Research progress of traditional Chinese medicine monomer in treating diabetic peripheral neuropathy: A review.

Diabetes peripheral neuropathy is one of the most common complications of diabetes. Early symptoms are insidious, while late symptoms mainly include numbness, pain, swelling, and loss of sensation in the limbs, which can lead to disability, foot ulcers, amputation, and so on. At present, the pathogenesis is also complex and diverse, and it is not yet clear. Western medicine treatment mainly focuses on controlling blood sugar and nourishing nerves, but the effect is not ideal. In recent years, it has been found that many drug monomers have shown good therapeutic and prognostic effects in the prevention and treatment of diabetes peripheral neuropathy, and related research has become a hot topic. To understand the specific mechanism of action of traditional Chinese medicine monomers in treatment, this article provides a review of their mechanism research and key roles. It mainly includes flavonoids, phenols, terpenes, saponins, alkaloids, polysaccharides, etc. By nuclear factor-κB (NF-κB), the signaling pathways of adenosine monophosphate-activated protein kinase (AMPK), Nrf2/ARE, SIRT1/p53, etc, can play a role in lowering blood sugar, antioxidant, anti-inflammatory, inhibiting cell apoptosis, and autophagy, promoting sciatic nerve regeneration, and have great potential in the prevention and treatment of this disease. A systematic summary of its related mechanisms of action was conducted, providing ideas for in-depth research and exploration of richer traditional Chinese medicine components, and also providing a relatively complete theoretical reference for clinical research on diabetes peripheral neuropathy treatment.

Protective and therapeutic effect of (S)-ginsenoside F1 on peripheral nerve degeneration targeting Schwann cells: a pharmaco-neuroanatomical approach.

Damaged peripheral nerves undergo peripheral neurodegenerative processes that are essential for the nerve regeneration. Peripheral neurodegenerative diseases, including diabetic peripheral neuropathy, are induced by irreversible nerve damage caused by abnormal peripheral nerve degeneration. However, until now, there have been no effective therapeutic treatments for these diseases. Ginsenosides are the most pharmacologically active compounds in Panax ginseng, and are being actively studied. Ginsenosides have a variety of effects, including neuroprotective, antioxidative, anti-cytotoxic, and anti-inflammatory effects. Here, we investigated the efficacy of 18 ginsenosides. We then tested the ability of the most effective ginsenoside, (S)-ginsenosides F1 (sF1), to inhibit peripheral neurodegenerative processes using mouse sciatic ex vivo culture, and several morphological and biochemical indicators. Our results suggest that sF1 could effectively protect Schwann cells against peripheral nerve degeneration.

Divanillyl sulfone suppresses NLRP3 inflammasome activation via inducing mitophagy to ameliorate chronic neuropathic pain in mice.

BACKGROUND: Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Divanillyl sulfone (DS), a novel structural derivative of 4,4'-dihydroxydibenzyl sulfoxide from a traditional Chinese medicine Gastrodia elata with anti-nociceptive effects, significantly alleviated neuropathic pain following intrathecal injection. Here, we aimed to investigate the underlying mechanisms of DS against neuropathic pain. METHODS: A chronic constrictive injury (CCI) mouse model of neuropathic pain induced by sciatic nerve ligation was performed to evaluate the effect of DS by measuring the limb withdrawal using Von Frey filament test. Immunofluorescence staining was used to assess the cell localizations and expressions of Iba-1, ASC, NLRP3, and ROS, the formation of autolysosome. The levels of NLRP3-related proteins (caspase-1, NLRP3, and IL-1ß), mitophagy-related proteins (LC3, Beclin-1, and p62), and apoptosis-related proteins (Bcl-XL and Bax) were detected by Western blotting. The apoptosis of BV-2 cell and caspase activity were evaluated by flow cytometry. RESULTS: DS significantly alleviated the neuropathic pain by increasing the mechanical withdrawal threshold and inhibiting the activation of NLRP3 in CCI-induced model mice. Our findings indicated that DS promoted the mitophagy by increasing the LC3II and Beclin 1 and decreasing the levels of p62 protein in BV-2 cell. This is accompanied by the inhibition of NLRP3 activation, which was shown as inhibited the expression of NLRP3 in lysates as well as the secretion of mature caspase-1 p10 and IL-1ß p17 in supernatants in cultured BV-2 microglia. In addition, DS could promote mitophagy-induced improvement of dysfunctional mitochondria by clearing intracellular ROS and restoring mitochondrial membrane potential. CONCLUSION: Together, our findings demonstrated that DS ameliorate chronic neuropathic pain in mice by suppressing NLRP3 inflammasome activation induced by mitophagy in microglia. DS may be a promising therapeutic agent for chronic neuropathic pain.

Icariin ameliorates partial sciatic nerve ligation induced neuropathic pain in rats: an evidence of in silico and in vivo studies.

OBJECTIVES: Neuropathic pain (NP) is a chronic inflammation of the sciatic nerve, associated with complex pathophysiological events like neuronal ectopic discharge with changes in neurotransmitters, growth factors, receptors/ion channels including N-methyl-d-aspartate receptors, Transient receptor cation channels, Voltage-gated calcium channels. All these events eventually lead to inflammation and apoptosis of the sciatic nerve in NP. Icariin (ICA), a natural flavonoid is well known for its anti-inflammatory potential. Hence, the present study is designed to evaluate its anti-inflammatory potential against neuropathic pain using in silico and in vivo studies. METHODS: In silico studies were conducted using targets of N-methyl-D-aspartate receptor subtype-2B (NR2B), The capsaicin receptor transient receptor cation channel subfamily-V member-1 (TRPV1), N-type voltage-gated calcium (CaV2.2) channels. In in vivo studies, after partial sciatic nerve ligation surgery to animals, received their respective treatment for 21 days, further TNF-α, IL-6, Bax (proapoptotic) and Bcl-2 (antiapoptotic) expressions were estimated. KEY FINDINGS: ICA decreased the expressions of TNF-α, IL-6, Bax and increased expression of Bcl-2. In silico studies revealed a good energy binding score towards NR2B, TRPV1 receptors and CaV2.2 ion Channel. CONCLUSIONS: ICA could be a promising agent in alleviating neuropathic pain by inhibiting NR2B, TRPV1 receptors and Cav2.2 channels, which induces anti-apoptotic potential and inhibits inflammation.

Bromelain reduced pro-inflammatory mediators as a common pathway that mediate antinociceptive and anti-anxiety effects in sciatic nerve ligated Wistar rats.

The involvement of pro-inflammatory mediators complicates the complex mechanism in neuropathic pain (NP). This study investigated the roles of bromelain against pro-inflammatory mediators as a mechanism that underpins its antinociceptive and anti-anxiety effects in the peripheral model of NP. Sixty-four male Wistar rats randomly divided into eight groups, were used for the study. A chronic constriction injury model of peripheral neuropathy was used to induce NP. Tail-immersion and von Frey filaments tests were used to assess hyperalgesia while open field and elevated plus mazes were used to assess anxiety-like behaviour. NF-кB, iNOS, nitrate, and pro-inflammatory cytokines were investigated in the plasma, sciatic nerve, and brain tissues using ELISA, spectrophotometer, and immunohistochemistry techniques after twenty-one days of treatment. Bromelain significantly (p < 0.05) improved the cardinal signs of NP and inhibited anxiety-like behaviours in ligated Wistar rats. It mitigated the increases in cerebral cortex interleukin (IL) -1ß, IL-6, and PGE2 levels. Bromelain reduced NF-кB, IL-1ß, IL-6, TNF-α, PGE2, and nitrate concentrations as well as the expression of iNOS in the sciatic nerve. Hence, the antinociceptive and anxiolytic effects of bromelain in the sciatic nerve ligation model of NP is in part due to its ability to reduce nitrosative and inflammatory activities.

Protective Effects of Curcumin Against Paclitaxel-Induced Spinal Cord and Sciatic Nerve Injuries in Rats.

Paclitaxel (PTX) is an antineoplastic agent commonly used in the treatment of solid tumors and is known to cause dose-limiting peripheral neurotoxicity. This study was performed to evaluate the protective effect of curcumin (CUR) against PTX-induced spinal cord and sciatic nerve injuries in rats. The rats were administered PTX (2 mg/kg, BW) intraperitoneally for the first 5 consecutive days followed by administration of CUR (100 and 200 mg/kg, BW daily in corn oil) orally for 10 days. Our results showed that CUR significantly reduced mRNA expression levels of NF-κB, TNF-α, IL-6, iNOS and GFAP whereas caused an increase in levels of Nrf2, HO-1 and NQO1 in the spinal cord and sciatic nerve of PTX-induced rats. In addition, CUR suppressed the activation of apoptotic and autophagic pathways by increasing Bcl-2 and Bcl-xL, and decreasing p53, caspase-3, Apaf-1, LC3A, LC3B and beclin-1 mRNA expression levels. The results showed that CUR also maintained the spinal cord and sciatic nerve histological architecture and integrity by both LFB staining and H&E staining. Immunohistochemical expressions of 8-OHdG, caspase-3 and LC3B in the PTX-induced spinal cord tissue were decreased after administration of CUR. Taken together, our findings demonstrated that CUR has protective effects on PTX-induced spinal cord and sciatic nerve injuries in rats.

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

We 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.

Jinmaitong ameliorates diabetic peripheral neuropathy in streptozotocin-induced diabetic rats by modulating gut microbiota and neuregulin 1.

Jinmaitong (JMT), a compound prescription of traditional Chinese medicine, has long been used as a therapy for diabetic peripheral neuropathy (DPN). However, the neuroprotective mechanisms of JMT and its effect on gut microbiota remained unknown. Here, we examined the effects of JMT on behavior, pathomorphology and gut microbiota in streptozotocin (STZ)-induced DPN rats. Compared to distilled water administration, JMT reversed decreases in mechanical withdraw threshold and intraepidermal nerve fiber density, improved neurological morphology of sciatic nerves, increased serum neuregulin 1 (NRG1) level and contactin-associated protein (Caspr)-positive paranodes, and decreased amyloid precursor protein (APP) accumulation in DPN rats. More importantly, JMT enriched nine species of the gut microbiota of DPN rats, helping to prevent dysbiosis. Among these species, p_Actinobacteria, p_Proteobacteria and c_Actinobacteria were negatively correlated with DPN phenotypes and positively correlated with serum NRG1 level. These results indicate that JMT may exert a neuroprotective effect by modulating phenotype-associated gut microbiota and increasing serum NRG1 level in STZ-induced DPN rats. JMT may therefore be an effective complementary and alternative anti-DPN therapy.

Combination therapy with ropivacaine-loaded liposomes and nutrient deprivation for simultaneous cancer therapy and cancer pain relief.

Autophagy allows cancer cells to respond changes in nutrient status by degrading and recycling non-essential intracellular contents. Inhibition of autophagy combined with nutrient deprivation is an effective strategy to treat cancer. Pain is a primary determinant of poor quality of life in advanced cancer patients, but there is currently no satisfactory treatment. In addition, effective treatment of cancer does not efficiently relieve cancer pain, but may increase pain in many cases. Hence, few studies focus on simultaneous cancer therapy and pain relief, and made this situation even worse. Method: Ropivacaine was loaded into tumor-active targeted liposomes. The cytotoxicity of ropivacaine-based combination therapy in B16 and HeLa cells were tested. Moreover, a mice model of cancer pain which was induced by inoculation of melanoma near the sciatic nerve was constructed to assess the cancer suppression and pain relief effects of ropivacaine-based combination therapy. Results: Ropivacaine and ropivacaine-loaded liposomes (Rop-DPRL) were novelly found to damage autophagic degradation. Replicated administration of Rop-DPRL and calorie restriction (CR) could efficiently repress the development of tumor. In addition, administration of Rop-DPRL could relieve cancer pain with its own analgestic ability in a short duration, while repeated administration of Rop-DPRL and CR resulted in continuous alleviation of cancer pain through reduction of VEGF-A levels in advanced cancer mice. Further, dual inhibition of phosphorylation of STAT3 at Tyr705 and Ser727 by Rop-DPRL and CR contribute to the reduction of VEGF-A. Conclusion: Combination therapy with Rop-DPRL and nutrient deprivation simultaneously suppresses cancer growth and relieves cancer pain.

Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats.

We evaluated the mechanisms underlying the spinal cord stimulation (SCS)-induced analgesic effect on neuropathic pain following spared nerve injury (SNI). On day 3 after SNI, SCS was performed for 6 h by using electrodes paraspinally placed on the L4-S1 spinal cord. The effects of SCS and intraperitoneal minocycline administration on plantar mechanical sensitivity, microglial activation, and neuronal excitability in the L4 dorsal horn were assessed on day 3 after SNI. The somatosensory cortical responses to electrical stimulation of the hind paw on day 3 following SNI were examined by using in vivo optical imaging with a voltage-sensitive dye. On day 3 after SNI, plantar mechanical hypersensitivity and enhanced microglial activation were suppressed by minocycline or SCS, and L4 dorsal horn nociceptive neuronal hyperexcitability was suppressed by SCS. In vivo optical imaging also revealed that electrical stimulation of the hind paw-activated areas in the somatosensory cortex was decreased by SCS. The present findings suggest that SCS could suppress plantar SNI-induced neuropathic pain via inhibition of microglial activation in the L4 dorsal horn, which is involved in spinal neuronal hyperexcitability. SCS is likely to be a potential alternative and complementary medicine therapy to alleviate neuropathic pain following nerve injury.

Electrophysiological, functional and histopathological assessments of high dose melatonin on regeneration after blunt sciatic nerve injury.

The aim of this study was to determine the curative effects of high-dose (100 mg/kg) melatonin on peripheral nerve injury. Forty male Wistar albino rats were randomized into four groups as sham, vehicle, melatonin, and ischemia and their right sciatic nerves were exposed. The process was terminated in the sham group. In the other groups, nerve injury was induced by clip compression. The vehicle group was intraperitoneally administered ethanol 0.1 cc (melatonin solvent), while the melatonin group was intraperitoneally administered a single dose of melatonin (100 mg/kg). Following the surgery, sciatic nerve functional index (SFI) was measured using walking track analysis on days 7, 14, and 21, and latency, amplitude, and muscle action potentials (MAP) field values were measured using electroneuromyography (ENMG) on day 21. Histopathologically, edema, axonal degeneration, myelin damage, and inflammatory response were evaluated in all groups. SFI values were noted to be statistically significantly different among the vehicle, melatonin, and ischemia groups, and the melatonin group showed a faster recovery. In the ENMG evaluations, higher amplitude and field values in the melatonin group indicated that melatonin accelerated peripheral nerve recovery. Histopathologically, although fibers with loss of myelin were identified in the melatonin group, the myelin sheath was preserved in general and the axonal structure was noted to be normal. A single injection of high-dose melatonin was found to preserve myelin sheath, prevent axonal loss, and accelerate functional recovery during the nerve regeneration in peripheral nerve injury.

Beneficial effects of fish oil enriched in omega-3 fatty acids on the development and maintenance of neuropathic pain.

OBJECTIVE: The aim of this work was to assess the preventive effect of an eicosapentaenoic acid/docosahexaenoic acid-concentrate fish oil on neuropathic pain development and regenerative features of sciatic nerve in rats. METHODS: In the present study, rats with chronic constriction injury (CCI) of the sciatic nerve and sham-operated ones received fish oil enriched in omega-3 fatty acids (0.36 or 0.72 g/kg per day, oral) or saline solution for 21 days, with thermal hyperalgesia and mechanical allodynia being assessed before and 3, 7, 14 and 21 days after injury. KEY FINDINGS: Fish oil enriched in omega-3 fatty acids (0.72 g/kg) reversed thermal hyperalgesia and significantly reduced mechanical allodynia. In addition, ω-3 treatment (0.72 g/kg) promoted the recovery of the Sciatic Functional Index as well as restored axonal density and morphology, without the formation of neuroma in the injured sciatic nerves after 21 days. CONCLUSION: We conclude that the fish oil enriched in omega-3 fatty acids administration relieves thermal hyperalgesia and mechanical allodynia effectively and also enhances the recovery process in rats with CCI of the sciatic nerve. These findings might contribute to new therapeutic approaches including omega-3 fatty acids in neuropathic pain treatment.

Neurotherapeutic effects of Ginkgo biloba extract and its terpene trilactone, ginkgolide B, on sciatic crush injury model: A new evidence.

Ginkgo biloba leaves extract (GBE) was subjected to neuroprotective-guided fractionation to produce eleven fractions with different polarities and constituents. The intermediate polar fraction was shown to be terpene trilactones-enriched fraction (TEGBE). Out of this fraction, pure ginkgolide B (G-B) was further purified and identified based on its spectral data. The effects of GBE and TEGBE were evaluated in comparison to that of G-B in the crush sciatic nerve injury rat model. To evaluate the neuroprotective effects, sixty Wistar male rats were randomly allocated into 6 groups: naive, sham, crush + normal saline, and three treatment groups; crush + GBE, crush + TEGBE, and crush + G-B. Treatments were given one hour following injury, and once daily for 14 days. Neurobehavioral tests, histomorphological examinations, and immunohistochemical analysis of the sciatic nerve and the spinal cord were performed at weeks 3 and 6 post-injury. GBE, TEGBE and G-B were shown to enhance the functional and sensory behavioral parameters and to protect the histological and the ultrastructural elements in the sciatic nerve. Additionally, all treatments prevented spinal cord neurons from further deterioration. It was shown that G-B has the most significant potential effects among all treatments with values that were nearly comparable to those of sham and naive groups.

Taurine protects against myelin damage of sciatic nerve in diabetic peripheral neuropathy rats by controlling apoptosis of schwann cells via NGF/Akt/GSK3ß pathway.

Diabetic peripheral neuropathy is a common complications of Type 2 Diabetes and its main pathological feature is myelin sheath damage of peripheral nerve that was induced by Schwann cells (SCs) apoptosis. Increasing evidence suggested that taurine might play a role in improving DPN because of its ability to prevent SCs apoptosis. In this study, we explore the effect of taurine on preventing SCs apoptosis and its underlying mechanism. Sprague Dawley rats were treated with streptozotocin to establish the diabetes model. Rats were randomly divided into control, diabetes, taurine treatment (as giving 0.5%, 1% and 2% taurine in drinking water) groups. RSC96 cell (a rat SCs line) was used for intervention experiments in vitro. Results showed that taurine significantly corrected morphology of damaged myelin sheath and inhibited SCs apoptosis in sciatic nerve of diabetic rats. Moreover, taurine prevented apoptosis of RSC96 cells exposed to high glucose. Mechanistically, taurine up-regulated NGF expression and phosphorylation levels of Akt and GSK3ß, while, blocking activation of NGF and phosphorylation of Akt and GSK3ß increased apoptosis of high glucose-exposed RSC96 cells with taurine supplement. These results revealed taurine improved the myelin sheath damage of sciatic nerve in diabetic rats by controlling SCs apoptosis via NGF/Akt/GSK3ß signaling pathways, which provides some clues that taurine might be effective and feasible candidate for the treatment of DPN.

Therapeutic effects of moxibustion simultaneously targeting Nrf2 and NF-κB in diabetic peripheral neuropathy.

Moxibustion is the main alternative medicine treatment that has been beneficial to diabetic peripheral neuropathy (DPN), a common complication secondary to diabetic microvascular injury. However, the underlying protective mechanism of moxibustion against neuroinflammation remains unclear. We hypothesized that moxibustion treats DPN by regulating the balance of nuclear factor-2 erythroid-related factor-2 (Nrf2)-nuclear factor-kappa light chain enhancer of B cells (NF-кB). In vivo, diabetes was induced in rats by injecting streptozotocin (STZ; 60 mg/kg; i.p.). Moxibustion was then applied to "Zusanli" (ST 36), "Guanyuan" (BL 26), and "Yishu" (EX-B 3) acupuncture points. Nerve conduction was detected. Serum interleukin (IL)-1ß, IL-6, and IL-8 levels were determined through enzyme-linked immunosorbent assay. NF-κB and Nrf2 proteins were examined through immunoblot analysis. The mRNA of NF-κB and Nrf2 was evaluated through RT-PCR. We found that the conduction velocity and amplitude of the action potentials of sciatic nerve conduction were reduced in the DPN model group but were rescued by moxibustion treatment. Moxibustion also improved the effect of DPN on other parameters, including ultrastructural changes, NF-κB and Nrf2 expression in the sciatic nerve, and serum IL-1ß, IL-6, and IL-8 levels. Our data suggested that moxibustion may alleviate neuroinflammation by inhibiting NF-κB and by activating Nrf2. Moxibustion may also provide therapeutic effects for patients with DPN by simultaneously targeting Nrf2 and NF-κB.

Reversing Effect of Insulin on Local Anesthetics-Induced Sciatic Nerve Block in Rats.

BACKGROUND: Local anesthetics are used in various purposes from topical and infiltration anesthesia to peripheral nerve or central neural blockade. Even though local anesthetics are relatively safe, they can have some toxic and adverse effects. Prolonged sensory and motor block is another example of an unwanted complication. The primary objective of this study was to determine whether insulin has a reversal effect on the peripheral (sciatic) nerve block with lidocaine or bupivacaine. METHODS: The surgically exposed sciatic nerves in rats were blocked with lidocaine or bupivacaine, and then 0.1 ml of normal saline or 0.1 ml normal saline containing 0.1 IU a short-acting form of insulin was administrated per body in each group. Before and after sciatic nerve block, as well as until recovery from the nerve block after normal saline or insulin treatment, nerve conduction studies such as monitoring loss and recovery of the waveforms and amplitudes were performed to evaluate the status of motor nerve conduction. RESULTS: Complete recovery time of nerve conduction status in lidocaine + normal saline group was 58 ± 16 min, whereas that in lidocaine + insulin group was 17 ± 3 min and the difference was statistically significant (p < 0.01). Complete recovery time of nerve conduction status in bupivacaine + normal saline group was 116 ± 16 min and that in bupivacaine + insulin group was 36 ± 4 min and the two groups were significantly different (p < 0.01). CONCLUSIONS: Insulin can reverse peripheral nerve block induced by lidocaine or bupivacaine.

Comparative effects of implanted electrodes with differing contact patterns on peripheral nerve regeneration and functional recovery.

Electrical stimulation could enhance nerve regeneration and functional recovery. The objective of this study was to evaluate the regenerative effects of implanted electrodes with different contacts in resected sciatic nerve. Sciatic nerve resection and microsurgical repair models were established and randomly divided into four groups (point contact, 1/4 circle contact; whole-circle contact; no electrodes as control). Electrical stimulation was performed and electrophysiological, morphological and histological exams (of the sciatic nerve and muscle) were conducted at 4 and 10 weeks post-implantation. Point and 1/4 circle contact groups showed significantly higher scores in the sciatic functional index (SFI), increased amplitude of compound muscle action potential (AMP) and motor nerve conduction velocity (MNCV) compared to the control group at both 4 and 10 weeks post-implantation. Point and 1/4 circle contact morphologically promoted sciatic nerve regeneration and reduced muscular atrophy with less mechanical injury to the nerve trunk observed compared with the whole-circle contact group at both 4 and 10 weeks post-implantation. Electrodes with point and 1/4 circle contacts represented an alternatively portable and effective method of electrical stimulation to facilitate injured sciatic nerve regeneration and reduce subsequent muscular atrophy, which might offer a promising approach for treating peripheral nerve injuries.

Enhanced Pain Sensitivity with Systemic Ultrastructural Changes of the Nervous Systems after Cobra Venom Injection is Reversed by Electroacupuncture Treatment.

BACKGROUND: Electroacupuncture (EA) has been proved to be effective in treating certain neuropathic pain conditions. The mechanisms of pain relief by EA are not fully understood. There have been sporadic reports of damage in the peripheral nervous system (PNS) and regions of the central nervous system (CNS) at the ultrastructural level following peripheral nerve injury. However, information about possible systemic changes in the PNS and CNS after nerve injury is scarce. OBJECTIVES: The goal of this study was to examine the ultrastructural changes of the nervous system induced by a local injection of cobra venom into the sciatic nerve and to compare the ultrastructural changes in rats with or without treatment with EA or pregabalin. STUDY DESIGN: An experimental study. SETTING: Department of Anesthesiology, Pain Medicine, and Critical Care Medicine, Aviation General Hospital of China Medical University. METHODS: In this study, using an established model of sciatic neuralgia induced by local injection of cobra venom into the sciatic nerve, we examined ultrastructural changes of the PNS and CNS and how they respond to EA and pregabalin treatment. EA and pregabalin were given daily from postoperative day (POD) 14 to 36. Based on previous works, the frequency of EA stimulation of the ST36 and GB34 acupoints was held to 2/100 Hz variable. Pain sensitivity in the sciatic neuralgia rats with and without treatments was assessed using the von Frey test. Ultrastructural alterations were examined bilaterally in the prefrontal cortex, hippocampus, medulla oblongata; and the cervical, thoracic, and lumbar spinal cords on PODs 14, 40, and 60. Ultrastructural examinations were also carried out on the bilateral sciatic nerves and dorsal root ganglion (DRG) at the cervical, thoracic and lumbar levels. In rats treated with EA or pregabalin, the ultrastructure was examined on PODs 40 and 60. RESULTS: Behavioral signs of pain and systemic ultrastructural changes including demyelination were observed at all levels of the PNS and CNS in rats with sciatic neuralgia. After intervention, the mechanical withdrawal thresholds of the EA group and pregabalin group were significantly higher than that of the cobra venom group (P < 0.05). Both EA and pregabalin treatments partially reversed increased cutaneous sensitivity to mechanical stimulation. However, only the EA treatment was able to repair the ultrastructural damages caused by cobra venom. LIMITATIONS: The results confirm that peripheral nerve injury led to the ultrastructural damage at different levels of the CNS as demonstrated with electron microscopy; however, we need to further verify this at both the molecular level and in light microscope level. Sciatic neuralgia induced by cobra venom is a chemical injury, and whether this exactly mimics a peripheral nerve mechanical injury is still unclear. CONCLUSIONS: Local cobra venom injection leads to systemic neurotoxicity. EA and pregabalin alleviate pain via different mechanisms. KEY WORDS: Sciatic neuralgia, cobra venom, demyelination, electroacupuncture, pregabalin, rat model.

Beneficial effects of Gelsemium-based treatment against paclitaxel-induced painful symptoms.

Chemotherapeutic drugs induce various side effects including painful peripheral neuropathy that represents a major concern. The widely used anticancer drug paclitaxel causes neurological side effects such as burning pain, allodynia, and hyperalgesia. Neuroprotective substances that may effectively counteract paclitaxel-induced neuropathic symptoms are needed. Here, we investigated the potential of Gelsemium sempervirens (GS) to counteract paclitaxel-evoked painful neuropathy in rats. Using the von Frey hair and acetone behavioral tests, we investigated the potential of GS centesimal (C) dilutions 3, 5, and 9C to prevent or to correct paclitaxel-induced cold allodynia and mechanical allodynia/hyperalgesia involved in neuropathic pain. We found that a prophylactic or corrective treatment with GS dilutions prevented or suppressed PAC-evoked cold allodynia and mechanical allodynia/hyperalgesia, by reversing to normal, decreased cold thermal and mechanical pain thresholds of PAC-treated rats. In particular, preventive or corrective treatments with GS dilution 3C counteracted PAC-evoked allodynic and hyperalgesic responses. Also, GS dilution 5C (in a lesser extent than 3C) significantly reduced PAC-induced mechanical allodynia/hyperalgesia while GS dilution 9C was ineffective. PAC-evoked neuropathic symptoms were efficiently reduced after 1 week treatment with GS dilutions 3 or 5C and the beneficial action increased after 2 weeks. GS dilutions, particularly 3C, also counteracted or prevented PAC-induced sciatic nerve axon alterations and decreased the density of intraepidermal nerve fibers. Altogether, these results obtained in the rat preclinical model suggest that GS dilution-based treatment may constitute an interesting option to explore for the long-term management of pain without undesirable effects.

Local low dose curcumin treatment improves functional recovery and remyelination in a rat model of sciatic nerve crush through inhibition of oxidative stress.

Traumatic injuries to peripheral nerves are frequent, however, specific pharmacological treatments are currently lacking. Curcumin has antioxidant, anti-inflammatory and neuroprotective properties but high oral doses are required for therapeutic use, particularly due to its low bioavailability. The aim of the present study was to investigate the effects of local and continuous treatment using low curcumin doses on functional recovery and nerve regeneration after rat sciatic nerve crush (SNC). Curcumin was administered by osmotic pumps with a catheter delivering the drug at the injury site (0.2 mg/day for 4 weeks). Functionally, early improvements in mechanical sensitivity, finger spacing of the injured paw, skilful walking and grip strength were observed in curcumin-treated animals. The curcumin treatment increased expression of compact myelin proteins (MPZ and PMP22), myelin sheath thickness and, correspondingly, increased motor and sensitive nerve conduction velocity. Microscopic analysis of gastrocnemius muscle indicated a curcumin-induced decrease in neurogenic lesions. Curcumin treatment reduced the production of reactive oxygen species (ROS) (which were notably produced by macrophages), lipid peroxidation and increased expression of transcription factor Nrf2. In silico analyses indicated that curcumin combines all the characteristics required to be an efficient lipid peroxidation inhibitor at the heart of biological membranes, hence protecting their degradation due to ROS. This antioxidant capacity is likely to contribute to the beneficial effects of curcumin after SNC injury. These results demonstrate that, when administrated locally, low doses of curcumin represent a promising therapy for peripheral nerve regeneration.