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 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 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 7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z Notonipetranone Attenuates Neuropathic Pain by Suppressing Oxidative Stress, Inflammatory and Pro-Apoptotic Protein Expressions

Molecules ◽  
2021 ◽  
Vol 26 (1) ◽  
pp. 181
Author(s):  
Amna Khan ◽  
Adnan Khan ◽  
Sidra Khalid ◽  
Bushra Shal ◽  
Eunwoo Kang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neuropathic Pain ◽  
Interleukin 1 ◽  
Related Factor ◽  
Dependent Manner ◽  
Glutathione S Transferase ◽  
Quinone Oxidoreductase ◽  
Apoptotic Protein ◽  
Apoptotic Proteins ◽  
Apoptosis And Inflammation

7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a sesquiterpenoid obtained from a natural source has proved to be effective in minimizing various side effects associated with opioids and nonsteroidal anti-inflammatory drugs. The current study focused on investigating the effects of ECN on neuropathic pain induced by partial sciatic nerve ligation (PSNL) by mainly focusing on oxidative stress, inflammatory and apoptotic proteins expression in mice. ECN (1 and 10 mg/kg, i.p.), was administered once daily for 11 days, starting from the third day after surgery. ECN post-treatment was found to reduce hyperalgesia and allodynia in a dose-dependent manner. ECN remarkably reversed the histopathological abnormalities associated with oxidative stress, apoptosis and inflammation. Furthermore, ECN prevented the suppression of antioxidants (glutathione, glutathione-S-transferase, catalase, superoxide dismutase, NF-E2-related factor-2 (Nrf2), hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase) by PSNL. Moreover, pro-inflammatory cytokines (tumor necrotic factor-alpha, interleukin 1 beta, interleukin 6, cyclooxygenase-2 and inducible nitric oxide synthase) expression was reduced by ECN administration. Treatment with ECN was successful in reducing the caspase-3 level consistent with the observed modulation of pro-apoptotic proteins. Additionally, ECN showed a protective effect on the lipid content of myelin sheath as evident from FTIR spectroscopy which showed the shift of lipid component bands to higher values. Thus, the anti-neuropathic potential of ECN might be due to the inhibition of oxidative stress, inflammatory mediators and pro-apoptotic proteins.

scholarly journals Nuclear PPAR-γ Activation Modulates Inflammation and Oxidative Stress in Attenuating Chemotherapy-Induced Neuropathic Pain in Vivo

2021 ◽  
pp. 167-179
Author(s):  
Haritha Pasupulati ◽  
Satyanarayana S. V. Padi ◽  
Sujatha Dodoala ◽  
Prasad V. S. R. G. Koganti
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
Mechanical Allodynia ◽  
Antinociceptive Effect ◽  
Thermal Hyperalgesia ◽  
Ppar Γ ◽  
Markers Of Inflammation ◽  
And Oxidative Stress

Background: Paclitaxel-induced painful neuropathy is a major dose-limiting side effect and can persist for up to two years after completing treatment that greatly affects both the course of chemotherapy and quality of life in cancer patients. Peroxisome proliferator-activated receptor (PPAR)-γ belongs to a family of nuclear receptors known for their transcriptional and regulatory roles in metabolism, inflammation, and oxidative stress. However, the role of PPAR-γ activation on paclitaxel-induced neuropathic pain is not yet known. Objective: To investigate whether pioglitazone, a PPAR-γ agonist reduce paclitaxel-induced neuropathic pain and to elucidate underlying mechanisms. Methodology: Peripheral neuropathy was induced by administration of paclitaxel (2 mg/kg per injection) intraperitoneally on four alternate days (days 0, 2, 4, 6). Thermal hyperalgesia and mechanical allodynia were assessed and the markers of inflammation and nitroso-oxidative stress were estimated. Results: Pioglitazone did not induce hypoalgesia and had no effect on locomotor activity. Repeated oral administration of pioglitazone (10 and 20 mg/kg,) for 2 weeks started 14 days after paclitaxel injection markedly attenuated paw withdrawal responses to thermal (hyperalgesia) and mechanical (allodynia) stimuli. Further, pioglitazone administration significantly reduced elevated level of pro-inflammatory cytokine, TNF-α, in both the dorsal root ganglia and the spinal cord accompanied by marked decrease in oxidative stress parameters as well as increase in activity of antioxidant defense enzyme, superoxide dismutase, in the spinal cord after paclitaxel injection. Conclusion: The results of the present study demonstrate that pioglitazone, a PPAR-γ agonist exerted antinociceptive effect in paclitaxel-induced neuropathic pain through inhibiting neuroimmune inflammation in both the periphery and spinal cord and by reducing nitroso-oxidative stress in spinal cord. Our findings strongly suggest pharmacological activation of PPAR-g as a promising therapeutic target in paclitaxel-induced peripheral neuropathy and provide rationale for the clinical evaluation.

scholarly journals ECN from Tussilago Farfara Attenuates Neuropathic Pain by Suppressing Oxidative Stress, Inflammatory and Pro-Apoptotic Proteins Expression in Surgical Model

2020 ◽  
Author(s):  
Amna Khan ◽  
Sidra Khalid ◽  
Adnan Khan ◽  
Bushra Shal ◽  
Eunwoo Kang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neuropathic Pain ◽  
Interleukin 1 ◽  
Related Factor ◽  
Dependent Manner ◽  
Quinone Oxidoreductase ◽  
Distress Symptoms ◽  
Tussilago Farfara ◽  
Apoptotic Proteins ◽  
Apoptosis And Inflammation

7β-(3-ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a sesquiterpenoid obtained from a natural origin (Tussilago farfara)has proved to be effective in minimizing various side effects associated with opioids and nonsteroidal anti-inflammatory drugs. The current study focused on investigating the effects of ECN on neuropathic pain induced by partial sciatic nerve ligation (PSNL) by mainly focusing on oxidative stress, inflammatory and apoptotic proteins expression in mice. Neuropathic pain was induced in mice by PSNL surgery performed on day 1 and ECN (1 and 10 mg/kg, i.p.), was administered once daily for 11 days, starting from the third day after surgery. ECN post-treatment was found to reduce hyperalgesia and allodynia in a dose dependent manner. ECN significantly reversed the severity of neuropathic pain by improving distress symptoms and survival rate. ECN remarkably reversed the histopathological abnormalities associated with oxidative stress, apoptosis and inflammation. Furthermore, ECN prevented the suppression of antioxidants (glutathione, glutathione-S-transferase, catalase, superoxide dismutase, NF-E2-related factor-2 (Nrf2), hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase) by PSNL. Moreover, pro-inflammatory cytokines (tumor necrotic factor alpha, interleukin 1 beta, interleukin 6, cyclooxygenase-2 and inducible nitric oxide synthase) expression was reduced by ECN administration. Treatment with ECN was successful in reducing caspase-3 level consistent with the observed modulation of pro-apoptotic proteins. Additionally, ECN showed protective effect on the lipid content of myelin sheath as evident from FTIR spectroscopy which showed the shift of lipid component bands to higher values. Thus, anti-neuropathic potential of ECN might be due to inhibition of oxidative stress, inflammatory mediators and pro-apoptotic proteins.

Rutaecarpine Protects from Neuropathic Pain in a Rat Model of Chronic Compression Injury

2021 ◽  
Vol 19 (4) ◽  
pp. 409-414
Author(s):  
Guizhen Yan ◽  
Hongkun Zhai ◽  
Chunhua Hou ◽  
Chunli Xing
Keyword(s):  
Oxidative Stress ◽  
Neuropathic Pain ◽  
Nerve Tissue ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Dependent Manner ◽  
Compression Injury ◽  
Stress Studies ◽  
Markers Of Oxidative Stress ◽  
Factor Α

Chronic compression injury elevates oxidative stress and inflammation leading to neuropathic pain that is alleviated by rutaecarpine in a dose-dependent manner. To understand the mechanism(s) underlying rutaecarpine effects on this process, changes in the expressions of the proteins and messenger ribonucleic acids for tumor necrosis factor-α, interlukin-6, and interleukin-1β were assessed. Also, the pathology of the sciatic nerve tissue was examined histologically. Furthermore, the expression of the levels of malondialdehyde, superoxide dismutase, and glutathione proteins were evaluated as markers of oxidative stress. Studies aimed at the understanding the mechanisms underlying actions of rutaecarpine suggested it to exert a protective effect on neuropathic pain in a chronic compression injury rat via activating nuclear-factor erythroid 2-related factor 2/Heme oxygenase-1 and inhibiting 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 gene pathways.

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 Pre-emptive PPAR-γ Activation Abolishes Development of Nerve Injury-induced Behavioral Hypersensitivity: Elucidating Underlying Mechanisms

2021 ◽  
pp. 23-37
Author(s):  
Seema Thakur ◽  
Haritha Pasupulati ◽  
Saurabh Sharma ◽  
Satyanarayana S. V. Padi
Keyword(s):  
Oxidative Stress ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Plasma Extravasation ◽  
Painful Condition ◽  
Cold Allodynia ◽  
Ppar Γ ◽  
Underlying Mechanisms

Background: Neuropathic pain is a chronic incapacitating painful condition for which there is no effective treatment. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that play key roles in modulating immune and inflammatory responses. The antinociceptive properties of PPAR-γ activation on development of neuropathic pain are not fully known. Objective: To determine the role of PPAR-γ activation on the development of neuropathic pain following chronic constriction injury and to elucidate underlying mechanisms. Methodology: Neuropathy was induced by chronic constriction injury of sciatic nerve in rats. Cold allodynia and thermal hyperalgesia were assessed and the markers of inflammation and nitroso-oxidative stress were estimated. Results: Pre-emptive administration of pioglitazone, a PPAR-γ agonist (3, 10 or 30 mg/kg, i.p. 1 hr before surgery and continued once daily for 2 weeks) dose-dependently attenuated paw withdrawal latency to cold (allodynia) and thermal (hyperalgesia) stimuli. Pioglitazone significantly reduced elevated TBARS, protein carbonylation, nitrite levels and markedly restored depleted GSH, and reduction in activities of SOD and catalase in injured nerves. Further, pioglitazone markedly reduced plasma extravasation and levels of pro-inflammatory cytokines TNF-α and IL-1β following nerve injury. Moreover, pioglitazone did not alter the locomotor activity. Pretreatment with PPAR-γ antagonist BADGE (30 mg/kg, i.p.) blocked the beneficial effects of pioglitazone. Essentially, pioglitazone promoted the long-lasing recovery and also prevented the development of neuropathic pain even after treatment termination. Conclusion: Pioglitazone, a PPAR-γ agonist receptor-dependently abolished the development of traumatic neuropathic pain and exerted long-lasting antinociceptive effects through reducing nitroso-oxidative stress and inflammation. Our findings strongly suggest that pre-emptive activation of PPAR-γ prevented or at least delayed the development of nerve injury-induced pain hypersensitivity.

scholarly journals Fumagillin Attenuates Spinal Angiogenesis, Neuroinflammation, and Pain in Neuropathic Rats After Chronic Constriction Injury

2021 ◽  
Author(s):  
Zhi-Hong Wen ◽  
Shi-Ying Huang ◽  
Hsiao-Mei Kuo ◽  
Chao-Ting Chen ◽  
Nan-Fu Chen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Chronic Constriction Injury ◽  
Angiogenesis Inhibitor ◽  
Thermal Hyperalgesia ◽  
Lumbar Spinal Cord ◽  
Astrocyte Activation ◽  
Anti Vegf ◽  
Tnf Α ◽  
The Impact

Abstract Background Angiogenesis in the central nervous system is visible in animal models of neuroinflammation and bone cancer pain. However, whether spinal angiogenesis exists and contributes to central sensitization in neuropathic pain remains unclear. This study analyzed the impact of angiogenesis on spinal neuroinflammation in neuropathic pain. Methods Rats with chronic constriction injury (CCI) to sciatic nerve underwent implantation of an intrathecal catheter. Fumagillin or vascular endothelial growth factor-A antibody (anti-VEGF-A) was administered intrathecally. Nociceptive behaviors, cytokine immunoassay, Western blot, and immunohistochemical analysis assessed the effect of angiogenesis inhibition on CCI-induced neuropathic pain. Results VEGF, cluster of differentiation 31 (CD31), and von Willebrand factor (vWF) expressions increased after CCI in the ipsilateral lumbar spinal cord compared to that in the contralateral side of CCI and control rats from postoperative day (POD) 7 to 28, with a peak at POD 14. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 concentrations, but not IL-10 levels, also increased in the ipsilateral spinal cord after CCI. Fumagillin and anti-VEGF-A reduced CCI-induced thermal hyperalgesia from POD 5 to 14 and mechanical allodynia from POD 3 to 14. Fumagillin reduced CCI-upregulated expressions of angiogenic factors and astrocytes. Furthermore, fumagillin decreased TNF-α and IL-6 amounts and increased IL-10 levels at POD 7 and 14, but not IL-1β concentrations. Conclusions Fumagillin significantly ameliorates CCI-induced nociceptive sensitization, spinal angiogenesis and astrocyte activation. Our results suggest that angiogenesis inhibitor treatment suppresses peripheral neuropathy-induced central angiogenesis, neuroinflammation, astrocyte activation, and neuropathic pain.

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

2012 ◽  
Vol 25 (1) ◽  
pp. 219-230 ◽  
Author(s):  
L.W. Chu ◽  
J.Y. Chen ◽  
K.L. Yu ◽  
K.I. Cheng ◽  
I.J. Chen ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Neuroprotective Effects ◽  
Peripheral Neuropathic Pain ◽  
Anti Inflammatory ◽  
Coa Reductase

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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