Neuroprotective and Anti-Inflammatory Activities of Atorvastatin in a Rat Chronic Constriction Injury Model

Atorvastatin is an HMG-CoA reductase inhibitor used to treat hypercholesterolemic conditions associated with hypertension. This study aims to investigate the anti-inflammatory and neuroprotective effects of atorvastatin on peripheral neuropathic pain. Peripheral neuropathic pain was induced by chronic constriction injury (CCI) in Sprague-Dawley rats. Rats were divided into 3 groups including sham-operated, CCI, and atorvastatin-treated. Atorvastatin (10 mg/kg) or phosphate-buffered saline was orally administered for 2 weeks. All animals were assessed by neurobehavioral tests before surgery and at days 3, 7, 14 after surgery. Inflammatory and neuroprotective factors were evaluated by Western blot analysis. eNOS, COX2 and iNOS in the sciatic nerve were also studied using immunohistochemistry. Atorvastatin attenuated CCI-induced nociceptive sensitization and thermal hyperalgesia in a time-dependent manner. Atorvastatin improved CCI-induced neurobehavioral/inflammatory activity by inhibition of TGF-β, PIκB/IκB, NFκB, COX2, iNOS, EP1 and EP4 in the sciatic nerve. Atorvastatin was also found to increase neuroprotection factors pAkt/Akt, eNOS and VEGF. Taken together, these data indicate that atorvastatin could protect the sciatic nerve against CCI-induced neuroinflammation and nociception.

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

Anais da Academia Brasileira de Ciências ◽

10.1590/s0001-37652012005000063 ◽

2012 ◽

Vol 84 (4) ◽

pp. 1091-1104 ◽

Cited By ~ 10

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.

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

Clinical Phytoscience ◽

10.1186/s40816-021-00263-7 ◽

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.

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

International Journal of Basic & Clinical Pharmacology ◽

10.18203/2319-2003.ijbcp20185171 ◽

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.

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Haematoxylon campechianum Extract Ameliorates Neuropathic Pain via Inhibition of NF-κB/TNF-α/NOX/iNOS Signalling Pathway in a Rat Model of Chronic Constriction Injury

Biomolecules ◽

10.3390/biom10030386 ◽

2020 ◽

Vol 10 (3) ◽

pp. 386 ◽

Cited By ~ 3

Author(s):

Mansour Sobeh ◽

Mona F. Mahmoud ◽

Samar Rezq ◽

Mohamed A.O. Abdelfattah ◽

Islam Mostafa ◽

...

Keyword(s):

Neuropathic Pain ◽

Sciatic Nerve ◽

Brain Stem ◽

Rat Model ◽

Structural Changes ◽

Chronic Constriction Injury ◽

Biological Activities ◽

Ethanol Extract ◽

Phenolic Constituents ◽

Anti Inflammatory

In this study, the phytochemical composition and the possible prophylactic effects of an aqueous ethanol extract of Haematoxylon campechianum flowers (HCF) on peripheral neuropathic pain in a chronic constriction injury (CCI) rat model are investigated. Rats with induced CCI were subjected to neuropathic pain behaviour tests and evaluated by chemical, thermal, and mechanical sensation tests and functional recovery of the brain stem and sciatic nerve at 7- and 14-day intervals. The effect of the extract on acute pain and inflammation is also investigated. The extract exerted both peripheral and central analgesic and anti-inflammatory properties in addition to antipyretic effects that are clear from targeting COX, LOX and PGE. It was found that CCI produced significant thermal and mechanical hyperalgesia, cold allodynia and deleterious structural changes in both sciatic nerve and brain stem. Treatments with HCF extract significantly improved cold and thermal withdrawal latency, mechanical sensibility and ameliorated deleterious changes of sciatic nerve and brain stem at different dose levels. The extract also ameliorated oxidative stress and inflammatory markers in brain stem and sciatic nerve. It suppressed the apoptotic marker, p53, and restored myelin sheath integrity. The effects of HCF extract were more potent than pregabalin. Fifteen secondary metabolites, mainly gallotannins and flavonoids, were characterized in the extract based on their retention times and MS/MS data. The identified phenolic constituents from the extract could be promising candidates to treat neuropathic pain due to their diverse biological activities, including antioxidant, anti-inflammatory and neuroprotective properties.

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

10.21203/rs.3.rs-723909/v1 ◽

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.

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

10.21203/rs.3.rs-238483/v1 ◽

2021 ◽

Author(s):

Huilian Bu ◽

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.

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1,3,4-Oxadiazole Derivative Attenuates Chronic Constriction Injury Induced Neuropathic Pain: A Computational, Behavioral, and Molecular Approach

Brain Sciences ◽

10.3390/brainsci10100731 ◽

2020 ◽

Vol 10 (10) ◽

pp. 731

Author(s):

Muhammad Faheem ◽

Syed Hussain Ali ◽

Abdul Waheed Khan ◽

Mahboob Alam ◽

Umair Ilyas ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Pain Perception ◽

Chronic Constriction Injury ◽

Neuroprotective Effect ◽

Underlying Mechanism ◽

Contributing Factors ◽

Neuroprotective Effects ◽

In Silico Studies

The production and up-regulation of inflammatory mediators are contributing factors for the development and maintenance of neuropathic pain. In the present study, the post-treatment of synthetic 1,3,4 oxadiazole derivative (B3) for its neuroprotective potential in chronic constriction injury-induced neuropathic pain was applied. In-silico studies were carried out through Auto Dock, PyRx, and DSV to obtain the possible binding and interactions of the ligands (B3) with COX-2, IL-6, and iNOS. The sciatic nerve of the anesthetized rat was constricted with sutures 3/0. Treatment with 1,3,4-oxadiazole derivative was started a day after surgery and continued until the 14th day. All behavioral studies were executed on day 0, 3rd, 7th, 10th, and 14th. The sciatic nerve and spinal cord were collected for further molecular analysis. The interactions in the form of hydrogen bonding stabilizes the ligand target complex. B3 showed three hydrogen bonds with IL-6. B3, in addition to correcting paw posture/deformation induced by CCI, attenuates hyperalgesia (p < 0.001) and allodynia (p < 0.001). B3 significantly raised the level of GST and GSH in both the sciatic nerve and spinal cord and reduced the LPO and iNOS (p < 0.001). B3 attenuates the pathological changes induced by nerve injury, which was confirmed by H&E staining and IHC examination. B3 down-regulates the over-expression of the inflammatory mediator IL-6 and hence provides neuroprotective effects in CCI-induced pain. The results demonstrate that B3 possess anti-nociceptive and anti-hyperalgesic effects and thus minimizes pain perception and inflammation. The possible underlying mechanism for the neuroprotective effect of B3 probably may be mediated through IL-6.

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

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190314110528 ◽

2019 ◽

Vol 18 (4) ◽

pp. 342-349 ◽

Cited By ~ 2

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.

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