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Espinoza N, Papadopoulos V. Role of Mitochondrial Dysfunction in Neuropathy. Int J Mol Sci 2025; 26:3195. [PMID: 40243998 PMCID: PMC11989173 DOI: 10.3390/ijms26073195] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/18/2025] Open
Abstract
Diabetes mellitus is characterized by a state of hyperglycemia, which can lead to severe complications if left untreated or poorly managed. Diabetic peripheral neuropathy (DPN) is one common complication. This condition is characterized by damage to the nerves that supply the legs and feet as well as problems with blood vessels, the heart, or urinary tract. To alleviate pain for patients, clinicians resort to long-term treatment regimens of nerve pain medications, which are usually either anticonvulsants or antidepressants. However, little is understood about the underlying mechanisms of DPN. Many pathogenic pathways have been proposed, one of which is mitochondrial dysfunction. Mitochondrial dysfunction includes a range of possible deficiencies given the number of functions controlled by or located in mitochondria, including their core function of bioenergetics. This review focuses on mitochondrial bioenergetics, including respiration/ATP synthesis and reactive oxygen species (ROS) production, as well as calcium homeostasis and apoptosis, and their potential as targets for the effective treatment of diabetic peripheral neuropathy.
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Affiliation(s)
| | - Vassilios Papadopoulos
- Department of Pharmacology and Pharmaceutical Sciences, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, Los Angeles, CA 90089, USA
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Fu J, Ni C, Ni H, Xu L, He Q, Pan H, Huang D, Sun Y, Luo G, Liu M, Yao M. Spinal Nrf2 translocation may inhibit neuronal NF-κB activation and alleviate allodynia in a rat model of bone cancer pain. J Neurochem 2021; 158:1110-1130. [PMID: 34254317 PMCID: PMC9292887 DOI: 10.1111/jnc.15468] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/23/2021] [Accepted: 07/02/2021] [Indexed: 01/11/2023]
Abstract
Bone cancer pain (BCP) is a clinical pathology that urgently needs to be solved, but research on the mechanism of BCP has so far achieved limited success. Nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) has been shown to be involved in pain, but its involvement in BCP and the specific mechanism have yet to be examined. This study aimed to test the hypothesis that BCP induces the transfer of Nrf2 from the cytoplasm to the nucleus and further promotes nuclear transcription to activate heme oxygenase-1 (HO-1) and inhibit the activation of nuclear factor-kappa B (NF-κB) signalling, ultimately regulating the neuroinflammatory response. Von-Frey was used for behavioural analysis in rats with BCP, whereas western blotting, real-time quantitative PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect molecular expression changes, and immunofluorescence was used to detect cellular localization. We demonstrated that BCP induced increased Nrf2 nuclear protein expression with decreased cytoplasmic protein expression in the spinal cord. Further increases in Nrf2 nuclear protein expression can alleviate hyperalgesia and activate HO-1 to inhibit the expression of NF-κB nuclear protein and inflammatory factors. Strikingly, intrathecal administration of the corresponding siRNA reversed the above effects. In addition, the results of double immune labelling revealed that Nrf2 and NF-κB were coexpressed in spinal cord neurons of rats with BCP. In summary, these findings suggest that the entry of Nrf2 into the nucleus promotes the expression of HO-1, inhibiting activation of the NF-κB signalling pathway, reducing neuroinflammation and ultimately exerting an anti-nociceptive effect.
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Affiliation(s)
- Jie Fu
- Department of Anesthesiology and Pain Research CenterThe First Hospital of Jiaxing or The Affiliated Hospital of Jiaxing UniversityJiaxingChina
| | - Chaobo Ni
- Department of Anesthesiology and Pain Research CenterThe First Hospital of Jiaxing or The Affiliated Hospital of Jiaxing UniversityJiaxingChina
| | - Hua‐Dong Ni
- Department of Anesthesiology and Pain Research CenterThe First Hospital of Jiaxing or The Affiliated Hospital of Jiaxing UniversityJiaxingChina
| | - Long‐Sheng Xu
- Department of Anesthesiology and Pain Research CenterThe First Hospital of Jiaxing or The Affiliated Hospital of Jiaxing UniversityJiaxingChina
| | - Qiu‐Li He
- Department of Anesthesiology and Pain Research CenterThe First Hospital of Jiaxing or The Affiliated Hospital of Jiaxing UniversityJiaxingChina
| | - Huan Pan
- Department of Anesthesiology and Pain Research CenterThe First Hospital of Jiaxing or The Affiliated Hospital of Jiaxing UniversityJiaxingChina
| | - Dong‐Dong Huang
- Department of Anesthesiology and Pain Research CenterThe First Hospital of Jiaxing or The Affiliated Hospital of Jiaxing UniversityJiaxingChina
| | - Yan‐Bao Sun
- Department of Anesthesiology and Pain Research CenterThe First Hospital of Jiaxing or The Affiliated Hospital of Jiaxing UniversityJiaxingChina
| | - Ge Luo
- Department of Anesthesiology and Pain Research CenterThe First Hospital of Jiaxing or The Affiliated Hospital of Jiaxing UniversityJiaxingChina
| | - Ming‐Juan Liu
- Department of Anesthesiology and Pain Research CenterThe First Hospital of Jiaxing or The Affiliated Hospital of Jiaxing UniversityJiaxingChina
| | - Ming Yao
- Department of Anesthesiology and Pain Research CenterThe First Hospital of Jiaxing or The Affiliated Hospital of Jiaxing UniversityJiaxingChina
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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: 35] [Impact Index Per Article: 7.0] [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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SMN deficiency causes pain hypersensitivity in a mild SMA mouse model through enhancing excitability of nociceptive dorsal root ganglion neurons. Sci Rep 2019; 9:6493. [PMID: 31019235 PMCID: PMC6482187 DOI: 10.1038/s41598-019-43053-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 12/12/2018] [Indexed: 12/14/2022] Open
Abstract
Spinal muscular atrophy (SMA) is a devastating motor neuron degeneration disease caused by a deficiency of the SMN protein. Majority of patients also suffer from chronic pain. However, the pathogenesis of pain in the context of SMA has never been explored. In this study, using various pain tests, we found that a mild SMA mouse model presents with multiple forms of pain hypersensitivity. Patch-clamp recording showed that nociceptive neurons in SMA mouse dorsal root ganglia (DRGs) are hyperexcitable and their sodium current densities are markedly increased. Using quantitative RT-PCR, western blotting and immunofluorescence, we observed enhanced expression of two main voltage-gated sodium channels Nav1.7 and Nav1.8 in SMA mouse DRGs, which is at least in part due to increase in both expression and phosphorylation of NF-κB p50/p65 heterodimer. Moreover, we revealed that plasma norepinephrine levels are elevated in SMA mice, which contributes to mechanical hypersensitivity via the β2-adrenergic receptor. Finally, we uncovered that β2-adrenergic signaling positively modulates expression as well as phosphorylation of p50 and p65 in SMA mouse DRGs. Therefore, our data demonstrate that SMA mice, similar to humans, also develop pain hypersensitivity, and highlight a peripheral signaling cascade that elicits the mechanical sensitization in the mouse model, suggesting potential targets for therapeutic intervention.
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Lutz BM, Wu S, Gu X, Atianjoh FE, Li Z, Fox BM, Pollock DM, Tao YX. Endothelin type A receptors mediate pain in a mouse model of sickle cell disease. Haematologica 2018; 103:1124-1135. [PMID: 29545351 PMCID: PMC6029538 DOI: 10.3324/haematol.2017.187013] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 03/13/2018] [Indexed: 12/12/2022] Open
Abstract
Sickle cell disease is associated with acute painful episodes and chronic intractable pain. Endothelin-1, a known pain inducer, is elevated in the blood plasma of both sickle cell patients and mouse models of sickle cell disease. We show here that the levels of endothelin-1 and its endothelin type A receptor are increased in the dorsal root ganglia of a mouse model of sickle cell disease. Pharmacologic inhibition or neuron-specific knockdown of endothelin type A receptors in primary sensory neurons of dorsal root ganglia alleviated basal and post-hypoxia evoked pain hypersensitivities in sickle cell mice. Mechanistically, endothelin type A receptors contribute to sickle cell disease-associated pain likely through the activation of NF-κB-induced Nav1.8 channel upregulation in primary sensory neurons of sickle cell mice. Our findings suggest that endothelin type A receptor is a potential target for the management of sickle cell disease-associated pain, although this expectation needs to be further verified in clinical settings.
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Affiliation(s)
- Brianna Marie Lutz
- Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.,Rutgers Graduate School of Biomedical Sciences, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Shaogen Wu
- Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA
| | - Xiyao Gu
- Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA
| | - Fidelis E Atianjoh
- Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.,Intensive Care Unit, MedStar Southern Maryland Hospital Center, Clinton, MD, USA
| | - Zhen Li
- Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA
| | - Brandon M Fox
- Cardio-Renal Physiology and Medicine, Department of Medicine, University of Alabama at Birmingham, AL, USA
| | - David M Pollock
- Cardio-Renal Physiology and Medicine, Department of Medicine, University of Alabama at Birmingham, AL, USA
| | - Yuan-Xiang Tao
- Rutgers Graduate School of Biomedical Sciences, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA.,Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA
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Wang Y, Ni H, Li H, Deng H, Xu LS, Xu S, Zhen Y, Shen H, Pan H, Yao M. Nuclear factor kappa B regulated monocyte chemoattractant protein-1/chemokine CC motif receptor-2 expressing in spinal cord contributes to the maintenance of cancer-induced bone pain in rats. Mol Pain 2018; 14:1744806918788681. [PMID: 29956585 PMCID: PMC6055241 DOI: 10.1177/1744806918788681] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 05/20/2018] [Accepted: 06/08/2018] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Chemokine, monocyte chemoattractant protein-1 (MCP-1), is a potential factor to cause cancer-induced bone pain (CIBP). NF-κB signaling is very important in mediating the expression of chemokines and may have a role in CIBP. However, the mechanism is still unclear. This study investigates the role of NF-κB in CIBP by regulating MCP-1/chemokine CC motif receptor-2 (CCR2) signaling pathway. METHODS A rat CIBP model was established by injecting Walker-256 cells into the tibia medullary cavity. Nine days later, animals were intrathecally administrated with MCP-1 neutralizing antibody, CCR2 antagonist (RS504393), or NF-кB inhibitor (BAY11-7081). Mechanical paw withdrawal threshold was used to assess pain behavior and sciatic functional index, and radiographic images were adopted to evaluate the damage of nerve and bone. The spinal cords were harvested for Western blot and quantitative reverse transcription polymerase chain reaction. The distribution of MCP-1, CCR2, and NF-кB was detected by double immunofluorescent staining. RESULTS CIBP caused remarkable bone destruction, injury of sciatic and femoral nerve, and persistent (>15 days) mechanical allodynia in rats. Tumor cell inoculation upregulate MCP-1 and NF-кB in activated neurons as well as CCR2 in neurons and microglia of the spinal cord. MCP-1 antibody, RS504393, and BAY11-7081 partially reversed CIBP-induced mechanical allodynia, and CIBP regulated the expression levels of pro-inflammatory cytokines, tumor necrosis factor-α and interferon-γ, and anti-inflammatory cytokine, interleukin 4, and BAY11-7081 lowered CIBP-induced MCP-1 and CCR2 expressions in a dose-dependent manner. CONCLUSION In conclusion, NF-кB signaling pathway regulates the expressions of MCP-1/CCR2-induced inflammatory factors in the spinal cord of CIBP rats.
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Affiliation(s)
- Yungong Wang
- Department of Anesthesiology and Pain Medicine, First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Huadong Ni
- Department of Anesthesiology and Pain Medicine, First Affiliated Hospital of Jiaxing University, Jiaxing, China
- The Second Clinical Medical College, Zhejiang Chinese Medicine University, Hangzhou, China
| | - Hongbo Li
- Department of Anesthesiology and Pain Medicine, First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Houshen Deng
- Department of Anesthesiology and Pain Medicine, First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Long S Xu
- Department of Anesthesiology and Pain Medicine, First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Shijie Xu
- Department of Anesthesiology and Pain Medicine, First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Ying Zhen
- Department of Anesthesiology and Pain Medicine, First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Hui Shen
- Department of Anesthesiology and Pain Medicine, First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Huan Pan
- Department of Anesthesiology and Pain Medicine, First Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Ming Yao
- Department of Anesthesiology and Pain Medicine, First Affiliated Hospital of Jiaxing University, Jiaxing, China
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Gonçalves NP, Vægter CB, Andersen H, Østergaard L, Calcutt NA, Jensen TS. Schwann cell interactions with axons and microvessels in diabetic neuropathy. Nat Rev Neurol 2017; 13:135-147. [PMID: 28134254 DOI: 10.1038/nrneurol.2016.201] [Citation(s) in RCA: 197] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annually. The most common complication of diabetes is peripheral neuropathy, which has a prevalence as high as 50% and is characterized by damage to neurons, Schwann cells and blood vessels within the nerve. The pathogenic mechanisms of diabetic neuropathy remain poorly understood, impeding the development of targeted therapies to treat nerve degeneration and its most disruptive consequences of sensory loss and neuropathic pain. Involvement of Schwann cells has long been proposed, and new research techniques are beginning to unravel a complex interplay between these cells, axons and microvessels that is compromised during the development of diabetic neuropathy. In this Review, we discuss the evolving concept of Schwannopathy as an integral factor in the pathogenesis of diabetic neuropathy, and how disruption of the interactions between Schwann cells, axons and microvessels contribute to the disease.
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Affiliation(s)
- Nádia P Gonçalves
- The International Diabetic Neuropathy Consortium (IDNC), Aarhus University, Nørrebrogade, 8000 Aarhus C, Denmark
| | - Christian B Vægter
- Danish Research Institute of Translational Neuroscience DANDRITE, Nordic-EMBL Partnership, Department of Biomedicine, Aarhus University, Ole Worms Alle 3, 8000 Aarhus C, Denmark
| | - Henning Andersen
- Department of Neurology, Danish Pain Research Center and IDNC, Aarhus University Hospital, Nørrebrogade, 8000 Aarhus C, Denmark
| | - Leif Østergaard
- Department of Neuroradiology and Center for Functionally Integrative Neuroscience, Aarhus University Hospital, Nørrebrogade, 8000 Aarhus C, Denmark
| | - Nigel A Calcutt
- Department of Pathology, University of California San Diego, Gilman Drive, La Jolla, California 92093, USA
| | - Troels S Jensen
- Department of Neurology, Danish Pain Research Center and IDNC, Aarhus University Hospital, Nørrebrogade, 8000 Aarhus C, Denmark
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Yuan B, Tang WH, Lu LJ, Zhou Y, Zhu HY, Zhou YL, Zhang HH, Hu CY, Xu GY. TLR4 upregulates CBS expression through NF-κB activation in a rat model of irritable bowel syndrome with chronic visceral hypersensitivity. World J Gastroenterol 2015; 21:8615-8628. [PMID: 26229403 PMCID: PMC4515842 DOI: 10.3748/wjg.v21.i28.8615] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 04/03/2015] [Accepted: 05/21/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the roles of toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB on cystathionine β synthetase (CBS) expression and visceral hypersensitivity in rats.
METHODS: This study used 1-7-wk-old male Sprague-Dawley rats. Western blot analysis was employed to measure the expression of TLR4, NF-κB and the endogenous hydrogen sulfide-producing enzyme CBS in colon dorsal root ganglia (DRG) from control and “irritable bowel syndrome” rats induced by neonatal colonic inflammation (NCI). Colon-specific DRG neurons were labeled with Dil and acutely dissociated to measure excitability with patch-clamp techniques. Immunofluorescence was employed to determine the co-expression of TLR4, NF-κB and CBS in DiI-labeled DRG neurons.
RESULTS: NCI significantly upregulated the expression of TLR4 in colon-related DRGs (0.34 ± 0.12 vs 0.72 ± 0.02 for the control and NCI groups, respectively, P < 0.05). Intrathecal administration of the TLR4-selective inhibitor CLI-095 significantly enhanced the colorectal distention threshold of NCI rats. CLI-095 treatment also markedly reversed the hyperexcitability of colon-specific DRG neurons and reduced the expression of CBS (1.7 ± 0.1 vs 1.1 ± 0.04, P < 0.05) and of the NF-κB subunit p65 (0.8 ± 0.1 vs 0.5 ± 0.1, P < 0.05). Furthermore, the NF-κB-selective inhibitor pyrrolidine dithiocarbamate (PDTC) significantly reduced the upregulation of CBS (1.0 ± 0.1 vs 0.6 ± 0.1, P < 0.05) and attenuated visceral hypersensitivity in the NCI rats. In vitro, incubation of cultured DRG neurons with the TLR4 agonist lipopolysaccharide significantly enhanced the expression of p65 (control vs 8 h: 0.9 ± 0.1 vs 1.3 ± 0.1; control vs 12 h: 0.9 ± 0.1 vs 1.3 ± 0.1, P < 0.05; control vs 24 h: 0.9 ± 0.1 vs 1.6 ± 0.1, P < 0.01) and CBS (control vs 12 h: 1.0 ± 0.1 vs 2.2 ± 0.4; control vs 24 h: 1.0 ± 0.1 vs 2.6 ± 0.1, P < 0.05), whereas the inhibition of p65 via pre-incubation with PDTC significantly reversed the upregulation of CBS expression (1.2 ± 0.1 vs 0.6 ± 0.0, P < 0.01).
CONCLUSION: Our results suggest that the activation of TLR4 by NCI upregulates CBS expression, which is mediated by the NF-κB signaling pathway, thus contributing to visceral hypersensitivity.
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Lei T, Jing D, Xie K, Jiang M, Li F, Cai J, Wu X, Tang C, Xu Q, Liu J, Guo W, Shen G, Luo E. Therapeutic effects of 15 Hz pulsed electromagnetic field on diabetic peripheral neuropathy in streptozotocin-treated rats. PLoS One 2013; 8:e61414. [PMID: 23637830 PMCID: PMC3630223 DOI: 10.1371/journal.pone.0061414] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 03/08/2013] [Indexed: 11/18/2022] Open
Abstract
Although numerous clinical studies have reported that pulsed electromagnetic fields (PEMF) have a neuroprotective role in patients with diabetic peripheral neuropathy (DPN), the application of PEMF for clinic is still controversial. The present study was designed to investigate whether PEMF has therapeutic potential in relieving peripheral neuropathic symptoms in streptozotocin (STZ)-induced diabetic rats. Adult male Sprague-Dawley rats were randomly divided into three weight-matched groups (eight in each group): the non-diabetic control group (Control), diabetes mellitus with 15 Hz PEMF exposure group (DM+PEMF) which were subjected to daily 8-h PEMF exposure for 7 weeks and diabetes mellitus with sham PEMF exposure group (DM). Signs and symptoms of DPN in STZ-treated rats were investigated by using behavioral assays. Meanwhile, ultrastructural examination and immunohistochemical study for vascular endothelial growth factor (VEGF) of sciatic nerve were also performed. During a 7-week experimental observation, we found that PEMF stimulation did not alter hyperglycemia and weight loss in STZ-treated rats with DPN. However, PEMF stimulation attenuated the development of the abnormalities observed in STZ-treated rats with DPN, which were demonstrated by increased hind paw withdrawal threshold to mechanical and thermal stimuli, slighter demyelination and axon enlargement and less VEGF immunostaining of sciatic nerve compared to those of the DM group. The current study demonstrates that treatment with PEMF might prevent the development of abnormalities observed in animal models for DPN. It is suggested that PEMF might have direct corrective effects on injured nerves and would be a potentially promising non-invasive therapeutic tool for the treatment of DPN.
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Affiliation(s)
- Tao Lei
- School of Biomedical Engineering, Fourth Military Medical University, Xi'an, China
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Li L, Xie R, Hu S, Wang Y, Yu T, Xiao Y, Jiang X, Gu J, Hu CY, Xu GY. Upregulation of cystathionine beta-synthetase expression by nuclear factor-kappa B activation contributes to visceral hypersensitivity in adult rats with neonatal maternal deprivation. Mol Pain 2012; 8:89. [PMID: 23249427 PMCID: PMC3545973 DOI: 10.1186/1744-8069-8-89] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 12/12/2012] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is characterized by chronic visceral hyperalgesia (CVH) that manifested with persistent or recurrent abdominal pain and altered bowel movement. However, the pathogenesis of the CVH remains unknown. The aim of this study was to investigate roles of endogenous hydrogen sulfide (H2S) producing enzyme cystathionine beta-synthetase (CBS) and p65 nuclear factor-kappa B subunits in CVH. RESULTS CVH was induced by neonatal maternal deprivation (NMD) in male rats on postnatal days 2-15 and behavioral experiments were conducted at the age of 7-15 weeks. NMD significantly increased expression of CBS in colon-innervating DRGs from the 7th to 12th week. This change in CBS express is well correlated with the time course of enhanced visceromoter responses to colorectal distention (CRD), an indicator of visceral pain. Administration of AOAA, an inhibitor of CBS, produced a dose-dependent antinociceptive effect on NMD rats while it had no effect on age-matched healthy control rats. AOAA also reversed the enhanced neuronal excitability seen in colon-innervating DRGs. Application of NaHS, a donor of H2S, increased excitability of colon-innervating DRG neurons acutely dissociated from healthy control rats. Intrathecal injection of NaHS produced an acute visceral hyperalgesia. In addition, the content of p65 in nucleus was remarkably higher in NMD rats than that in age-matched controls. Intrathecal administration of PDTC, an inhibitor of p65, markedly reduced expression of CBS and attenuated nociceptive responses to CRD. CONCLUSION The present results suggested that upregulation of CBS expression, which is mediated by activation of p65, contributes to NMD-induced CVH. This pathway might be a potential target for relieving CVH in patients with IBS.
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Affiliation(s)
- Lin Li
- Department of Gastroenterology, the Second Affiliated Hospital, Soochow University, Suzhou, 215123, P. R. China
- Institute of Neuroscience, Key Laboratory of Pain Basic Research and Clinic Therapy, Department of Neurobiology, Soochow University, Suzhou, 215123, P R China
| | - Ruihua Xie
- Department of Gastroenterology, the Second Affiliated Hospital, Soochow University, Suzhou, 215123, P. R. China
- Institute of Neuroscience, Key Laboratory of Pain Basic Research and Clinic Therapy, Department of Neurobiology, Soochow University, Suzhou, 215123, P R China
| | - Shufen Hu
- Institute of Neuroscience, Key Laboratory of Pain Basic Research and Clinic Therapy, Department of Neurobiology, Soochow University, Suzhou, 215123, P R China
| | - Yongmeng Wang
- Institute of Neuroscience, Key Laboratory of Pain Basic Research and Clinic Therapy, Department of Neurobiology, Soochow University, Suzhou, 215123, P R China
| | - Tianzhu Yu
- Institute of Neuroscience, Key Laboratory of Pain Basic Research and Clinic Therapy, Department of Neurobiology, Soochow University, Suzhou, 215123, P R China
| | - Ying Xiao
- Institute of Neuroscience, Key Laboratory of Pain Basic Research and Clinic Therapy, Department of Neurobiology, Soochow University, Suzhou, 215123, P R China
| | - Xinghong Jiang
- Institute of Neuroscience, Key Laboratory of Pain Basic Research and Clinic Therapy, Department of Neurobiology, Soochow University, Suzhou, 215123, P R China
| | - Jianguo Gu
- Department of Anesthesiology and the Graduate Program in Neuroscience, The University of Cincinnati College of Medicine, PO Box 670531, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA
| | - Chuang-Ying Hu
- Department of Gastroenterology, the Second Affiliated Hospital, Soochow University, Suzhou, 215123, P. R. China
| | - Guang-Yin Xu
- Department of Gastroenterology, the Second Affiliated Hospital, Soochow University, Suzhou, 215123, P. R. China
- Institute of Neuroscience, Key Laboratory of Pain Basic Research and Clinic Therapy, Department of Neurobiology, Soochow University, Suzhou, 215123, P R China
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Saleh A, Roy Chowdhury SK, Smith DR, Balakrishnan S, Tessler L, Martens C, Morrow D, Schartner E, Frizzi KE, Calcutt NA, Fernyhough P. Ciliary neurotrophic factor activates NF-κB to enhance mitochondrial bioenergetics and prevent neuropathy in sensory neurons of streptozotocin-induced diabetic rodents. Neuropharmacology 2012; 65:65-73. [PMID: 23022047 DOI: 10.1016/j.neuropharm.2012.09.015] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 09/12/2012] [Accepted: 09/14/2012] [Indexed: 01/26/2023]
Abstract
Diabetes causes mitochondrial dysfunction in sensory neurons that may contribute to peripheral neuropathy. Ciliary neurotrophic factor (CNTF) promotes sensory neuron survival and axon regeneration and prevents axonal dwindling, nerve conduction deficits and thermal hypoalgesia in diabetic rats. In this study, we tested the hypothesis that CNTF protects sensory neuron function during diabetes through normalization of impaired mitochondrial bioenergetics. In addition, we investigated whether the NF-κB signal transduction pathway was mobilized by CNTF. Neurite outgrowth of sensory neurons derived from streptozotocin (STZ)-induced diabetic rats was reduced compared to neurons from control rats and exposure to CNTF for 24 h enhanced neurite outgrowth. CNTF also activated NF-κB, as assessed by Western blotting for the NF-κB p50 subunit and reporter assays for NF-κB promoter activity. Conversely, blockade of NF-κB signaling using SN50 peptide inhibited CNTF-mediated neurite outgrowth. Studies in mice with STZ-induced diabetes demonstrated that systemic therapy with CNTF prevented functional indices of peripheral neuropathy along with deficiencies in dorsal root ganglion (DRG) NF-κB p50 expression and DNA binding activity. DRG neurons derived from STZ-diabetic mice also exhibited deficiencies in maximal oxygen consumption rate and associated spare respiratory capacity that were corrected by exposure to CNTF for 24 h in an NF-κB-dependent manner. We propose that the ability of CNTF to enhance axon regeneration and protect peripheral nerve from structural and functional indices of diabetic peripheral neuropathy is associated with targeting of mitochondrial function, in part via NF-κB activation, and improvement of cellular bioenergetics.
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Affiliation(s)
- Ali Saleh
- Division of Neurodegenerative Disorders, St Boniface Hospital Research Centre, Winnipeg, MB, Canada
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Negative Regulators of Schwann Cell Differentiation—Novel Targets for Peripheral Nerve Therapies? J Clin Immunol 2012; 33 Suppl 1:S18-26. [DOI: 10.1007/s10875-012-9786-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 08/27/2012] [Indexed: 01/01/2023]
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