scholarly journals Mineralocorticoid Receptor Blocker Eplerenone Reduces Pain Behaviors In Vivo  and Decreases Excitability in Small-diameter Sensory Neurons from Local Inflamed Dorsal Root Ganglia In Vitro 

2012 ◽  
Vol 117 (5) ◽  
pp. 1102-1112 ◽  
Author(s):  
Fei Dong ◽  
Wenrui Xie ◽  
Judith A. Strong ◽  
Jun-Ming Zhang
Keyword(s):  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Mineralocorticoid Receptor ◽  
Small Diameter ◽  
Mechanical Hypersensitivity ◽  
Proinflammatory Role ◽  
Immunohistochemical Studies

Background Inflammation of the dorsal root ganglia (DRG) may contribute to low back pain, postherpetic neuralgia, and neuropathic pain. The mineralocorticoid receptor (MR) plays a proinflammatory role in many nonrenal tissues, but its role in peripheral pain at the DRG level is not well studied. Methods Local inflammation of the L5 DRG with the immune activator zymosan rapidly leads to mechanical hypersensitivity and increased excitability of sensory neurons. Using this pain model, the authors applied the MR antagonist eplerenone locally to the inflamed DRG. Excitability of small-diameter sensory neurons was examined in acute primary culture by using patch clamp techniques. Results Local eplerenone significantly reduced the mechanical hypersensitivity and shortened its duration. The same dose was ineffective systemically. Immunohistochemical studies showed the MR was present in most neurons and rapidly translocated to the nucleus 1 day after local DRG inflammation. Activation of satellite glia (defined by expression of glial fibrillary acidic protein) in the inflamed DRG was also reduced by local eplerenone. Increased excitability of small-diameter sensory neurons 1 day after inflammation could be observed in vitro. Eplerenone applied in vitro (8-12 h) could reverse this increased excitability. Eplerenone had no effect in neurons isolated from normal, uninflamed DRG. The MR agonist aldosterone (10 nM) applied in vitro increased excitability of neurons isolated from normal DRG. Conclusions The MR may have a pronociceptive role in the DRG. Some of its effects may be mediated by neuronal MR. The MR may represent a novel therapeutic target in some pain syndromes.

Neuronal intermediate filament expression in rat dorsal root ganglia sensory neurons: An in vivo and in vitro study

Neuroscience ◽  
2008 ◽  
Vol 153 (4) ◽  
pp. 1153-1163 ◽  
Author(s):  
M. Fornaro ◽  
J.M. Lee ◽  
S. Raimondo ◽  
S. Nicolino ◽  
S. Geuna ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Intermediate Filament ◽  
Dorsal Root ◽  
In Vitro Study ◽  
Vitro Study

Systematic investigation and comparison of US FDA-approved immunosuppressive drugs FK506, cyclosporine and rapamycin for neuromuscular regeneration following chronic nerve compression injury

2021 ◽  
Vol 16 (11) ◽  
pp. 989-1003
Author(s):  
Lucas Degrugillier ◽  
Katharina M Prautsch ◽  
Dirk J Schaefer ◽  
Raphael Guzman ◽  
Daniel F Kalbermatten ◽  
...  
Keyword(s):  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Nerve Compression ◽  
In Vivo Model ◽  
Compression Injury ◽  
Potent Effect ◽  
Therapeutic Benefits ◽  
Chronic Nerve Compression

Aim: To compare therapeutic benefits of different immunophilin ligands for treating nerve injuries. Materials & methods: Cyclosporine, FK506 and rapamycin, were evaluated first in vitro on a serum-free culture of embryonic dorsal root ganglia followed by a new in vivo model of chronic nerve compression. Results: Outcomes of the in vitro study have shown a potent effect of cyclosporine and FK506, on dorsal root ganglia axonal outgrowth, comparable to the effect of nerve growth factor. Rapamycin exhibited only a moderate effect. The in vivo study revealed the beneficial effects of cyclosporine, FK506 and rapamycin for neuromuscular regeneration. Cyclosporine showed the better maintenance of the tissues and function. Conclusion: Cyclosporine, FK506 and rapamycin drugs showed potential for treating peripheral nerve chronic compression injuries.

scholarly journals Hydrogen Peroxide Induces Muscle Nociception via Transient Receptor Potential Ankyrin 1 Receptors

2017 ◽  
Vol 127 (4) ◽  
pp. 695-708 ◽  
Author(s):  
Daisuke Sugiyama ◽  
Sinyoung Kang ◽  
Nicholas Arpey ◽  
Preeyaphan Arunakul ◽  
Yuriy M. Usachev ◽  
...  
Keyword(s):  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Deep Muscle ◽  
Plantar Incision ◽  
Dorsal Root Ganglia Neurons ◽  
Transient Receptor

Abstract Background H2O2 has a variety of actions in skin wounds but has been rarely studied in deep muscle tissue. Based on response to the transient receptor potential ankyrin 1 antagonists after plantar incision, we hypothesized that H2O2 exerts nociceptive effects via the transient receptor potential ankyrin 1 in muscle. Methods Nociceptive behaviors in rats (n = 269) and mice (n = 16) were evaluated after various concentrations and volumes of H2O2 were injected into the gastrocnemius muscle or subcutaneous tissue. The effects of H2O2 on in vivo spinal dorsal horn neuronal activity and lumbar dorsal root ganglia neurons in vitro were evaluated from 26 rats and 6 mice. Results Intramuscular (mean ± SD: 1,436 ± 513 s) but not subcutaneous (40 ± 58 s) injection of H2O2 (100 mM, 0.6 ml) increased nociceptive time. Conditioned place aversion was evident after intramuscular (–143 ± 81 s) but not subcutaneous (–2 ± 111 s) injection of H2O2. These H2O2-induced behaviors were blocked by transient receptor potential ankyrin 1 antagonists. Intramuscular injection of H2O2 caused sustained in vivo activity of dorsal horn neurons, and H2O2 activated a subset of dorsal root ganglia neurons in vitro. Capsaicin nerve block decreased guarding after plantar incision and reduced nociceptive time after intramuscular H2O2. Nociceptive time after intramuscular H2O2 in transient receptor potential ankyrin 1 knockout mice was shorter (173 ± 156 s) compared with wild-type mice (931 ± 629 s). Conclusions The greater response of muscle tissue to H2O2 may help explain why incision that includes deep muscle but not skin incision alone produces spontaneous activity in nociceptive pathways.

Proteasome Inhibitor Associated Neuropathy Is Mechanism Based

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2646-2646 ◽  
Author(s):  
Lee Silverman ◽  
Vilmos Csizmadia ◽  
Katherine Brewer ◽  
Chris Simpson ◽  
Carl Alden
Keyword(s):  
Nervous System ◽  
Peripheral Neuropathy ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Proteasome Inhibition ◽  
Ubiquitinated Proteins ◽  
Vitro Data ◽  
In Vitro Data

Abstract Background: Peripheral neuropathy is a common side effect of chemotherapeutics, particularly taxanes, platinums, vinca alkaloids, and proteasome inhibitors (PIs). There are currently three chemical scaffolds of PIs in clinical development: leucine boronates, lactacystin analogs, and epoximicin derivatives. Among these, only a leucine boronate, VELCADE, is currently approved for use in humans. Approximately 39% of patients treated with VELCADE develop peripheral neuropathy. Preclinical data suggest that peripheral neuropathy may develop as a consequence of functional effects in the dorsal root ganglia (Silverman et al. 2006; Toxicologic Pathology34:989). Moreover, in vitro data suggests that these effects may be the result of a reorganization of cytoskeletal elements and an accumulation of ubiquitinated proteins in the neuronal cytoplasm (Csizmadia et al. 2008; Neurotoxicology29:232). In vivo and in vitro data suggest that PI-associated neuropathy develops following treatment with PIs of differing chemical scaffolds, consistent with a mechanism based effect. A better understanding of the mechanism underlying PI-associated peripheral neuropathy could potentially lead to improved management strategies for this adverse event while maintaining therapeutic benefit. Aims: To investigate if PI-associated neuropathy is mechanism based (a consequence of proteasome inhibition), and If mechanism based, to further understand the mechanism by which proteasome inhibition results in peripheral neuropathy. Methods: The effects of treating in vitro neuronal cell cultures (PC-12 rat pheochromocytoma cell line treated with nerve growth factor [NGF] in order to induce neuronal differentiation) with leucine boronate, lactacystin analog, or epoximicin PIs, as well as with taxol and cisplatinum, were examined by Western immunoblot and immunohistochemistry specific for ubiquitinated proteins. Additionally, the morphologic effects on the peripheral nervous system of mice treated with leucine boronate or lactacystin analog PIs were examined. Results: Treatment of PC-12 cells with leucine boronate, lactacystin analog or epoximicin PIs but not with taxol or cisplatinum resulted in perinuclear accumulations of ubiquitinated proteins. In in vivo models, morphologic lesions were observed in the peripheral nervous system of mice treated with both leucine boronate and lactacystin analog PIs. In a time course study with a prototypical PI, dorsal root ganglia was identified as the primary target leading to secondary peripheral nerve degeneration. Routine hematoxylin and eosin histologic analysis showed an accumulation of eosinophilic material within the dorsal root ganglia neurons. Immunohistochemistry showed these accumulations to contain ubiquitinated proteins, consistent with the in vitro observations. The in vivo effects were similar following treatment with either a leucine boronate or a lactacystin analog PI. Summary: Our in vitro and in vivo studies identified a morphologic effect which among the chemotherapeutics which cause peripheral neuropathy is uniquely associated with PIs. Moreover, these findings were seen regardless of the chemical scaffold.

scholarly journals Axotomy-Induced Expression of Calcium-Activated Chloride Current in Subpopulations of Mouse Dorsal Root Ganglion Neurons

2003 ◽  
Vol 90 (6) ◽  
pp. 3764-3773 ◽  
Author(s):  
Sylvain André ◽  
Hassan Boukhaddaoui ◽  
Brice Campo ◽  
Mohammed Al-Jumaily ◽  
Véronique Mayeux ◽  
...  
Keyword(s):  
Nerve Injury ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Large Diameter ◽  
Chloride Current ◽  
Regenerative Growth ◽  
Ganglion Neurons ◽  
Medium Diameter

Whole cell patch-clamp recordings of calcium-activated chloride current [ ICl(Ca)] were made from adult sensory neurons of naive and axotomized mouse L4–L6 lumbar dorsal root ganglia after 1 day of culture in vitro. A basal ICl(Ca) was specifically expressed in a subset of naive medium-diameter neurons (30–40 μm). Prior nerve injury, induced by sciatic nerve transection 5 days before experiments, increased both ICl(Ca) amplitude and its expression in medium-diameter neurons. Moreover, nerve injury also induced ICl(Ca) expression in a new subpopulation of neurons, the large-diameter neurons (40–50 μm). Small-diameter neurons (inferior to 30 μm) never expressed ICl(Ca). Regulated ICl(Ca) expression was strongly correlated with injury-induced regenerative growth of sensory neurons in vitro and nerve regeneration in vivo. Cell culture on a substrate not permissive for growth, d,l-polyornithine, prevented both elongation growth and ICl(Ca) expression in axotomized neurons. Regenerative growth and the induction of ICl(Ca) expression take place 2 days after injury, peak after 5 days of conditioning in vivo, slowly declining thereafter to control values. The selective expression of ICl(Ca) within medium- and large-diameter neurons conditioned for rapid, efficient growth suggests that these channels play a specific role in postinjury behavior of sensory neuron subpopulations such as neuropathic pain and/or axonal regeneration.

BDNF-TrkB and proBDNF-p75NTR/Sortilin Signaling Pathways are Involved in Mitochondria-Mediated Neuronal Apoptosis in Dorsal Root Ganglia after Sciatic Nerve Transection

2020 ◽  
Vol 19 (1) ◽  
pp. 66-82 ◽  
Author(s):  
Xianbin Wang ◽  
Wei Ma ◽  
Tongtong Wang ◽  
Jinwei Yang ◽  
Zhen Wu ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Signaling Pathways ◽  
Nerve Injury ◽  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Neuronal Apoptosis ◽  
Nerve Transection ◽  
Sciatic Nerve Transection

Background: Brain-Derived Neurotrophic Factor (BDNF) plays critical roles during development of the central and peripheral nervous systems, as well as in neuronal survival after injury. Although proBDNF induces neuronal apoptosis after injury in vivo, whether it can also act as a death factor in vitro and in vivo under physiological conditions and after nerve injury, as well as its mechanism of inducing apoptosis, is still unclear. Objective: In this study, we investigated the mechanisms by which proBDNF causes apoptosis in sensory neurons and Satellite Glial Cells (SGCs) in Dorsal Root Ganglia (DRG) After Sciatic Nerve Transection (SNT). Methods: SGCs cultures were prepared and a scratch model was established to analyze the role of proBDNF in sensory neurons and SGCs in DRG following SNT. Following treatment with proBDNF antiserum, TUNEL and immunohistochemistry staining were used to detect the expression of Glial Fibrillary Acidic Protein (GFAP) and Calcitonin Gene-Related Peptide (CGRP) in DRG tissue; immunocytochemistry and Cell Counting Kit-8 (CCK8) assay were used to detect GFAP expression and cell viability of SGCs, respectively. RT-qPCR, western blot, and ELISA were used to measure mRNA and protein levels, respectively, of key factors in BDNF-TrkB, proBDNF-p75NTR/sortilin, and apoptosis signaling pathways. Results: proBDNF induced mitochondrial apoptosis of SGCs and neurons by modulating BDNF-TrkB and proBDNF-p75NTR/sortilin signaling pathways. In addition, neuroprotection was achieved by inhibiting the biological activity of endogenous proBDNF protein by injection of anti-proBDNF serum. Furthermore, the anti-proBDNF serum inhibited the activation of SGCs and promoted their proliferation. Conclusion: proBDNF induced apoptosis in SGCs and sensory neurons in DRG following SNT. The proBDNF signaling pathway is a potential novel therapeutic target for reducing sensory neuron and SGCs loss following peripheral nerve injury.

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