.
| | - Chun Zhou
- Department of Stomatology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
| | - Cheng Huang
- Department of Stomatology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
| | - Junye Zhang
- Department of Stomatology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
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19
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Knockdown of TRIM52 alleviates LPS-induced inflammatory injury in human periodontal ligament cells through the TLR4/NF-κB pathway. Biosci Rep 2021; 40:225951. [PMID: 32735017 PMCID: PMC7418211 DOI: 10.1042/bsr20201223] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/15/2020] [Accepted: 07/17/2020] [Indexed: 12/21/2022] Open
Abstract
Tripartite motif-containing (TRIM) 52 (TRIM52) is a vital regulator of inflammation. However, the function and mechanisms of TRIM52 in lipopolysaccharide (LPS)-induced inflammatory injury of human periodontal ligament cells (HPDLCs) in periodontitis remain undefined. In the present research, gene expression was determined using a quantitative polymerase chain reaction and Western blot. The effect of TRIM52 on LPS-induced inflammatory injury was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and enyzme-linked immunosorbent assay (ELISA). We found that TRIM52 expression was up-regulated in LPS-treated HPDLCs. Knockdown of TRIM52 alleviated LPS-induced proliferative inhibition and apoptosis promotion in HPDLCs, as evidenced by a decrease in cleaved caspase-3 expression and caspase-3 activity. Silencing TRIM52 suppressed LPS-induced inflammatory response of HPDLCs, as indicated by the decrease in interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α) levels, and increase in IL-10 levels. TRIM52 knockdown inhibited LPS-induced activation of TLR4/nuclear factor-κ B (NF-κB) signaling pathway. Taken together, knockdown of TRIM52 mitigated LPS-induced inflammatory injury via the TLR4/NF-κB signaling pathway, providing an effective therapeutic target for periodontitis.
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20
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Ullah R, Ali G, Subhan F, Naveed M, Khan A, Khan J, Halim SA, Ahmad N, Zakiullah, Al-Harrasi A. Attenuation of nociceptive and paclitaxel-induced neuropathic pain by targeting inflammatory, CGRP and substance P signaling using 3-Hydroxyflavone. Neurochem Int 2021; 144:104981. [PMID: 33549629 DOI: 10.1016/j.neuint.2021.104981] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/30/2021] [Accepted: 01/31/2021] [Indexed: 12/13/2022]
Abstract
Paclitaxel is an anti-microtubule agent, most widely used chemotherapeutic agent for the treatment of malignant solid tumors. However, it is associated with some severe side effects including painful neurotoxicity with reporting of neuropathic pain and sensory abnormalities by patients during and after paclitaxel therapy. Peripheral neuropathy was induced by the administration of paclitaxel (4 mg/kg on days 1, 3, 5, and 7). In this study, the anti-nociceptive and anti-inflammatory propensity of 3-Hydroxyflavone (3HF) in mice and the preventive effect of 3HF against paclitaxel-induced peripheral neuropathy in Sprague Dawley (SD) rats were investigated. Moreover, tactile and cold allodynia, thermal and tail immersion hyperalgesia, and effects on motor-coordination were also evaluated. Furthermore, the expression of proinflammatory cytokines i.e. Calcitonin gene-related peptide (CGRP), and Substance P from the spinal cord was examined through RT-PCR. Additionally, a computational structural biology approach was applied to search the potential therapeutic targets and to predict the binding mechanism of 3HF. Treatment of 3HF alleviated the nociceptive pain, paw edema, development of tactile and cold allodynia, and hyperalgesia. Similarly, treatment with 3HF suppressed the paclitaxel-induced increase in mRNA expression of several inflammatory cytokines including tumor necrosis factor -α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), CGRP, and Substance P. However, the daily treatment of 3HF did not affect the motor behaviors of rats. The inhibitory mechanism of 3HF in neuropathic pain is predicted with extensive computational bioinformatics approach which indicates that the 3HF effectively interacts with the binding domains of Nuclear factor-kappa B (NF-κB), CGRP receptor and the receptor of Substance P to exert its inhibitory activities. However, the computationally predicted binding affinities revealed that the potential of binding of the compound with Substance P receptor (Neurokinin 1 receptor) is higher than the other receptors; there NK1R could be the most possible binding target of 3HF. These findings indicate that 3HF has anti-nociceptive, anti-inflammatory, and anti-neuropathic pain effects against paclitaxel-induced neuropathic pain.
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Affiliation(s)
- Rahim Ullah
- Department of Pharmacy, University of Peshawar, Peshawar, 25120, Pakistan.
| | - Gowhar Ali
- Department of Pharmacy, University of Peshawar, Peshawar, 25120, Pakistan.
| | - Fazal Subhan
- Department of Pharmacy, Cecos University of Science and Technology, Peshawar, Pakistan.
| | - Muhammad Naveed
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary.
| | - Ajmal Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Oman.
| | - Jawad Khan
- Department of Pharmacy, University of Peshawar, Peshawar, 25120, Pakistan.
| | - Sobia Ahsan Halim
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Oman.
| | - Nisar Ahmad
- Department of Pharmacy, National University of Pakistan, Pasrur Road, Sialkot, Punjab, Pakistan.
| | - Zakiullah
- Department of Pharmacy, University of Peshawar, Peshawar, 25120, Pakistan.
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Oman.
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21
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Lyu FJ, Cui H, Pan H, MC Cheung K, Cao X, Iatridis JC, Zheng Z. Painful intervertebral disc degeneration and inflammation: from laboratory evidence to clinical interventions. Bone Res 2021; 9:7. [PMID: 33514693 PMCID: PMC7846842 DOI: 10.1038/s41413-020-00125-x] [Citation(s) in RCA: 232] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 10/01/2020] [Accepted: 10/09/2020] [Indexed: 02/06/2023] Open
Abstract
Low back pain (LBP), as a leading cause of disability, is a common musculoskeletal disorder that results in major social and economic burdens. Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration, a significant contributor to LBP. Inflammatory mediators also play an indispensable role in discogenic LBP. The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies. Here, an overview of the advances in inflammation-related pain in disc degeneration is provided, with a discussion on the role of inflammation in IVD degeneration and pain induction. Puncture models, mechanical models, and spontaneous models as the main animal models to study painful disc degeneration are discussed, and the underlying signaling pathways are summarized. Furthermore, potential drug candidates, either under laboratory investigation or undergoing clinical trials, to suppress discogenic LBP by eliminating inflammation are explored. We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.
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Affiliation(s)
- Feng-Juan Lyu
- grid.79703.3a0000 0004 1764 3838School of Medicine, South China University of Technology, Guangzhou, China
| | - Haowen Cui
- grid.12981.330000 0001 2360 039XDepartment of Spine Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hehai Pan
- grid.12981.330000 0001 2360 039XGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China ,grid.12981.330000 0001 2360 039XBreast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kenneth MC Cheung
- grid.194645.b0000000121742757Department of Orthopedics & Traumatology, The University of Hong Kong, Hong Kong, SAR China
| | - Xu Cao
- grid.21107.350000 0001 2171 9311Department of Orthopedic Surgery, Johns Hopkins University, Baltimore, MD USA
| | - James C. Iatridis
- grid.59734.3c0000 0001 0670 2351Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Zhaomin Zheng
- grid.12981.330000 0001 2360 039XDepartment of Spine Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China ,grid.12981.330000 0001 2360 039XPain Research Center, Sun Yat-sen University, Guangzhou, China
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22
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Ni W, Zheng X, Hu L, Kong C, Xu Q. Preventing oxaliplatin-induced neuropathic pain: Using berberine to inhibit the activation of NF-κB and release of pro-inflammatory cytokines in dorsal root ganglions in rats. Exp Ther Med 2020; 21:135. [PMID: 33376517 DOI: 10.3892/etm.2020.9567] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 11/13/2020] [Indexed: 01/18/2023] Open
Abstract
Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a serious, undesirable effect of cancer treatment which is particularly difficult to prevent. Berberine and its derivatives have been reported to display robust antioxidant and analgesic effects in rat models of diabetic neuropathic pain and peripheral nerve injury. However, the analgesic role of berberine on oxaliplatin-induced CIPNP remains unknown. The present study aimed to explore the analgesic effect of berberine on CIPNP. Sprague Dawley rats were used to create the CIPNP animal model by oxaliplatin administration. Behavioral tests were performed by von Frey test, acetone drop test, hot plate test, and motor coordination. The protein expression levels of NF-κB p65 and phosphorylated p65 in dorsal root ganglions (DGRs) were detected by western blot analysis. Finally, TNF-α and IL-6 levels in DRGs were measured using specific ELISA kits. The results from the behavioral analysis demonstrated that a single injection of berberine ameliorated the mechanical and cold allodynia and thermal hyperalgesia in the model rats in a dose-dependent manner. Cumulative administration of berberine prevented the mechanical and cold allodynia and thermal hyperalgesia in the development of CIPNP induced by oxaliplatin. This prophylactic effect of berberine was associated with reduced phosphorylation of p65 and with decreased levels of pro-inflammatory cytokines IL-6 and TNF-α. The present study indicated that berberine may have a role in preventing the development of CIPNP and may serve as a therapeutic compound for the treatment of CIPNP.
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Affiliation(s)
- Wan Ni
- Department of Pain Medicine, The Second Clinical Medical College, Yangtze University, Jingzhou, Hubei 434020, P.R. China
| | - Xiaolan Zheng
- Department of Gastroenterology, The Fifth People's Hospital of Wuhan City, Wuhan, Hubei 430050, P.R. China
| | - Ling Hu
- Department of Anesthesiology, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, Hubei 430064, P.R. China
| | - Chao Kong
- Department of Anesthesiology, The Second Clinical Medical College, Yangtze University, Jingzhou, Hubei 434020, P.R. China
| | - Qingbang Xu
- Department of Pain Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430032, P.R. China
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Role of CGRP in Neuroimmune Interaction via NF-κB Signaling Genes in Glial Cells of Trigeminal Ganglia. Int J Mol Sci 2020; 21:ijms21176005. [PMID: 32825453 PMCID: PMC7503816 DOI: 10.3390/ijms21176005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/13/2020] [Accepted: 08/18/2020] [Indexed: 12/18/2022] Open
Abstract
Activation of the trigeminal system causes the release of various neuropeptides, cytokines, and other immune mediators. Calcitonin gene-related peptide (CGRP), which is a potent algogenic mediator, is expressed in the peripheral sensory neurons of trigeminal ganglion (TG). It affects the inflammatory responses and pain sensitivity by modulating the activity of glial cells. The primary aim of this study was to use array analysis to investigate the effect of CGRP on the glial cells of TG in regulating nuclear factor kappa B (NF-κB) signaling genes and to further check if CGRP in the TG can affect neuron-glia activation in the spinal trigeminal nucleus caudalis. The glial cells of TG were stimulated with CGRP or Minocycline (Min) + CGRP. The effect on various genes involved in NF-κB signaling pathway was analyzed compared to no treatment control condition using a PCR array analysis. CGRP, Min + CGRP or saline was directly injected inside the TG and the effect on gene expression of Egr1, Myd88 and Akt1 and protein expression of cleaved Caspase3 (cleav Casp3) in the TG, and c-Fos and glial fibrillary acidic protein (GFAP) in the spinal section containing trigeminal nucleus caudalis was analyzed. Results showed that CGRP stimulation resulted in the modulation of several genes involved in the interleukin 1 signaling pathway and some genes of the tumor necrosis factor pathway. Minocycline pre-treatment resulted in the modulation of several genes in the glial cells, including anti-inflammatory genes, and neuronal activation markers. A mild increase in cleav Casp3 expression in TG and c-Fos and GFAP in the spinal trigeminal nucleus of CGRP injected animals was observed. These data provide evidence that glial cells can participate in neuroimmune interaction due to CGRP in the TG via NF-κB signaling pathway.
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Advanced Strategies for the Regeneration of Lumbar Disc Annulus Fibrosus. Int J Mol Sci 2020; 21:ijms21144889. [PMID: 32664453 PMCID: PMC7402314 DOI: 10.3390/ijms21144889] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/02/2020] [Accepted: 07/08/2020] [Indexed: 12/15/2022] Open
Abstract
Damage to the annulus fibrosus (AF), the outer region of the intervertebral disc (IVD), results in an undesirable condition that may accelerate IVD degeneration causing low back pain. Despite intense research interest, attempts to regenerate the IVD have failed so far and no effective strategy has translated into a successful clinical outcome. Of particular significance, the failure of strategies to repair the AF has been a major drawback in the regeneration of IVD and nucleus replacement. It is unlikely to secure regenerative mediators (cells, genes, and biomolecules) and artificial nucleus materials after injection with an unsealed AF, as IVD is exposed to significant load and large deformation during daily activities. The AF defects strongly change the mechanical properties of the IVD and activate catabolic routes that are responsible for accelerating IVD degeneration. Therefore, there is a strong need to develop effective therapeutic strategies to prevent or reconstruct AF damage to support operational IVD regenerative strategies and nucleus replacement. By the way of this review, repair and regenerative strategies for AF reconstruction, their current status, challenges ahead, and future outlooks were discussed.
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Yao G, Man YH, Li AR, Guo Y, Dai Y, Wang P, Zhou YF. NO up-regulates migraine-related CGRP via activation of an Akt/GSK-3β/NF-κB signaling cascade in trigeminal ganglion neurons. Aging (Albany NY) 2020; 12:6370-6384. [PMID: 32276265 PMCID: PMC7185139 DOI: 10.18632/aging.103031] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 02/24/2020] [Indexed: 02/05/2023]
Abstract
The release of the neuropeptide CGRP from the trigeminal ganglion neurons (TGNs) plays a central role in migraine. Whereas CGRP can activate NO release from ganglionic glial cells, NO in turn enhances CGRP release. However, it remains unclear how NO promotes CGRP release. Here, we report that the NO donor SNAP triggered CGRP release from cultured primary TGNs. This event was associated with GSK-3β activation and Akt inactivation. Immunofluorescent staining revealed that GSK-3β primarily located in neurons. Furthermore, GSK-3β inhibition resulted in a marked reduction in expression of CGRP as well as other migraine-related factors, including substance P, cholecystokinin, and prostaglandin E2. Last, exposure to SNAP also activated NF-κB, while NF-κB inhibition prevented the induction of CGRP by SNAP. Interestingly, this event was blocked by GSK-3β inhibition, in association with inhibition of NF-κB/p65 expression and nuclear translocation. Together, these findings argue that NO could stimulate TGNs to release of CGRP as well as other migraine-related factors, likely by activating GSK-3β, providing a novel mechanism underlying a potential feed-forward loop between NO and CGRP in migraine. They also raise a possibility that GSK-3β might act to trigger migraine through activation of NF-κB, suggesting a link between neuroinflammation and migraine.
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Affiliation(s)
- Gang Yao
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China.,School of Life Sciences, Northeast Normal University, Changchun, Jilin, China
| | - Yu-Hong Man
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - An-Ran Li
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yu Guo
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yun Dai
- Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Ping Wang
- Department of Otolaryngology - Head and Neck Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yi-Fa Zhou
- School of Life Sciences, Northeast Normal University, Changchun, Jilin, China
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Zhang BY, Zhang YL, Sun Q, Zhang PA, Wang XX, Xu GY, Hu J, Zhang HH. Alpha-lipoic acid downregulates TRPV1 receptor via NF-κB and attenuates neuropathic pain in rats with diabetes. CNS Neurosci Ther 2020; 26:762-772. [PMID: 32175676 PMCID: PMC7298987 DOI: 10.1111/cns.13303] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/17/2020] [Accepted: 03/01/2020] [Indexed: 12/14/2022] Open
Abstract
Aims Painful diabetic neuropathy (PDN) is a refractory complication of diabetes. The study aimed to investigate the role of α‐lipoic acid (ALA) on the regulation of transient receptor potential vanilloid‐1 (TRPV1) in dorsal root ganglion (DRG) neurons of rats with diabetes. Methods Whole‐cell patch‐clamp recordings were employed to measure neuronal excitability in DiI‐labeled DRG neurons of control and streptozotocin (STZ)‐induced diabetic rats. Western blotting and immunofluorescence assays were used to determine the expression and location of NF‐κBp65 and TRPV1. Results STZ‐induced hindpaw pain hypersensitivity and neuronal excitability in L4‐6 DRG neurons were attenuated by intraperitoneal injection with ALA once a day lasted for one week. TRPV1 expression was enhanced in L4‐6 DRGs of diabetic rats compared with age‐matched control rats, which was also suppressed by ALA treatment. In addition, TRPV1 and p65 colocated in the same DRG neurons. The expression of p65 was upregulated in L4‐6 DRGs of diabetic rats. Inhibition of p65 signaling using recombinant lentiviral vectors designated as LV‐NF‐κBp65 siRNA remarkably suppressed TRPV1 expression. Finally, p65 expression was downregulated by ALA treatment. Conclusion Our findings demonstrated that ALA may alleviate neuropathic pain in diabetes by regulating TRPV1 expression via affecting NF‐κB.
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Affiliation(s)
- Bing-Yu Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Yi-Lian Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Qian Sun
- Center for Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Ping-An Zhang
- Center for Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Xi-Xi Wang
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Guang-Yin Xu
- Center for Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Ji Hu
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Hong-Hong Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
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Jiang C, Guo Q, Jin Y, Xu JJ, Sun ZM, Zhu DC, Lin JH, Tian NF, Sun LJ, Zhang XL, Wu YS. Inhibition of EZH2 ameliorates cartilage endplate degeneration and attenuates the progression of intervertebral disc degeneration via demethylation of Sox-9. EBioMedicine 2019; 48:619-629. [PMID: 31631036 PMCID: PMC6838408 DOI: 10.1016/j.ebiom.2019.10.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 09/23/2019] [Accepted: 10/03/2019] [Indexed: 12/11/2022] Open
Abstract
Background Cartilaginous endplate (CEP) degeneration is considered as one of the major causes of intervertebral disc degeneration (IVDD) which causes low back pain. Recent studies have proved that epigenetic alteration is involved in a variety of diseases. This work explored the role of histone methyltransferase enhancer of zeste homologue 2 (EZH2) in CEP degeneration, as well as its underlying epigenetic mechanisms, and confirmed the effect of EZH2 knockdown on delaying IVDD development. Methods Western blotting, immunofluorescence staining, and ChIP assay were applied to demonstrate the molecular mechanism of EZH2 in CEP tissue. The therapeutic potential of EZH2 was investigated using puncture-induced rat models. Findings The EZH2 expression was upregulated in human and rat CEP tissue. It was also found that the overexpression of EZH2 suppressed the expression of Collagen II, aggrecan and Sox-9, and promoted the expression of ADTAMTS5 and MMP13 in rat endplate chondrocytes (EPCs), which could be reversed by EZH2 silencing. The correlation between EZH2 and Sox-9 was further explored, while overexpression of Sox-9 could reverse the effect of EZH2 in rat EPCs. Moreover, inhibition of EZH2 upregulated the level of Sox-9 by demethylating H3K27me3 at Sox-9 promoter sites, revealing the regulatory mechanism of EZH2 on Sox-9. Meanwhile, puncture-induced rat models showed that EZH2 knockdown exerted a protective effect on CEP and disc degeneration. Interpretation This study reveals that EZH2 inhibition is a promising strategy for mitigating the symptoms and progression of IVDD. Funding : This study was funded by the Natural Science Foundation of Zhejiang Province (Y16H060034). Authors declare that the funders had no involvement in the study design, data analysis and interpretation of the results.
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Affiliation(s)
- Chao Jiang
- Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Qiang Guo
- Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Yu Jin
- Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Jia-Jing Xu
- Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Ze-Ming Sun
- Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Ding-Chao Zhu
- Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Jia-Hao Lin
- Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Nai-Feng Tian
- Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China
| | - Liao-Jun Sun
- Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China.
| | - Xiao-Lei Zhang
- Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China.
| | - Yao-Sen Wu
- Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325000, China.
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Does diet play a role in reducing nociception related to inflammation and chronic pain? Nutrition 2019; 66:153-165. [DOI: 10.1016/j.nut.2019.04.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 03/22/2019] [Accepted: 04/01/2019] [Indexed: 02/07/2023]
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Abstract
CGRP has long been suspected as a mediator of arthritis pain, although evidence that CGRP directly mediates human musculoskeletal pain remains circumstantial. This chapter describes in depth the evidence surrounding CGRP's association with pain in musculoskeletal disorders and also summarises evidence for CGRP being a direct cause of pain in other conditions. CGRP-immunoreactive nerves are present in musculoskeletal tissues, and CGRP expression is altered in musculoskeletal pain. CGRP modulates musculoskeletal pain through actions both in the periphery and central nervous system. Human observational studies, research on animal arthritis models and the few reported randomised controlled trials in humans of treatments that target CGRP provide the context of CGRP as a possible pain biomarker or mediator in conditions other than migraine.
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Affiliation(s)
- David A Walsh
- Pain Centre Versus Arthritis, NIHR Nottingham Biomedical Research Centre and Division of ROD, University of Nottingham, Nottingham, UK.
- Rheumatology, Sherwood Forest Hospitals NHS Foundation Trust, Nottinghamshire, UK.
| | - Daniel F McWilliams
- Pain Centre Versus Arthritis, NIHR Nottingham Biomedical Research Centre and Division of ROD, University of Nottingham, Nottingham, UK
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