Potamogeton perfoliatus L. Extract Attenuates Neuroinflammation and Neuropathic Pain in Sciatic Nerve Chronic Constriction Injury-Induced Peripheral Neuropathy in Rats

Sciatic nerve injury is often associated with neuropathic pain and neuroinflammation in the central and peripheral nervous systems. In our previous work, Potamogeton perfoliatus L. displayed anti-inflammatory, antipyretic and analgesic properties, predominantly via the inhibition of COX-2 enzyme and attenuation of oxidative stress. Herein, we extended our investigations to study the effects of the plant’s extract on pain-related behaviors, oxidative stress, apoptosis markers, GFAP, CD68 and neuro-inflammation in sciatic nerve chronic constriction injury (CCI) rat model. The levels of the pro-inflammatory marker proteins in sciatic nerve and brainstem were measured with ELISA 14 days after CCI induction. Pretreatment with the extract significantly attenuated mechanical and cold allodynia and heat hyperalgesia with better potential than the reference drug, pregabalin. In addition, CCI lead to the overexpression of prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), tumor necrosis alpha (TNFα), nuclear factor κB (NF-κB), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and NADPH oxidase-1 (NOX-1) and decreased the catalase level in sciatic nerve and brainstem. The observed neuro-inflammatory changes were accompanied with glial cells activation (increased GFAP and CD68 positive cells), apoptosis (increased Bax) and structural changes in both brainstem and sciatic nerve. The studied extract attenuated the CCI-induced neuro-inflammatory changes, oxidative stress, and apoptosis while it induced the expression of Bcl-2 and catalase in a dose dependent manner. It also decreased the brainstem expression of CD68 and GFAP indicating a possible neuroprotection effect. Taking together, P. perfoliatus may be considered as a novel therapy for neuropathic pain patients after performing the required clinical trials.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

Salix tetrasperma Roxb. Extract Alleviates Neuropathic Pain in Rats via Modulation of the NF-κB/TNF-α/NOX/iNOS Pathway

Antioxidants ◽

10.3390/antiox8100482 ◽

2019 ◽

Vol 8 (10) ◽

pp. 482 ◽

Cited By ~ 6

Author(s):

Sobeh ◽

Mahmoud ◽

Rezq ◽

Alsemeh ◽

Sabry ◽

...

Keyword(s):

Neuropathic Pain ◽

Sciatic Nerve ◽

Brain Stem ◽

Antioxidant Activities ◽

Enzyme Linked Immunosorbent Assay ◽

Dependent Manner ◽

P53 Expression ◽

Tnf Α ◽

Cox 2

Patients with neuropathic pain experience chronic painful tingling, burning, and prickling sensations accompanied with hyperalgesia and/or allodynia. In this study, 38 secondary metabolites of a methanol extract from Salix tetrasperma flowers were identified by liquid chromatography-mass spectrometry (HPLC-MS/MS). The extract showed substantial anti-inflammatory, central and peripheral anti-nociceptive, antipyretic, and antioxidant activities in vitro and in different animal models. In the chronic constriction injury (CCI) rat model, the extract was able to attenuate and significantly relieve hyperalgesia and allodynia responses in a dose dependent manner and restore the myelin sheath integrity and Schwann cells average number in the sciatic nerve. The enzyme-linked immunosorbent assay (ELISA) showed that the extract significantly reduced the expression of various pro-inflammatory biomarkers including nuclear factor kabba B (NF-κB), tumor necrosis factor alpha (TNF-α), prostaglandin E2 (PGE2), 5-lipoxygenase (5-LOX), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and the oxidative stress biomarker NADPH oxidase 1 (NOX1), in brain stem and sciatic nerve tissues. These findings were supported by in vitro enzyme inhibition assays (COX-1, COX-2 and 5-LOX). Moreover, the extract significantly reduced p53 expression in the brain stem tissue. These findings support the use of S. tetrasperma in folk medicine to alleviate pain. It could be a promising natural product for further clinical investigations to treat inflammation, nociceptive pain and chronic neuropathic pain.

Download Full-text

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9577874 ◽

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.

Download Full-text

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

International Journal of Immunopathology and Pharmacology ◽

10.1177/039463201202500124 ◽

2012 ◽

Vol 25 (1) ◽

pp. 219-230 ◽

Cited By ~ 23

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.

Download Full-text

Ameliorative potential of Vernonia cinerea on chronic constriction injury of sciatic nerve induced neuropathic pain in rats

Anais da Academia Brasileira de Ciências ◽

10.1590/0001-3765201420130404 ◽

2014 ◽

Vol 86 (3) ◽

pp. 1435-1450 ◽

Cited By ~ 5

Author(s):

VENKATA R.K. THIAGARAJAN ◽

PALANICHAMY SHANMUGAM ◽

UMA M. KRISHNAN ◽

ARUNACHALAM MUTHURAMAN

Keyword(s):

Neuropathic Pain ◽

Sciatic Nerve ◽

Chronic Constriction Injury ◽

Ethanolic Extract ◽

Thiobarbituric Acid ◽

Nerve Tissue ◽

Control Group ◽

Dependent Manner ◽

Pretreated Group ◽

Vernonia Cinerea

The aim of the present study is to investigate the ameliorative potential of ethanolic extract of whole plant of Vernonia cinerea in the chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rats. Behavioral parameters such as a hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests were performed to assess the degree of thermal, chemical and mechanical hyperalgesia and allodynia. Biochemical changes in sciatic nerve tissue were ruled out by estimating thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total calcium levels. Ethanolic extract of Vernonia cinerea and pregabalin were administered for 14 consecutive days starting from the day of surgery. CCI of sciatic nerve has been shown to induce significant changes in behavioral, biochemical and histopathological assessments when compared to the sham control group. Vernonia cinerea attenuated in a dose dependent manner the above pathological changes induced by CCI of the sciatic nerve, which is similar to attenuation of the pregabalin pretreated group. The ameliorating effect of ethanolic extract of Vernonia cinerea against CCI of sciatic nerve induced neuropathic pain may be due to the presence of flavonoids and this effect is attributed to anti-oxidative, neuroprotective and calcium channel modulator actions of these compounds.

Download Full-text

Thymus algeriensis and Thymus fontanesii exert neuroprotective effect against chronic constriction injury-induced neuropathic pain in rats

Scientific Reports ◽

10.1038/s41598-020-77424-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Samar Rezq ◽

Amira E. Alsemeh ◽

Luigi D’Elia ◽

Assem M. El-Shazly ◽

Daria Maria Monti ◽

...

Keyword(s):

Oxidative Stress ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Caspase 3 ◽

Chronic Constriction Injury ◽

Hacat Cells ◽

Protective Effects ◽

Chronic Neuropathic Pain ◽

Thymus Algeriensis ◽

Post Surgery

AbstractWe have previously demonstrated that the Thymus algeriensis and Thymus fontanesii extracts have powerful anti-inflammatory, antipyretic, and analgesic effects against acute pain models. We profiled their chemical composition and found many phenolic acids, flavonoids, and phenolic diterpenes. In this work, we investigated their antioxidant properties on HaCaT cells exposed to UVA-induced oxidative stress and examined their effects against chronic neuropathic pain and the underlying mechanisms. Through a rat chronic constriction injury (CCI) model, we induced chronic neuropathic pain by placing 4 loose ligatures around the right sciatic nerve for 14 days. Thermal and mechanical hyperalgesia in addition to cold and dynamic allodynia were tested on the day before surgery and on the 7th and 14th post-surgery days. Key markers of the nitrosative and oxidative stresses, in addition to markers of inflammation, were measured at day 14 post surgery. Histopathological examination and immunostaining of both synaptophysin and caspase-3 of sciatic nerve and brain stem were also performed. Results of this study showed that T. algeriensis extract suppresses UVA oxidative stress in HaCaT cells via activation of the Nrf-2 pathway. Both extracts attenuated hyperalgesia and allodynia at 7- and 14-days post-surgery with more prominent effects at day 14 of surgery. Their protective effects against neuropathic pain were mediated by inhibiting NOX-1, iNOS, by increasing the enzyme activity of catalase, and inhibition of inflammatory mediators, NF-κB, TNF-α, lipoxygenase, COX-2 enzymes, and PGE2. Furthermore, they improved deleterious structural changes of the brainstem and sciatic nerve. They also attenuated the increased caspase-3 and synaptophysin. The data indicate that both extracts have neuroprotective effects against chronic constriction injury-induced neuropathic pain. The observed protective effects are partially mediated through attenuation of oxidative and nitrosative stress and suppression of both neuroinflammation and neuronal apoptosis, suggesting substantial activities of both extracts in amelioration of painful peripheral neuropathy.

Download Full-text

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.

Download Full-text