scholarly journals Selected Thiadiazine-Thione Derivatives Attenuate Neuroinflammation in Chronic Constriction Injury Induced Neuropathy

2021 ◽  
Vol 14 ◽  
Author(s):  
Sonia Qureshi ◽  
Gowhar Ali ◽  
Muhammad Idrees ◽  
Tahir Muhammad ◽  
Il-Keun Kong ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Acetic Acid ◽  
Chronic Constriction Injury ◽  
Therapeutic Potential ◽  
Neuronal Degeneration ◽  
Docking Studies ◽  
Van Der Waals Interactions ◽  
Spinal Cord Tissue ◽  
Dependent Manner ◽  
Clear Cut

Neuropathic pain refers to a lesion or disease of peripheral and/or central somatosensory neurons and is an important body response to actual or potential nerve damage. We investigated the therapeutic potential of two thiadiazine-thione [TDT] derivatives, 2-(5-propyl-6-thioxo-1, 3, 5-thiadiazinan-3-yl) acetic acid [TDT1] and 2-(5-propyl-2-thioxo-1, 3, 5-thiadiazinan-3-yl) acetic acid [TDT2] against CCI (chronic constriction injury)-induced neuroinflammation and neuropathic pain. Mice were used for assessment of acute toxicity of TDT derivatives and no major toxic/bizarre responses were observed. Anti-inflammatory activity was assessed using the carrageenan test, and both TDT1 and TDT2 significantly reduced carrageenan-induced inflammation. We also used rats for the induction of CCI and performed allodynia and hyperalgesia-related behavioral tests followed by biochemical and morphological analysis using RT-qPCR, immunoblotting, immunohistochemistry and immunofluorescence. Our findings revealed that CCI induced clear-cut allodynia and hyperalgesia which was reversed by TDT1 and TDT2. To determine the function of TDT1 and TDT2 in glia-mediated neuroinflammation, Iba1 mRNA and protein levels were measured in spinal cord tissue sections from various experimental groups. Interestingly, TDT1 and TDT2 substantially reduced the mRNA expression and protein level of Iba1, implying that TDT1 and TDT2 may mitigate CCI-induced astrogliosis. In silico molecular docking studies predicted that both compounds had an effective binding affinity for TNF-α and COX-2. The compounds interactions with the proteins were dominated by both hydrogen bonding and van der Waals interactions. Overall, these results suggest that TDT1 and TDT2 exert their neuroprotective and analgesic potentials by ameliorating CCI-induced allodynia, hyperalgesia, neuroinflammation and neuronal degeneration in a dose-dependent manner.

scholarly journals Dexmedetomidine Relieves Neuropathic Pain in Rats With Chronic Constriction Injury via the Keap1–Nrf2 Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Yatao Liu ◽  
Wei Liu ◽  
Xiao-Qing Wang ◽  
Zhan-Hai Wan ◽  
Yong-Qiang Liu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Rat Model ◽  
Chronic Constriction Injury ◽  
Tissue Injury ◽  
Quantitative Polymerase Chain Reaction ◽  
Immunohistochemical Analysis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Spinal Cord Tissue ◽  
Antioxidant Genes

This study aimed to determine the role of dexmedetomidine (Dex) in neuropathic pain (NP) after chronic constriction injury (CCI) in a rat model as well as its underlying mechanism. First, a CCI rat model was established. After treatment with Dex, the severity of NP was ascertained by monitoring paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) at different time points. Immunohistochemical analysis was performed to determine the levels of Keap1 and Nrf2 in the spinal cord. Furthermore, the levels of Keap1–Nrf2–HO-1 pathway molecules, apoptotic proteins, and antioxidant genes in the spinal cord or isolated primary microglia were determined using quantitative polymerase chain reaction and western blotting. The release of proinflammatory cytokines was detected via enzyme-linked immunosorbent assay. To evaluate Dex-treated CCI-induced NP via the Keap1–Nrf2–HO-1 pathway, the rats were intrathecally injected with lentivirus to upregulate or downregulate the expression of Keap1. We found that Dex inhibited pathological changes and alleviated sciatic nerve pain as well as repressed inflammation, apoptosis, and redox disorders of the spinal cord in CCI rats. Keap1 protein expression was substantially downregulated, whereas Nrf2 and HO-1 expressions were significantly upregulated in the spinal cord after Dex administration. Additionally, Keap1 overexpression counteracted Dex-mediated inhibition of NP. Keap1 overexpression led to a decrease in Nrf2 and HO-1 levels as well as PWT and PWL but led to an aggravation of inflammation and antioxidant disorders and increased apoptosis. Keap1 silencing alleviated NP in rats with CCI, as evidenced by an increase in PWT and PWL. Keap1 depletion resulted in the alleviation of inflammation and spinal cord tissue injury in CCI rats. Collectively, these findings suggest that Dex inhibits the Keap1–Nrf2–HO-1-related antioxidant response, inflammation, and apoptosis, thereby alleviating NP in CCI rats.

scholarly journals Nrf2 Activation Attenuates Chronic Constriction Injury-induced Neuropathic Pain via Induction of PGC-1α-mediated Mitochondrial Biogenesis in the Spinal Cord

2021 ◽  
Author(s):  
Jia Sun ◽  
Jia-Yan Li ◽  
Long-Qing Zhang ◽  
Dan-Yang Li ◽  
Jia-Yi Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Chronic Constriction Injury ◽  
Clinical Investigation ◽  
Thermal Hyperalgesia ◽  
Related Factor ◽  
Dependent Manner

Abstract BackgroundNeuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a potent regulator of antioxidant response system. In this study, we investigated whether RTA-408 (a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms.MethodsNeuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von-Frey test and Hargreaves plantar test. The L4-6 spinal cord was collected to examine the activation of Nrf2 and MB.ResultsRTA-408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose-dependent manner. Furthermore, RTA-408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2 dependent manner. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) is the key regulator of MB. We found that PGC-1α activator also exhibited a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA-408 was reversed by the pre-injection of PGC-1α inhibitor.ConclusionsNrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.

scholarly journals Botulinum toxin type A relieve neuropathic pain by suppressing the expression of CXCL13/CXCR5 and GAT-1 in chronic constriction injury rats

2021 ◽  
Author(s):  
Huilian Bu ◽  
Huilian Bu ◽  
Pengfei Jiao ◽  
Pengfei Jiao ◽  
Xiaochong Fan ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Botulinum Toxin ◽  
Sciatic Nerve ◽  
Analgesic Effect ◽  
Chronic Constriction Injury ◽  
Botulinum Toxin Type A ◽  
Type A ◽  
Botulinum Toxin Type ◽  
Dependent Manner ◽  
Axon Transport

Abstract Botulinum toxin type A (BTX-A) was widely used to treat neuropathic pain in clinic. The underlying analgesic mechanism of BTX-A involves in axonal transport. The chemokine (C-X-C motif) ligand 13 (CXCL13) and GABA transporter 1 (GAT-1) played important roles in chronic pain. We established a chronic constriction injury (CCI) model. The pain behaviors of rats were measured by testing paw withdrawal thresholds (PWTs) and paw withdrawal latencies (PWLs). The level of proteins was measured by western blots. In our results, the CCI rats showed decrease of PWTs and PWLs, which were relieved by BTX-A. BTX-A reversed the over-expression of CXCL13 and GAT-1 in spinal cord, DRG, sciatic nerve and plantar in CCI rats and characterized in dose-dependent manner. The inhibition of BTX-A on proteins we examined didn’t show significant trend among time points. The analgesic effect of BTX-A disappeared after the axon transport of sciatic nerve blocked by the colchicine. But the PWTs of the colchicine treated CCI rats were higher than non- colchicine-treated CCI rats. Colchicine decreased the levels of CXCL13 and GAT-1 in CCI rats. What’s more, the proteins we examined peaked at the sciatic nerve in the non-colchicine group, but the phenomenon disappeared in the colchicine group. In conclusion, the BTX-A and colchicine relieve neuropathic pain and suppress the increase of CXCL13 and GAT-1. Colchicine prevents the analgesic effect of BTX-A by blocking axon transport. The axon transport may play roles in the peripheral mechanisms of neuropathic pain.

Attenuating Effect of Portulaca oleracea Extract on Chronic Constriction Injury Induced Neuropathic Pain in Rats: An Evidence of Anti-oxidative and Anti-inflammatory Effects

2019 ◽  
Vol 18 (4) ◽  
pp. 342-349 ◽  
Author(s):  
Fatemeh Forouzanfar ◽  
Hossein Hosseinzadeh ◽  
Mohammad B. Khorrami ◽  
Samira Asgharzade ◽  
Hassan Rakhshandeh
Keyword(s):  
Neuropathic Pain ◽  
Chronic Constriction Injury ◽  
Portulaca Oleracea ◽  
Dependent Manner ◽  
Tnf Α ◽  
Antinociceptive Effects ◽  
Drug Treatments ◽  
Thiol Content ◽  
Anti Inflammatory ◽  
Dose Dependent

Background: Neuropathic pain responds poorly to drug treatments. The present study investigated the therapeutic effect of Portulaca oleracea, in chronic constriction injury (CCI)-induced neuropathic pain in rats. Objective & Methods: Neuropathic pain was performed by putting four loose ligatures around the sciatic nerve. CCI resulted in the development of heat hyperalgesia, mechanical allodynia and cold allodynia accompanied by an increase in the contents of TNF-α, IL1β, malondialdehyde, with a reduction in total thiol content. Results: Administration of Portulaca oleracea (100 and 200 mg/kg intraperitoneal) for 14 days in CCI rats significantly alleviated pain-related behaviors, oxidative damage and inflammatory cytokines in a dose-dependent manner. Conclusion: In conclusion, it is suggested that the antinociceptive effects of Portulaca oleracea might be due to antioxidant and anti-inflammatory properties.

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.

scholarly journals Long-term Application of Glycine Transporter Inhibitors Acts Antineuropathic and Modulates Spinal N-methyl-d-aspartate Receptor Subunit NR-1 Expression in Rats

2014 ◽  
Vol 121 (1) ◽  
pp. 160-169 ◽  
Author(s):  
Franziska Barthel ◽  
Andrea Urban ◽  
Lukas Schlösser ◽  
Volker Eulenburg ◽  
Robert Werdehausen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Side Effects ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Receptor Subunit ◽  
Aspartate Receptor

Abstract Background: Dysfunction of spinal glycinergic neurotransmission is a major pathogenetic factor in neuropathic pain. The synaptic glycine concentration is controlled by the two glycine transporters (GlyT) 1 and 2. GlyT inhibitors act antinociceptive in various animal pain models when applied as bolus. Yet, in some studies, severe neuromotor side effects were reported. The aim of the current study was to elucidate whether continuous inhibition of GlyT ameliorates neuropathic pain without side effects and whether protein expression of GlyT1, GlyT2, or N-methyl-d-aspartate receptor subunit NR-1 in the spinal cord is affected. Methods: In the chronic constriction injury model of neuropathic pain, male Wistar rats received specific GlyT1 and GlyT2 inhibitors (ALX5407 and ALX1393; Sigma-Aldrich®, St. Louis, MO) or vehicle for 14 days via subcutaneous osmotic infusion pumps (n = 6). Mechanical allodynia and thermal hyperalgesia were assessed before, after chronic constriction injury, and every 2 days during substance application. At the end of behavioral assessment, the expression of GlyT1, GlyT2, and NR-1 in the spinal cord was determined by Western blot analysis. Results: Both ALX5407 and ALX1393 ameliorated thermal hyperalgesia and mechanical allodynia in a time- and dose-dependent manner. Respiratory or neuromotor side effects were not observed. NR-1 expression in the ipsilateral spinal cord was significantly reduced by ALX5407, but not by ALX1393. The expression of GlyT1 and GlyT2 remained unchanged. Conclusions: Continuous systemic inhibition of GlyT significantly ameliorates neuropathic pain in rats. Thus, GlyT represent promising targets in pain research. Modulation of N-methyl-d-aspartate receptor expression might represent a novel mechanism for the antinociceptive action of GyT1 inhibitors.

scholarly journals Nrf2 Activation Attenuates Chronic Constriction Injury-Induced Neuropathic Pain via Induction of PGC-1α-Mediated Mitochondrial Biogenesis in the Spinal Cord

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Jia Sun ◽  
Jia-Yan Li ◽  
Long-Qing Zhang ◽  
Dan-Yang Li ◽  
Jia-Yi Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Related Factor ◽  
Dependent Manner ◽  
Nrf2 Activation

Background. Neuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a potent regulator of the antioxidant response system. In this study, we investigated whether RTA-408 (RTA, a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms. Methods. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von Frey test and Hargreaves plantar test. The L4-6 spinal cord was collected to examine the activation of Nrf2 and MB. Results. RTA-408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose-dependent manner. Furthermore, RTA-408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2-dependent manner. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) is the key regulator of MB. We found that the PGC-1α activator also induced a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA-408 was reversed by the preinjection of the PGC-1α inhibitor. Conclusions. Nrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.

scholarly journals Pre-Emptive Treatment of Lidocaine Attenuates Neuropathic Pain and Reduces Pain-Related Biochemical Markers in the Rat Cuneate Nucleus in Median Nerve Chronic Constriction Injury Model

2012 ◽  
Vol 2012 ◽  
pp. 1-9
Author(s):  
Chi-Te Lin ◽  
Yi-Ju Tsai ◽  
Hsin-Ying Wang ◽  
Seu-Hwa Chen ◽  
Tzu-Yu Lin ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Median Nerve ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Electrophysiological Recording ◽  
Dependent Manner ◽  
Cuneate Nucleus ◽  
Treatment Dose ◽  
Lidocaine Pretreatment ◽  
Dose Dependent

This study investigates the effects of lidocaine pre-emptive treatment on neuropathic pain behavior, injury discharges of nerves, neuropeptide Y (NPY) and c-Fos expression in the cuneate nucleus (CN) after median nerve chronic constriction injury (CCI). Behavior tests demonstrated that the pre-emptive lidocaine treatment dose dependently delayed and attenuated the development of mechanical allodynia within a 28-day period. Electrophysiological recording was used to examine the changes in injury discharges of the nerves. An increase in frequency of injury discharges was observed and peaked at postelectrical stimulation stage in the presaline group, which was suppressed by lidocaine pre-emptive treatment in a dose-dependent manner. Lidocaine pretreatment also reduced the number of injury-induced NPY-like immunoreactive (NPY-LI) fibers and c-Fos-LI neurons within the CN in a dose-dependent manner. Furthermore, the mean number of c-Fos-LI neurons in the CN was significantly correlated to the NPY reduction level and the sign of mechanical allodynia following CCI.

scholarly journals Sanguinarine Attenuates Neuropathic Pain in a Rat Model of Chronic Constriction Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Ping Li ◽  
Yan-Xiu Wang ◽  
Guang Yang ◽  
Zun-Cheng Zheng ◽  
Chao Yu
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
P38 Mapk ◽  
Spinal Dorsal Horn ◽  
Chronic Constriction Injury ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Withdrawal Threshold ◽  
Spinal Dorsal ◽  
Plant Medicine

Objective. There is still no effective treatment of neuropathic pain. Sanguinarine is a natural plant medicine with anti-inflammatory effects, but its effect on neuropathic pain remains unclear. This study was aimed at investigating the potential of sanguinarine to attenuate neuropathic pain. Methods. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Rats were randomly divided into several groups: sham, CCI, CCI+SG (1.00 mg/kg), CCI+SG (2.50 mg/kg), and CCI+SG (6.25 mg/kg). SG was injected intraperitoneally from the day of surgery every three days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded before surgery and on days 1, 3, 7, and 14 after surgery. The microglia in the spinal dorsal horn were examined by immunofluorescence. p38 MAPK expression in the spinal dorsal horn was detected by PCR and Western blot analysis. Cytokine levels in the spinal dorsal horn were measured by ELISA. Results. MWT and TWL were significantly reduced in the CCI group, but sanguinarine recovered MWT and TWL in the CCI group. In addition, sanguinarine inhibited the activation of microglia and decreased the expression of p-p38 and TNF-α, IL-1β, and IL-6 in the spinal dorsal horn of the CCI group in a dose-dependent manner. Conclusions. Our results suggest that sanguinarine can attenuate neuropathic pain via inhibiting the activation of microglia and the activation of the p38 MAPK signaling pathway.

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