scholarly journals Amorfrutins Relieve Neuropathic Pain through the PPARγ/CCL2 Axis in CCI Rats

PPAR Research ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Pengfei Gao ◽  
Jiayu Wang ◽  
Zhen Su ◽  
Fayin Li ◽  
Xianlong Zhang
Keyword(s):  
Public Health ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Proinflammatory Cytokines ◽  
Public Health Problem ◽  
Elisa Assay ◽  
Concurrent Administration ◽  
Nociceptive Responses ◽  
New Treatment ◽  
Antagonist Gw9662

Neuropathic pain is a public health problem. Although many pharmaceuticals are used to treat neuropathic pain, effective and safe drugs do not yet exist. In this study, we tested nociceptive responses in CCI rats, and ELISA assay was performed to examine the expression of proinflammatory cytokines. We found that amorfrutins significantly reduce the pain behaviors in CCI rats and suppress the expression of proinflammatory cytokines (TNFα, IL-6, and IL-1β) and chemokines (CCL2/CCR2) in the spinal cord. However, concurrent administration of a PPARγ antagonist, GW9662, reversed the antihyperalgesic effect induced by amorfrutins. The results indicate that amorfrutins inhibit the inflammation and chemokine expression by activating PPARγ, thus relieving neuropathic pain in CCI rats. Therefore, PPARγ-CCL2/CCR2 pathway might represent a new treatment option for neuropathic pain.

scholarly journals Intrathecal polymer-based interleukin-10 gene delivery for neuropathic pain

2006 ◽  
Vol 2 (4) ◽  
pp. 293-308 ◽  
Author(s):  
Erin D. Milligan ◽  
Ryan G. Soderquist ◽  
Stephanie M. Malone ◽  
John H. Mahoney ◽  
Travis S. Hughes ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Neuropathic Pain ◽  
Gene Delivery ◽  
Proinflammatory Cytokines ◽  
Interleukin 1 ◽  
Clinical Problem ◽  
Interleukin 10 ◽  
Synthetic Polymers ◽  
High Doses

AbstractResearch on communication between glia and neurons has increased in the past decade. The onset of neuropathic pain, a major clinical problem that is not resolved by available therapeutics, involves activation of spinal cord glia through the release of proinflammatory cytokines in acute animal models of neuropathic pain. Here, we demonstrate for the first time that the spinal action of the proinflammatory cytokine, interleukin 1 (IL-1) is involved in maintaining persistent (2 months) allodynia induced by chronic-constriction injury (CCI). The anti-inflammatory cytokine IL-10 can suppress proinflammatory cytokines and spinal cord glial amplification of pain. Given that IL-1 is a key mediator of neuropathic pain, developing a clinically viable means of long-term delivery of IL-10 to the spinal cord is desirable. High doses of intrathecal IL-10-gene therapy using naked plasmid DNA (free pDNA-IL-10) is effective, but the dose required limits its potential clinical utility. Here we show that intrathecal gene therapy for neuropathic pain is improved sufficiently using two, distinct synthetic polymers, poly(lactic-co-glycolic) and polyethylenimine, that substantially lower doses of pDNA-IL-10 are effective. In conclusion, synthetic polymers used as i.t. gene-delivery systems are well-tolerated and improve the long-duration efficacy of pDNA-IL-10 gene therapy.

Activation of TRPM8 cold receptor triggers allodynia-like behavior in spinally injured rats

2013 ◽  
Vol 4 (1) ◽  
pp. 33-37 ◽  
Author(s):  
Tianle Gao ◽  
Jingxia Hao ◽  
Zsuzsanna Wiesenfeld-Hallin ◽  
Xiao-Jun Xu
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Neuropathic Pain ◽  
Topical Application ◽  
Mechanical Allodynia ◽  
Trp Channels ◽  
Cold Stimulation ◽  
Cold Allodynia ◽  
Nociceptive Responses ◽  
Cord Injury

AbstractAimsPain in response to innocuous cold stimulation (cold allodynia) is a common symptom in patients with neuropathic pain. Cold allodynia is difficult to treat and its mechanisms are poorly understood. Several transient receptor potential (TRP) channels have been shown to be the molecular sensors for cold stimulation in a temperature-dependent manner, but the contribution of various TRP channels in mediating cold allodynia in neuropathic pain is unclear. We have previously shown that spinally injured rats developed neuropathic pain-like behaviors, including marked cold allodynia. We now assessed the role of TRP channels in mediating cold allodynia in rats after ischemic spinal cord injury.Methods Methods: Spinal cord injury was produced using a photochemical method. The mechanical allodynia was assessed by examining the vocalization thresholds to graded mechanical touch/pressure applied with von Frey hairs. Temperature controlled cold stimulation was produced by a Peltier thermode (active surface 25 mm × 50 mm) connected to a MSA Thermal Simulator (Somedic, Sweden) with baseline temperature of 32 °C. The rate of temperature change was 0.5 °C/s. The temperature required to elicit cold allodynia was examined. The responses of the rats to topical application of icilin or menthol, agonists of transient receptor potential melastain 8 (TRPM8), were also studied.ResultsNormal rats did not exhibit nociceptive responses to cooling stimulation to the trunk and back area (minimal temperature +6°C) and they also did not react aversively to topical application of icilin or menthol. After spinal cord injury, the rats developed mechanical allodynia at the trunk and back just rostral to the dermatome of the injured spinal segments. In the same area, rats exhibited significant nociceptive responses to cooling from day 1 after injury, lasting for at least 70 days which is the longest time of observation. For the first two weeks after injury, the majority of spinally injured rats had a nociceptive response to cooling above 17°C. At day 70, about 50% of rats responded to cooling above 17 °C. Topical application of 400 μM icilin or 4mM menthol also elicited pain-like responses in spinally injured rats and these two cold mimetics also significantly exacerbated existing mechanical allodynia.ConclusionOur results showed that activation of the TRPM8 channel by menthol or icilin triggers allodynia in spinally injured rats and increases, rather than decreases, mechanical allodynia. TRPM8 channels which respond to cooling above 17 ° C may be involved at least in part in mediating cold allodynia in the rat model of neuropathic spinal cord injury pain.ImplicationsThe work introduced a method of quantitative testings of responses of rats to cold stimulation and may contribute to the understanding of mechanisms of cold allodynia after injury to the nervous system.

scholarly journals STING/NF-κB/IL-6-mediated inflammation in microglia contributes to spared nerve injury (SNI)-induced neuropathic pain

2021 ◽  
Author(s):  
Jia Sun ◽  
Ya-Qun Zhou ◽  
Bing-Yang Xu ◽  
Jia-Yan Li ◽  
Long-Qing Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Signaling Pathway ◽  
Dorsal Horn ◽  
Proinflammatory Cytokines ◽  
Spinal Cord Dorsal Horn ◽  
Spared Nerve Injury ◽  
Downstream Effectors ◽  
Spinal Cord Dorsal ◽  
Underlying Mechanisms

Abstract Background Innate immune response acts as a first line of host defense against damage and are initiated following the recognition of pathogen-associated molecular patterns (PAMPs). For double-stranded DNA (dsDNA) sensing, interferon gene stimulator (STING) was discovered to be an integral sensor, and could mediate the immune and inflammatory response. However, it is unclear the underlying mechanisms of STING in the development of neuropathic pain. Methods Neuropathic pain model was established by spared nerve injury (SNI). STING agonist DMXAA was introduced into BV-2 cells to assess the inflammatory response in microglia cells. Selective STING antagonist C-176 were administered in the early and late stage following SNI and the mechanical sensitivity and thermal responsiveness were assessed using Von Frey filaments and hot plate tests separately. To investigate the underlying mechanisms, recombinant IL-6 was injected intrathecally and its downstream effectors were examined. The level of dsDNA in the peripheral blood following SNI was assessed using Elisa analysis. STING signaling pathway and its downstream effectors were assessed by qPCR, western blots, Elisa and immunofluorescence staining. Meanwhile, microglia activation and proinflammatory cytokines expression were also assessed in the spinal cord. Results We found dsDNA was significantly increased and STING signaling pathway was activated in dorsal horn microglia following SNI, and our study using BV-2 cells showed that DMXAA significantly activated STING/TANK-binding kinase 1 (TBK1)/nuclear factor-kappa B (NF-κB) pathway, and increased the production of proinflammatory cytokines, as well as phosphorylated the Janus-activated kinase 2/signal transducer activator of transcription 3 (JAK2/STAT3) signal in microglia. Early but not late intrathecal injection of C-176 attenuated SNI-induced pain hypersensitivity, microglia activation, proinflammatory factors and phosphorylated JAK2/STAT3 in the spinal cord dorsal horn. Last, the analgesic effect of C-176 were greatly abolished by recombinant IL-6 following SNI. Conclusions We provided evidence clarifying dsDNA mediated activation of microglial STING signaling pathway, after which promoting expression of proinflammatory cytokines that are required for central sensitization in the spinal cord dorsal horn of SNI model. Further analysis showed that microglial STING/TBK1/NF-κB may contribute to hyperalgesia initiation via IL-6/JAK2/STAT3 signaling. Pharmacological blockade of STING may be a promising target during the initiation of neuropathic pain.

scholarly journals Electroacupuncture Treatment Suppresses Transcription Factor IRF8 in Spinal Cord of Rats with Spared Nerve Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Ying Wang ◽  
Meng Xue ◽  
Yang-yang Xia ◽  
Qian Jiang ◽  
Zhi-hua Huang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Transcription Factor ◽  
Neuropathic Pain ◽  
Protein Expression ◽  
Nerve Injury ◽  
Microglial Activation ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Spared Nerve Injury ◽  
Mrna And Protein Expression

Objective. Neuropathic pain with complex mechanisms has become a major public health problem that greatly impacts patients’ quality of life. Therefore, novel and more effective strategies against neuropathic pain need further investigation. Electroacupuncture (EA) has an ameliorating effect on neuropathic pain following spared nerve injury (SNI), but the underlying mechanism remains to be fully clarified. Interferon regulatory factor 8 (IRF8), a critical transcription factor, was reported to be involved in the modulation of neuropathic pain. Here, we focused on exploring whether 2 Hz EA stimulation exerts an inhibitory action on spinal IRF8 in SNI rats. Methods. In this study, SNI rats were treated with 2 Hz EA once every other day for 21 days. Paw withdrawal threshold (PWT) was applied to determine the analgesic effect of 2 Hz EA on SNI rats. The spinal IRF8 and CX3CRl expressions were detected with qRT-PCR and western blot, and immunofluorescence staining was used to evaluate colocation of IRF8 or CX3CRl with microglial activation marker CD11b in the spinal cord. Results. It was found that SNI induced significant elevation of spinal IRF8 and CX3CRl mRNA and protein expression. Additionally, immunofluorescence results showed that SNI elicited the coexpression of IRF8 with CD11b, as well as CX3CRl with CD11b in the spinal cord. Meanwhile, 2 Hz EA treatment of SNI rats not only reduced IRF8 and CX3CRl mRNA and protein expression, but also reversed the coexpression of IRF8 or CX3CRl with CD11b in the spinal cord, along with an attenuation of SNI-evoked mechanical hypersensitivity. Conclusion. This experiment highlighted that 2 Hz EA can inhibit IRF8 expression and microglial activation in the spinal cord of SNI rats. Hence, targeting IRF8 may be a promising therapeutic strategy for 2 Hz EA treatment of neuropathic pain.

scholarly journals Diabetes, Inflammation, Proinflammatory Cytokines, and Diabetic Nephropathy

2006 ◽  
Vol 6 ◽  
pp. 908-917 ◽  
Author(s):  
Juan F. Navarro ◽  
Carmen Mora
Keyword(s):  
Public Health ◽  
Diabetic Nephropathy ◽  
Proinflammatory Cytokines ◽  
Inflammatory Process ◽  
Public Health Problem ◽  
Critical Factors ◽  
Therapeutic Goals ◽  
Relevant Role ◽  
Therapeutic Considerations ◽  
Relevant Factors

Diabetes and its complications have become a public health problem. Diabetic nephropathy is the main cause of renal failure. In spite of our higher knowledge on this complication, the intimate mechanisms leading to the development and progression of renal injury are not yet fully known. Activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Moreover, inflammation, and more specifically proinflammatory cytokines and other molecules with a relevant role within the inflammatory process, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective may lead to important new therapeutic considerations and new therapeutic goals for the treatment of diabetic nephropathy.

Kindesmisshandlung und deren Langzeitfolgen – Analyse einer repräsentativen deutschen Stichprobe

2019 ◽  
Vol 67 (2) ◽  
pp. 100-111 ◽  
Author(s):  
Andreas Witt ◽  
Rebecca Brown ◽  
Paul L. Plener ◽  
Elmar Brähler ◽  
Jörg M. Fegert ◽  
...  
Keyword(s):  
Public Health ◽  
Health Problem ◽  
Public Health Problem ◽  
Nachhaltige Entwicklung

Zusammenfassung. Kindesmisshandlung stellt einen bedeutenden Risikofaktor für die Entwicklung dar. Einzelne Formen von Kindesmisshandlung treten häufig nicht isoliert auf, sondern das gemeinsame Auftreten verschiedener Formen von Kindesmisshandlung stellt eher die Regel als die Ausnahme dar. Neben den langfristigen und vielfältigen individuellen Folgen führt Kindesmisshandlung jährlich zu einer hohen gesamtgesellschaftlichen Belastung. Die WHO hat Kindesmisshandlung als großes Public Health Problem identifiziert und die Vereinten Nationen haben den Kampf gegen Kindesmisshandlung zum Ziel in ihrer Agenda für nachhaltige Entwicklung gemacht. In dem vorliegenden Beitrag werden die Häufigkeit sowie das gemeinsame Auftreten unterschiedlicher Formen von Kindesmisshandlung sowie deren Assoziation mit psychischen und somatischen Folgen auf Basis einer bevölkerungsrepräsentativen Stichprobe untersucht und dargestellt. Die Ergebnisse verdeutlichen den Zusammenhang zwischen der Kumulation verschiedener Formen von Misshandlung und negativen Folgen für die Betroffenen. So ist das Risiko für negative Konsequenzen beim Erleben von vier oder mehr Formen von Misshandlung um das bis zu 10-fache erhöht. Viel zu selten werden die kumulativen Effekte von mehreren Belastungen berücksichtigt. Gerade weil die Wirkweisen über die Misshandlung, die Gesundheit beeinflusst, zunehmend gut untersucht sind, muss dieses Wissen im Gesundheitswesen stärker bei der Konzeption von Präventions- und Interventionsmaßnahmen berücksichtigt werden.

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