scholarly journals PDTC ameliorates neuropathic pain by inhibiting microglial activation via blockage of the TNFα-CX3CR1 pathway

2021 ◽  
Vol 65 (1) ◽  
Author(s):  
Xilei Li ◽  
Zhi Ye ◽  
Qulian Guo ◽  
E Wang ◽  
Yundan Pan
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Microglial Activation ◽  
Thermal Hyperalgesia ◽  
Microglia Activation ◽  
Pyrrolidine Dithiocarbamate ◽  
Mechanical Stimuli ◽  
Necrosis Factor Alpha ◽  
Intrathecal Infusion

Previous studies have suggested that pyrrolidine dithiocarbamate (PDTC), a nuclear factor κB (NF-κB) inhibitor, play a role in deterring nerve injury-induced neuropathic pain (NP) The activation of NF-κB pathway may contribute to spinal microglial activation, CX3CR1 and tumor necrosis factor-alpha (TNF-a) up-regulation. The aim of this study was to clarify whether PDTC could inhibit the development of neuropathic pain via decreasing TNF-a-induced CX3CR1 up-regulation. Sprague-Dawley rats were randomly divided into sham group and NP group. Rats in each group were treated with intrathecal infusion of PDTC (100 or 1000 pmol/d) or saline. The sciatic nerve chronic constriction injury (CCI) model was used to induce NP in rats. Mechanical stimuli and radiant heat were used to evaluate mechanical allodynia and thermal hyperalgesia. Spinal microglial marker OX42 and TNF-a were detected by immunohistochemistry. In vitro BV-2 microglia activation was induced by TNF-a incubation, and the levels of CX3CR1 were assessed by Western blot and reverse transcription-polymerase chain reaction. Pain behavior and immunohistochemistry results showed that intrathecal infusion of PDTC at 100 or 1000 pmol/d prevented the development of mechanical and thermal hyperalgesia, spinal microglial activation and TNF-a expression induced by sciatic nerve CCI in rats. In vitro experiment results showed that PDTC inhibited the TNF-a-induced CX3CR1 up-regulation in BV-2 microglial cells. In conclusion, intrathecal infusion of PDTC could attenuate the pain-related behaviors induced by sciatic nerve CCI through suppressing the spinal microglia activation and TNF-a up-regulation in rats. The NF-κB activation might be responsible for TNF-a-induced CX3CR1 up-regulation in microglia.

scholarly journals Protocatechuic acid as an inhibitor of the JNK/CXCL1/CXCR2 pathway relieves neuropathic pain in CCI rats

2021 ◽  
Author(s):  
Hong-xia Chang ◽  
Yue-feng Zhao
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Satellite Cells ◽  
Protocatechuic Acid ◽  
Thermal Hyperalgesia ◽  
Tnf Α ◽  
Chemokine Ligand ◽  
New Perspective

Emerging evidence has shown that protocatechuic acid (PCA) has antioxidant and anti-inflammatory effects. Evidence suggests that PCA can alleviate the injury of sciatic nerve, while the mechanism of its therapeutic effect on neuralgia remains unknown.         Chromium bowel ligation was used in vivo to establish a chronic constriction injury (CCI) rat model to induce sciatic nerve pain. Subsequently, two doses of PCA were used to treat CCI rats. In vitro, 10 ng/mL TNF-α was used to stimulate glial satellite cells derived from the dorsal root ganglia (DRG) L4-L6 of the sciatic nerve to simulate sciatic nerve pain. PCA relieved mechanical allodynia and thermal hyperalgesia in CCI rats. CCK-8 assay revealed that PCA inhibited the proliferation of glial satellite cells induced by TNF-α. Moreover, ELISA demonstrated that PCA could improve the inflammatory response of rats caused by CCI and cells induced by TNF-α. Next, RT-qPCR and Western blot assays showed that PCA blocked the c-Jun N-terminal kinase/the chemokine ligand 1/CXC chemokine receptor 2 (JNK/CXCL1/CXCR2) pathway by inhibiting CXCL1 levels in cells induced by TNF-α and DRG in CCI rats. In conclusion, PCA can alleviate neuropathic pain in CCI rats and improve oxidative stress by inhibiting the JNK/CXCL1/CXCR2 signaling pathway. Thus, these findings provide a new perspective for the treatment of neuropathic pain caused by CCI.

scholarly journals Alpha lipoic acid attenuated neuropathic pain induced by chronic constriction Injury of sciatic nerve in rats

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Prasad Neerati ◽  
Harika Prathapagiri
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
Sciatic Nerve ◽  
Lipoic Acid ◽  
Normal Saline ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Alpha Lipoic Acid ◽  
Chronic Neuropathic Pain ◽  
Neuropathic Pain Syndrome

Abstract Background Chronic neuropathic pain syndrome is associated with impaired quality of life and is poorly manageable. Alpha lipoic acid (ALA) is a powerful antioxidant and showed its effectiveness on diabetic neuropathy and other acute peripheral nerve injuries but it was not evaluated in the chronic neuropathic pain, chronic constriction injury (CCI) in rat model by using duloxetine (DLX) as standard. Methodology The main objective of the study was to expedite ALA effect on chronic peripheral neuropathy induced by CCI of sciatic nerve in rats. In this study, male Wister rats were randomly divided into six groups (n = 8) including, normal saline, sham operated, surgery control, DLX 30mg/kg treated, ALA treated 25mg/kg, and ALA+DLX. The CCI of sciatic nerve was conducted on all animals except normal saline group and studied for 21 days (i.e. 14 days treatment period & 7 days treatment free period) by using different behavioral, biochemical and, histopathology studies. Results ALA showed minor but significant decrease of thermal hyperalgesia, cold allodynia, malondialdehyde (MDA), total protein, lipid peroxidation, and nitric oxide levels and significant increase of motor coordination, glutathione level and decreased axonal degeneration significantly. These effects sustained even during treatment free period. ALA enhanced the effect of DLX when given in combination by showing sustained effect. In conclusion, ALA acted as potent antioxidant may be this activity is responsible for the potent neuroprotective effect. Conclusion Hence, ALA attenuated the nueroinflammation mediated by chronic peripheral neuropathy. Further studies are warranted with ALA to develop as a clinically relevant therapeutic agent for the treatment of neuropathic pain.

scholarly journals Comparative efficacy of pregabalin and baclofen in the rodent chronic constriction injury model of neuropathic pain

2018 ◽  
Vol 8 (1) ◽  
pp. 133
Author(s):  
Saurabh Kohli ◽  
Taruna Sharma ◽  
Juhi Kalra ◽  
Dilip C. Dhasmana
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Mechanical Hyperalgesia ◽  
Comparative Efficacy ◽  
First Line ◽  
Injury Model ◽  
Different Types ◽  
Chronic Constriction Injury Model

Background: Neuropathic pain is associated with prolonged disability and is usually not responsive to conventional analgesics like NSAIDs and opioids. Even the recommended first-line drugs are effective in less than 50% patients. Thus, drugs with different mechanisms of action are needed. Baclofen, a GABA-B agonist has shown benefit in different types of neuropathic pains and is compared against pregabalin.Methods: The sciatic nerve was ligated in 2 groups of 6 rats each as per the chronic constriction injury model of neuropathic pain on day 0. After 14 days the effect of single doses of pregabalin (30mg/kg) and baclofen (5mg/kg) intraperitoneally were assessed over a 2 hours period. Thermal and mechanical hyperalgesia were assessed as measures of neuropathic pain by the hotplate and pin-prick method respectively.Results: Significant thermal and mechanical hyperalgesia was produced 14 days after sciatic nerve ligation in both the groups (p <0.05). Both pregabalin (p <0.001) and baclofen (p <0.01) were effective in decreasing thermal hyperalgesia throughout the two hours study period, but pregabalin was more effective as compared to baclofen (p <0.05) at 30, 60 and 120minutes. Both the drugs produced a significant decrease in mechanical hyperalgesia (p <0.01) throughout the study period. Again, pregabalin was the more effective drug (p <0.05) at all time points.Conclusions: Significant thermal and mechanical hyperalgesia was seen 14 days after sciatic nerve ligation. Both pregabalin and baclofen were effective in reversing the hyperalgesia, but pregabalin was the more effective of the two drugs at all time points.

scholarly journals Salvia officinalis, Rosmarinic and Caffeic Acids Attenuate Neuropathic Pain and Improve Function Recovery after Sciatic Nerve Chronic Constriction in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Zineb El Gabbas ◽  
Kenza Bezza ◽  
Jawad Laadraoui ◽  
Mehdi Ait Laaradia ◽  
Aaziz Kebbou ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Functional Recovery ◽  
Thermal Sensation ◽  
Biological Activities ◽  
Hematological Parameters ◽  
Thermal Hyperalgesia ◽  
Salvia Officinalis ◽  
Histopathological Analysis ◽  
Phenolic Constituents

The leaves of Salvia officinalis L. have a traditional reputation for the management of pain in Morocco. This study was conducted to investigate the curative effects of Salvia officinalis (SO) and its major constituents Rosmarinic (ROS) and Caffeic acids (CAF) on peripheral neuropathic pain in mice. Chronic constriction injury (CCI) was induced in mice, and neuropathic pain behaviors tests were evaluated by mechanical, chemical, thermal sensation tests and functional recovery of the sciatic nerve at different time intervals, i.e., (day 0, 1, 7, 14, and 21). Ethanolic extract of SO (100 and 200 mg/kg, p.o.), ROS (10 and 20 mg/kg, i.p.), CAF (30 and 40 mg/kg, i.p.), and CLOM (5 mg/kg, i.p., a positive control) was given for 21 days after surgery. Hematological and biochemical parameters were also measured as well as histopathological analysis. CCI produced significant development in mechanical and thermal hyperalgesia, cold allodynia, and rise in the sciatic functional index in mice. Chronic treatments with SO extract, ROS, CAF, and CLOM for 3 weeks significantly increased mechanical sensibility, cold, and thermal withdrawal latency and enhanced functional recovery of the injured nerve. The same treatments remarkably ameliorated hematological parameters and did not alter biochemical levels. The histopathological findings had revealed the protective effect of SO, ROS, and CAF against the CCI-induced damage. Our data support the use of SO in folk medicine to alleviate pain. Their main phenolic constituents could be promising antineuropathic compounds, which may be attributed to their biological activities including anti-inflammatory, antioxidant, and neuroprotective effects. SO leaves may be a good candidate to treat neuropathic pain.

N -Phenylethyl Amitriptyline in Rat Sciatic Nerve Blockade

2002 ◽  
Vol 96 (6) ◽  
pp. 1435-1442 ◽  
Author(s):  
Peter Gerner ◽  
Mustafa Mujtaba ◽  
Mohammed Khan ◽  
Yukari Sudoh ◽  
Kamen Vlassakov ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Therapeutic Range ◽  
Local Anesthetic ◽  
Na Channel ◽  
Patch Clamp Technique ◽  
Rat Sciatic Nerve ◽  
Nerve Model

Background The antidepressant amitriptyline is commonly used orally for the treatment of chronic pain, particularly neuropathic pain, which is thought to be caused by high-frequency ectopic discharge. Among its many properties, amitriptyline is a potent Na(+) channel blocker in vitro, has local anesthetic properties in vivo, and confers additional blockade at high stimulus-discharge rates (use-dependent blockade). As with other drug modifications, adding a phenylethyl group to obtain a permanently charged quaternary ammonium derivative may improve these advantageous properties. Methods The electrophysiologic properties of N-phenylethyl amitriptyline were assessed in cultured neuronal GH(3) cells with the whole cell mode of the patch clamp technique, and the therapeutic range and toxicity were evaluated in the rat sciatic nerve model. Results In vitro, N-phenylethyl amitriptyline at 10 microm elicits a greater block of Na(+) channels than amitriptyline (resting block of approximately 90% vs. approximately 15%). This derivative also retains the attribute of amitriptyline in evoking high-degree use-dependent blockade during repetitive pulses. In vivo, duration to full recovery of nociception in the sciatic nerve model was 1,932 +/- 72 min for N-phenylethyl amitriptyline at 2.5 mm (n = 7) versus 72 +/- 3 min for lidocaine at 37 mm (n = 4; mean +/- SEM). However, there was evidence of neurotoxicity at 5 mm. Conclusion N-phenylethyl amitriptyline appears to have a narrow therapeutic range but is much more potent than lidocaine, providing a block duration several times longer than any clinically used local anesthetic. Further work in animal models of neuropathic pain will assess the potential use of this drug.

scholarly journals ATP mediates neuropathic pain in neuromyelitis optica via microglial activation

2020 ◽  
Author(s):  
Teruyuki Ishikura ◽  
Makoto Kinoshita ◽  
Mikito Shimizu ◽  
Yoshiaki Yasumizu ◽  
Daisuke Motooka ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Neuromyelitis Optica ◽  
Transcriptome Analysis ◽  
Mechanical Allodynia ◽  
Microglial Activation ◽  
Atp Release ◽  
Common Symptom ◽  
Pain Model ◽  
Pharmacological Inhibition

Abstract Background Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. The aim of this study was to establish a novel animal model of NMOSD pain and to investigate its pathogenic mechanism. Methods We established an NMOSD pain model by injecting anti-AQP4 recombinant autoantibodies (AQP4-Ab) from NMOSD patient plasmablasts into rat spinal cords. We performed transcriptome analysis and pharmacological inhibition to elucidate the core mechanism of allodynia in the model. Results Development of mechanical allodynia was confirmed in the NMOSD pain model. AQP4-Ab mediated extracellular ATP release in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the NMOSD pain model. Furthermore, transcriptome analysis revealed microglial activation and elevated levels of IL-1β in NMOSD spinal cord. Inhibition of microglial activation and neutralization of IL-1β also attenuated neuropathic pain in the NMOSD rat model. In human patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders. Conclusion A novel NMOSD pain model was established. ATP, microglial activation, and IL-1β secretion orchestrate the pathogenesis of NMOSD neuropathic pain.

Levo-corydalmine attenuates microglia activation and neuropathic pain by suppressing ASK1-p38 MAPK/NF-κB signaling pathways in rat spinal cord

2020 ◽  
Vol 45 (3) ◽  
pp. 219-229 ◽  
Author(s):  
Wen-Ling Dai ◽  
Yi-Ni Bao ◽  
Ji-Fa Fan ◽  
Shan-Shan Li ◽  
Wan-Li Zhao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Protein Kinase ◽  
P38 Mapk ◽  
Calcium Binding ◽  
Microglia Activation ◽  
Mitogen Activated Protein Kinase ◽  
Intragastric Administration ◽  
Tnf Α

Background and objectivesNeuropathic pain is partially refractory to currently available treatments. Although some studies have reported that apoptosis signal-regulating kinase 1 (ASK1) may inhibit chronic pain, the mechanisms underlying this process have not been fully elucidated.MethodsChronic constriction injury (CCI) of the rat sciatic nerve was used to establish a neuropathic pain model. Nociception was assessed using von Frey hair and Hargreaves’ methods. Western blot and immunofluorescence were used to detect the cell signaling pathway. BV2 cell line was cultured for in vitro evaluation.ResultsOur results indicated that spinal ASK1 was co-expressed with the microglia marker ionized calcium binding adaptor 1. Additionally, intrathecal administration of ASK1 inhibitor suppressed the activation of spinal microglia and attenuated CCI-induced neuropathic pain. The ASK1 inhibitor also decreased the levels of phosphorylated ASK1 (p-ASK1), p65, p38 mitogen-activated protein kinase (MAPK) and tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) messenger RNA in lipopolysaccharide-stimulated BV2 microglia cells. Intragastric administration of levo-corydalmine (l-CDL) significantly attenuated CCI-induced neuropathic pain and inhibited the expression of p-ASK1 in the spinal cord. l-CDL conspicuously suppressed the activation of spinal microglia in vitro and in vivo. Translocation of nuclearfactor-kappa B (NF-κB) and upregulation of p-p65, TNF-α, IL-1β were inhibited by l-CDL. Further, the analgesic effects of l-CDL were associated with reduced levels of phosphorylated protein kinase C (PKC γ), c-JunNH2-terminal kinase, and extracellular signal-regulated kinase.ConclusionsThis study showed that the expression of ASK1 in spinal microglia and ASK1 inhibitor suppressed microglia activation via suppression of p38 MAPK/NF-κB, which ultimately attenuated CCI-induced neuropathic pain. l-CDL also inhibited the ASK1-P38 MAPK/NF-κB axis to attenuate CCI-induced neuropathic pain.

scholarly journals Ameliorative potential of Butea monosperma on chronic constriction injury of sciatic nerve induced neuropathic pain in rats

2012 ◽  
Vol 84 (4) ◽  
pp. 1091-1104 ◽  
Author(s):  
Venkata R.K. Thiagarajan ◽  
Palanichamy Shanmugam ◽  
Uma M. Krishnan ◽  
Arunachalam Muthuraman ◽  
Nirmal Singh
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Ethanolic Extract ◽  
Thiobarbituric Acid ◽  
Positive Control ◽  
Nerve Tissue ◽  
Dependent Manner ◽  
Butea Monosperma

The present study was designed to investigate the ameliorative role of ethanolic extract from leaves of Butea monosperma in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rats. Hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests were performed to assess the degree of thermal hyperalgesia, cold chemical allodynia, mechanical hyperalgesia & allodynia in the left hind paw and tail thermal hyperalgesia. Further on, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total calcium levels were estimated to assess the biochemical changes in the sciatic nerve tissue. Histopathological changes were also observed in the sciatic nerve tissue. Ethanolic extract of Butea monosperma leaves and pregabalin (serving as positive control) were administered for 14 consecutive days starting from the day of surgery. CCI resulted in significant changes in behavioural and biochemical parameters. Pretreatment of Butea monosperma attenuated CCI induced development of behavioural, biochemical and histopathological alterations in a dose dependent manner, which is comparable to that of pregabalin pretreated group. These findings may be attributed to its potential anti-oxidative, neuroprotective and calcium channel modulatory actions of Butea monosperma.

Possible modulation of PPAR-γ cascade against depression caused by neuropathic pain in rats

2017 ◽  
Vol 28 (6) ◽  
Author(s):  
Shanky Garg ◽  
Vishwajit Ravindra Deshmukh ◽  
Pranav Prasoon
Keyword(s):  
Oxidative Stress ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Critical Role ◽  
Thermal Hyperalgesia ◽  
Treated Group ◽  
Force Swim Test ◽  
Ppar Γ ◽  
Behavioral Studies ◽  
Immobility Time

AbstractBackground:Sciatic nerve ligation causes neuropathic pain with chronic constriction injury (CCI). However, there is no published report on the effect of pioglitazone as an antidepressant in the treatment of depression induced by neuropathic pain with CCI in rats. The aim of this study was to evaluate the effect of pioglitazone as an antidepressant by targeting oxidative stress by the peripheral neuropathic pain model using the CCI of the sciatic nerve.Methods:Behavioral studies were carried out to measure thermal hyperalgesia and cold allodynia as markers of neuropathic pain and force swim test for depression. These were followed by estimation of biochemical parameters which include lipid peroxidation (LPO), reduced glutathione, catalase, nitrite and superoxide dismutase (SOD) in the rat brains as a measure of oxidative stress. We administered two intraperitoneal doses of pioglitazone (4.5 and 9.0 mg/kg, i.p.) to the treated group for 28 consecutive days from the day of injury and behavioral as well as biochemical evaluations were performed.Results:The results suggested that the administration of pioglitazone significantly countered the neuropathic pain induced depression as interpreted through elevated pain threshold of tactile allodynia and thermal hyperalgesia followed by decreased immobility time in the 9.0 mg/kg dose group.Conclusions:It may be concluded that the oxidative stress plays a critical role in the pathogenesis of neuropathic pain and depression as evidenced by the behavioral studies and the changes in the levels of lipid peroxidase, nitrite, catalase, and glutathione and SOD.

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