Mitigation of sciatica injury-induced neuropathic pain through active metabolites derived from medicinal plants.

Sciatica characterized by irritation, inflammation, and compression of the lower back nerve, is considered one of the most common back ailments globally. Currently, the therapeutic regimens for sciatica are experiencing a paradigm shift from the conventional pharmacological approach toward exploring potent phytochemicals from medicinal plants. There is a dire need to identify novel phytochemicals with anti-neuropathic potential. This review aimed to identify the potent phytochemicals from diverse medicinal plants capable of alleviating neuropathic pain associated with sciatica. This review describes the pathophysiology of sciatic nerve pain, its cellular mechanisms, and the pharmacological potential of various plants and phytochemicals using animal-based models of sciatic nerve injury-induced pain. Extensive searches across databases such as Medline, PubMed, Web of Science, Scopus, ScienceDirect, and Google Scholar were conducted. The findings highlights 39 families including Lamiaceae, Asteraceae, Fabaceae, and Apocyanaceae and Cucurbitaceae, effectively treating sciatic nerve injury-induced pain. Flavonoids made up 53% constituents, phenols and terpenoids made up 15%, alkaloids made up 13%, and glycosides made up 6% to be used in neuorpathic pain. Phytochemicals derived from various medicinal plants can serve as potential therapeutic targets for both acute and chronic sciatic injury-induced neuropathic pain.

Therapeutic effects of cinnamon bark oil on sciatic nerve injury in rats.

OBJECTIVE: The aim of this study was to investigate the effects of cinnamon bark essential oil (CBO) on analgesia, motor activity, balance, and coordination in rats with sciatic nerve damage. MATERIALS AND METHODS: Rats were divided into three groups as simply randomized. The right sciatic nerve (RSN) of the Sham group was explored. Only vehicle solution was applied for 28 days. The RSN of the sciatic nerve injury (SNI) group was explored. Damage was created by unilateral clamping, and vehicle solution was applied for 28 days. The RSN of the sciatic nerve injury+cinnamon bark essential oil (SNI+CBO) group was explored. SNI was created by unilateral clamping and CBO was applied for 28 days. In the experiment study, motor activity, balance, and coordination measurements were made with rotarod and accelerod tests. A hot plate test was performed for analgesia measurements. Histopathology studies were carried out with the sciatic nerve tissues. RESULTS: In the rotarod test, there was a statistically significant difference between the SNI group and the SNI+CBO group (p<0.05). According to the accelerod test findings, there was a statistically significant difference between the SNI group with the Sham and SNI+CBO groups. In the hot plate test, there was a statistically significant difference between the SNI group with the Sham and SNI+CBO groups (p<0.05). In comparison to the Sham group and the SNI group, the SNI+CBO group was shown to have the greatest expression level of vimentin. CONCLUSIONS: We have concluded that CBO can be used as an adjuvant treatment in cases of SNI, increased pain, nociception, impaired balance, motor activity, and coordination. Our results will be supported by further studies.

Antihypernociceptive effects of Petersianthus macrocarpus stem bark on neuropathic pain induced by chronic constriction injury in rats.

Petersianthus macrocarpus (Lecythidaceae) stem bark is traditionally used in West and Central Africa for the treatment of boils and pain. The present study examined the chemical composition of the aqueous and methanolic stem bark extracts of P. macrocarpus by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) . Their antinociceptive effect was evaluated using chronic constriction injury (CCI)-induced neuropathic pain in a rat model. On the ninth day post-surgery, the pain perception (allodynia and hyperalgesia) of the animals was assessed after the administration of aqueous and methanolic extracts at the doses of 100 and 200 mg/kg. In addition, the effect of the extracts was evaluated on nitric oxide activity and on the expression of pro-inflammatory cytokines (TNF-α, IL-1ß, and NF-κB). The LC-ESI-MS analysis revealed the presence of ellagic acid as the major constituent in the methanol extract. Both extracts at the employed doses (100 and 200 mg/kg), significantly (p < 0.01 and p < 0.001) reduced the spontaneous pain, tactile and cold allodynia, and mechanical hyperalgesia. The methanolic extract used at the dose of 200 mg/kg significantly reduced the nitric oxide level (p < 0.001) and the gene expression levels of NF-κB (p < 0.05) and TNF-α (p < 0.01) in the brain. These data may indicate that stem bark extracts of P. macrocarpus possess a potent anti-hypernociceptive effect on CCI neuropathic pain. The inhibition of the nitric oxide pathway as well as the reduction in NF-κB and TNF-α gene expression in the brain may at least partially contribute to this effect. The results further support the use of this plant by traditional healers in pain conditions.

Efficacy of a fixed combination of palmitoylethanolamide and acetyl-l-carnitine (PEA+ALC FC) in the treatment of neuropathies secondary to rheumatic diseases.

BACKGROUND: The neurologic complications of rheumatic diseases (RDs) are highly variable, and their manifestations are linked to the pathogenesis and clinical phenotype of the specific RDs. In rheumatoid arthritis, for example, the peripheral nervous system is most commonly involved and mononeuritis multiplex, nerve entrapment and vasculitic sensorimotor neuropathies are not uncommon. Often the therapy for these disorders is not easy and is characterized by the use of different drugs. Palmitoylethanolamide (PEA) has been tested in a wide variety of animal models and has been evaluated in several clinical studies for nerve compression syndromes, demonstrating that PEA acts as an effective and safe analgesic compound. Acetyl-L-Carnitine (ALC) has also been shown to be an effective and safe treatment in painful peripheral neuropathy. In the last years the synergistic effect between PEA and ALC has been demonstrated. The aim of our study was to evaluate the efficacy of supplementation of standard therapy (STh) with Kalanit® (Chiesi Italia Spa; Parma, Italy) in patients with peripheral neuropathy secondary to RDs. METHODS: Patients at the time of enrollment were affected by RDs with neuropathy from <12 months, documented by electromyography. The analyzed patients were treated with the STh chosen according to their rheumatic disease (RA or SpA) and for their neuropathy (e.g. analgesic, NSAIDs, pregabalin or gabapentin) as per clinical practice. The sample was divided into 2 groups: group 1, patients treated with STh, to which a fixed combination of PEA (600 mg) + ALC (500 mg) (Kalanit®) was added twice a day for 2 weeks and then once a day for 6 months; group 2, patients treated only with STh. Each patient underwent clinical evaluations and questionnaires were administered in order to evaluate their neuropathy and the efficacy of the therapy. RESULTS: In group 1, 18 patients suffering from sciatic pain, 16 patients from carpal tunnel syndrome and 8 patients with peripheral neuropathy of the lower limbs were included and PEA + ALC FC was added to STh. These patients were compared with patients from group 2, who had the same pathology and demographic characteristics: 20 patients with sciatic pain, 15 with carpal tunnel syndrome and 5 with peripheral neuropathy of the lower limbs, respectively; this group was treated with STh only. Patients treated with PEA + ALC FC had a significant improvement in pain VAS compared to patients treated with group 2 in all the diseases analyzed (P value: sciatic pain 0.032, carpal tunnel syndrome 0.025 and lower limbs neuropathy 0.041). Patients in group 1 showed a significant improvement compared to patients treated in group 2 also from a specific score. Specifically, LBP-IQ showed significant improvement in group one (P value: 0.031), as did CHFD (P=0.011) and NPQ (P=0.025). CONCLUSIONS: The synergistic effect of PEA and ALC seems to have a further advantage in the treatment of this type of pathology, including the anti-inflammatory effect but also in terms of therapy optimization and therefore of better adherence to treatments. Our study shows that it is important to identify the type of pain to follow an accurate diagnostic algorithm, considering the clinical characteristics of the patient and carefully evaluate the indication, preferring a multimodal approach.

A network-based analysis and experimental validation of traditional Chinese medicine Yuanhu Zhitong Formula in treating neuropathic pain.

ETHNOPHARMACOLOGICAL RELEVANCE: The Yuanhu Zhitong Formula (YZF) consists of traditional Chinese herbs Corydalis Rhizoma (Corydalis yanhusuo (Y.H.Chou & Chun C.Hsu) W.T.Wang ex Z.Y.Su & C.Y.Wu; Chinese name, Yanhusuo) and Angelicae Dahuricae Radix (Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav.; Chinese name, Baizhi), which is usually administrated for painful conditions. It is well acknowledged that YZF has pharmacological effects on pain relief; nevertheless, limited data are available on its mechanism. AIM OF THE STUDY: This study aimed to explore the potential mechanism underlying YZF on nociception of rats. Also, the comprehensive mechanism of YZF was preliminarily determined based on network pharmacology on neuropathic pain. MATERIALS AND METHODS: A spared nerve injury (SNI) model was established to reveal the effects of YZF administration on nociceptive behavior in rats. Von-Frey tests were used to evaluate the paw withdrawal mechanical thresholds in rats administrated with YZF or vehicle. The "drug-ingredients" and "disease-drug-target" networks were established with a network pharmacology approach. The analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) profiles were performed based on the common targets between the herbs and neuropathic pain. Hub genes, identified with CytoHubba, were validated by Western blotting analysis. RESULTS: SNI rats developed significant nociceptive behavior as soon as 3 days after nerve injury, which was reversed by consecutive treatment with 300 mg/kg YZF for 7 days. Besides, 50 potential bioactive components in YZF with 1074 targets were identified. Then, 217 putative common genes related to YZF and neuropathic pain were identified for further study. After established a protein-protein interaction network, 12 subnetworks with CytoHubba and 10 predictive hub genes were obtained based on the maximal clique centrality model. Western blotting analysis indicated that SNI rats exhibited increased APP (Amyloid-beta precursor protein), SRC (Proto-oncogene tyrosine-protein kinase Src), and phosphorylation of JNK1 (Mitogen-activated protein kinase 8, JNK) and ERK1/2 (Mitogen-activated protein kinase 3/1). Obviously, continuous administration of YZF robustly reversed such changes. CONCLUSIONS: This study revealed that YZF modulates the nociceptive behavior in SNI rats. Moreover, the drug may be useful in the treatment of neuropathic pain through multi-components, multi-targets, and multi-pathways. Nevertheless, more attention should be paid to discriminating the potential ingredients in YZF contributing to its analgesic effects in the treatment of neuropathic pain.

Ginsenoside Rd attenuates mouse experimental autoimmune neuritis by modulating monocyte subsets conversion.

Guillain-Barré Syndrome (GBS), characterized by peripheral nerve demyelination and axonal damage, is initiated and aggravated through various of immunopathogenesis. Ginsenoside Rd, main active components extracted from ginseng saponins, is known to exhibit immune-regulate functions in many immune-mediated diseases. However, the evidence of preventive effect of Ginsenoside Rd on GBS is lacking. Experimental autoimmune neuritis (EAN) mice, classic model of GBS, were established and treated with GSRd or vehicle. Clinical score and nerve tissue histomorphology were evaluated. Monocytes in peripheral blood and tissue were detected by flow cytometry analysis and immunofluorescence staining. For the in vitro study, GSRd and vehicle were added in the culture medium to assess their regulatory function on monocytes phenotype. In vivo data showed a protective role of GSRd on alleviating symptoms and tissue damage on Day 20 and 25. Administration of GSRd increased non-classical Ly6Clo monocytes in both peripheral blood and injured nerve tissue, and also switched tissue macrophages phenotype into resolution-phase. In vitro study indicated similar role of GSRd on monocytes differentiation status. Transcription factors like Nr4a1 were elevated after GSRd treatment. These findings revealed the protective role of GSRd against EAN, and potential preventive function on GBS patients.

Ameliorative effects of escin on neuropathic pain induced by chronic constriction injury of sciatic nerve.

ETHNOPHARMACOLOGY RELEVANCE: Escin is a natural mixture of triterpene saponins extracted from the seeds of Aesculus wilsonii Rehd. And has been reported to possess the therapeutic effects against neuropathic pain (NP). However, the underlying mechanisms remain unclear. AIM OF THE STUDY: The present study aimed to investigate the therapeutic effects and explore the underlying mechanisms of escin on rats of NP induced by chronic constriction injury (CCI) of sciatic nerve. MATERIALS AND METHODS: Rats were treated with escin (7, 14, and 28 mg/kg, i. g.) daily from the third day after the surgery (day 0) for consecutive 14 days. Regular behavior and thermal threshold were measured on days 0, 3, 5, 7, 10 and 14. Investigations into mechanisms involved measurement of inflammatory factors and biochemical factors in dorsal root ganglion (DRG). Inflammatory pain responses and nerve injuries were induced by the CCI model. Tonic pain model and acute inflammatory model induced by formalin or carrageenan were established to evaluated the pharmacological effects of escin on acute inflammatory pain. Corresponding behaviors were monitored and relevant gene expression such as c-fos, mu opioid receptor (MOR) and KCNK1 were detected by qRT-PCR. Investigate the neuroprotective effects of escin on PC12 cell injury induced by lipopolysaccharide (LPS). Cell morphology was observed under inverted microscope and neuroprotective effect of escin on cell activity was assessed by MTT assay. RESULTS: Escin could widen thermal threshold, downregulate the concentration of inflammatory factors like tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, suppress the gene expression of toll-like receptor 4 (TLR4), nuclear factor κB (NF-κB), decrease the level of glial fibrillary acidic protein (GFAP) and nerve growth factor (NGF) remarkably. In addition, escin significantly lowered the duration of licking, numbers of flinches and increase in paw edema, showing great therapeutic effects on inflammatory pain responses. Moreover, the activity of injured PC12 cells was significantly improved after escin administrated. CONCLUSION: Escin exerted the ameliorative effects on NP induced by CCI which may be related to downregulating the release of pro-inflammatory cytokines, suppressing TLR-4/NF-κB signal pathway, thereafter decreasing the level of GFAP and NGF.

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.

Neuroprotective Effect of Nypa fruticans Wurmb by Suppressing TRPV1 Following Sciatic Nerve Crush Injury in a Rat.

Peripheral nerve injury can result in severe functional impairment and decreased quality of life due to loss of sensory and motor function. Nypa fruticans wurmb (NF) has been used in diverse folk remedies in East Asia. We have previously shown that Nypa fruticans wurmb extract has antinociceptive and anti-inflammatory effects by suppressing TRPV1 in the sciatic nerve injury. The present study investigated the effects of NF on the control of TRPV1 in relation to neuroprotective effects of a sciatic nerve crush injury. To evaluate the neuroprotective effects, an animal behavior test and a physiological function test were performed. Functional recovery and nerve recovery were improved in the NF and NF + SB (SB366791; TRPV1 antagonist) treated group. In the histomorphology evaluation, the neuronal regenerative effect of NF on the injured sciatic nerve was confirmed via hematoxylin and eosin (H&E) staining. In this study, the NF and NF + SB treated group showed neuroprotective and functional recovery effects from the sciatic nerve crush injury. Furthermore, the expression of NF-κB and iNOS showed a significantly suppressive effect on NF (p < 0.01), SB (p < 0.01), and NF + SB (p < 0.01) treated group at the 7th and 14th day compared to the vehicle group. This study confirmed the neuroprotective effects of NF on suppressing TRPV1 in a sciatic nerve crush injury. The findings of this study establish the effect of NF as a neurotherapeutic agent to protect the peripheral nerve after a sciatic nerve crush injury.

An integrated strategy for discovering effective components of Shaoyao Gancao decoction for treating neuropathic pain by the combination of partial least-squares regression and multi-index comprehensive method.

ETHNOPHARMACOLOGICAL RELEVANCE: Neuropathic pain, the incidence of which ranges from 5 to 8% in the general population, remains challenge in the treatment. Shaoyao Gancao decoction (SGD) is a Chinese classical formula used to relieve pain for thousands of years and has been applied for neuropathic pain nowadays. However, the effective components of SGD for the treatment of neuropathic pain remains unclear. AIMS OF STUDY: To investigate the effect and potential mechanism of SGD against neuropathic pain and further reveal the effective components of SGD in the treatment of neuropathic pain. MATERIALS AND METHODS: Spared nerve injury (SNI) model rats of neuropathic pain were orally given SGD to intervene, the components in vivo after SGD administration were determined, behavior indicators, biochemical parameters, and metabolomics were applied for assessing the efficacy. Then correlation between components and biomarkers was analyzed by pearson correlation method. To further measure the contribution of components to efficacy, the combination of partial least-squares regression (PLSR) and multi-index comprehensive method was carried out, according to the corresponding contribution degree of the results, the components with large contribution degree were considered as the effective components. RESULTS: SGD exhibited a significant regulatory effect on neuropathic pain, which could increase the pain threshold and decrease the levels of SP, ß-EP, PGE2 and NO. With the high resolution of UPLC-Q-TOF/MS technology, a total of 128 compounds from SGD were identified and 44 of them were absorbed in blood. Besides, 40 serum biomarkers were identified after intervention of SGD and the metabolic pathways were constructed. The key metabolic pathways including Glycerophospholipid metabolism, Linoleic acid metabolism, Alpha-linolenic acid metabolism, Glycosylphosphatidylinositol-anchor biosynthesis and Arachidonic acid metabolism may be related to the regulation of neuropathic pain. Metabolomics combined with PLSR and multi-index comprehensive method was utilized to discover 5 components including paeonol, DL-Arabinose, benzoic acid, hispaglabridin A and paeonilactone C as effective components of SGD in the treatment of neuropathic pain. This strategy was used to explore the effective components of SGD and elucidate its possible analgesic mechanism. CONCLUSION: This study demonstrate that SGD significantly relieved neuropathic pain and elucidated the effective components of SGD for treating neuropathic pain, the strategy as an illustrative case study can be applied to other classical formula and is beneficial to improve the quality and efficacy.

Augmented Buyang Huanwu Decoction facilitates axonal regeneration after peripheral nerve transection through the regulation of inflammatory cytokine production.

ETHNOPHARMACOLOGICAL RELEVANCE: Herbal formulation Buyang Huanwu Decoction (BYHWD) has been used to treat cardiovascular disorders including cerebral ischemia. Recent studies showed its effects on promoting axonal regeneration after nerve injury. However, compositional reformulation supplemented with herbal components that regulates inflammation may increase its efficacy for nerve repair. AIM OF THE STUDY: We prepared a new herbal decoction by adding selected herbal components to BYHWD (augmented BYHWD; ABHD) and investigated the effect of ABHD on the production of inflammatory cytokines and axonal regeneration using an animal model of nerve transection and coaptation (NTC). MATERIALS AND METHODS: A rat model of NTC was performed on the sciatic nerve. The sciatic nerve and dorsal root ganglion (DRG) were isolated and used for immunofluorescence staining and western blot analysis. DRG tissue was also used to prepare primary neuron culture and the length of neurites was analyzed. Sensorimotor nerve activities were assessed by rotarod and von Frey tests. RESULTS: Three herbal components that facilitated neurite outgrowth were chosen to formulate ABHD. ABHD administration into the sciatic nerve 1 week or 3 months after NTC facilitated axonal regeneration. Cell division cycle 2 (Cdc2) and brain-derived neurotrophic factor (BDNF) proteins were induced from the reconnected distal portion of the sciatic nerve and the levels were further elevated by in vivo administration of ABHD. Phospho-Erk1/2 level was increased by ABHD treatment as well, implying its role in mediating retrograde transport of BDNF signals into the neuronal cell body. Production of inflammatory cytokines IL-1ß and TNF-α was induced in the reconnected nerve but attenuated by ABHD treatment. Behavioral tests revealed that ABHD treatment improved functional recovery of sensorimotor activities. CONCLUSIONS: A newly formulated ABHD is effective at regulating the production of inflammatory cytokines and promoting axonal regeneration after nerve transection and may be considered to develop therapeutic strategies for peripheral nerve injury disorders.

Strychnos nux-vomica L. seed preparation promotes functional recovery and attenuates oxidative stress in a mouse model of sciatic nerve crush injury.

BACKGROUND: Peripheral nerve injury is a debilitating condition that may lead to partial or complete motor, sensory and autonomic function loss and lacks effective therapy until date. Therefore, it is quite imperative to explore impending remedies for rapid and accurate functional retrieval following such conditions. Natural product-based intervention can prove effective to facilitate the process of functions regain. METHODS: Here, we investigated the effect of processed Strychnos nux-vomica seeds at a dose of 250 mg/kg body weight in a mouse model of induced Sciatic nerve lesion in promoting the recovery of the functions. A compression injury was induced in the Sciatic nerve of the right leg in the mice. Sensory function recovery was evaluated by hot-plate and formalin tests, whereas the motor function retrieval was assessed by measuring muscle grip strength, sciatic functional index, and muscle mass restoration. Oxidative stress and blood cell count were measured by biochemistry and haematological analyses. RESULTS: This study indicates that Strychnos nux-vomica seeds enhance the rate of recovery of both sensory and motor functions. It helps restore the muscle mass, attenuates total oxidant status and enhances the total anti-oxidant capacity of the biological system. Moreover, the treated animals manifested an enhanced glucose tolerance aptitude and augmented granulocyte and platelet counts. Improved oxidant control, enhanced glucose sensitivity and amended granulocyte and platelet counts are likely to contribute to the advantageous effects of Strychnos nux-vomica, and warrant further in-depth studies for deciphering possible mechanisms and identification of active constituent(s) responsible for these effects. CONCLUSION: Strychnos nux-vomica seed offers functional recovery promoting effects following a mechanical injury to the Sciatic nerve and the possible reasons behind this effect can be reduced oxidative stress and improved glycaemic control. Further and detailed investigations can unravel this mystery.

Effect of ethanolic extract of Solanum virginianum Linn. on neuropathic pain using chronic constriction injury rat model and molecular docking studies.

The present research work was designed to examine the neuroprotective effect of ethanolic extract of Solanum virginianum Linn. (SV) in chronic construction injury (CCI) of sciatic nerve-induced neuropathic pain in rats. The extract was initially standardized by high-performance thin-layer chromatography using solasodine as a biomarker and was then subjected to assess the degree of mechanical allodynia, thermal allodynia, mechanical hyperalgesia, thermal hyperalgesia and biochemical evaluations. Administration of SV (100 and 200 mg/kg; p.o.) and pregabalin (10 mg/kg; p.o.) as a reference standard significantly debilitated hyperalgesia and allodynia and notably restored the altered antioxidant level and pro-inflammatory cytokine (IL-1ß and TNF-α) expression in a dose-dependent manner. Further, to appraise the mechanistic approach of solasodine, docking simulation studies were done on the 3D structure of the voltage-gated N-type calcium channel (Cav 2.2), R-type calcium channel (Cav 2.3) and sodium channel (Nav 1.7), and the results revealed that solasodine properly positioned into Phe 19, Leu 32, Met 51 and Met 71 (FLMM pocket) of Cav 2.2 and Cav 2.3 and being a competitor of Ca2+/N-lobe it may inactivate these calcium channels but did not bind into the desired binding pocket of Nav 1.7. Thus, the study confirmed the role of solasodine as a major biomarker for the observed neuroprotective nature of Solanum virginianum.

Aqueous extract from Luehea divaricata Mart. Leaves reduces nociception in rats with neuropathic pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Luehea divaricata, popularly known in Brazil as "açoita-cavalo", has been widely explored by different ethnic groups native to Brazil to treat different pathologic conditions, including inflammatory pain. However, no report could be found on the effect that extract of L. divaricata has on neuropathic pain. This is an important topic because convergent and divergent mechanisms underlie inflammatory vs. neuropathic pain indicate that there may not always be a clear mechanistic delineation between these two conditions. AIM OF THE STUDY: The study aimed to determine antioxidant activity and macronutrient composition of aqueous extract from leaves of L. divaricata, and the effect of oral administration on nociception in rats with chronic constriction injury (CCI) of sciatic nerve-induced neuropathic pain, one of the most commonly employed animal models of neuropathic pain. MATERIALS AND METHODS: The antioxidant activity of the extract was evaluated by total phenolic content and DPPH, ABTS●+ and ORAC methods. Vitexin was determined by HPLC to show that the composition of the extract of the present study is similar to that used in previous studies with this genus. Total sugar and sucrose concentrations were assessed by the anthrone method, while glucose and triacilglycerides were determined using commercially available kits. Fructose concentration was calculated from values for total sugars, glucose and sucrose. Total protein was determined by Bradford assay. The effect on DNA strand breaking was investigated by inhibition of strand breaking of supercoiled DNA by hydroxyl radical. The antinociceptive effects of aqueous extract (100, 300, 500, and 1000 mg/kg, i.g.) were evaluated on thermal and mechanical thresholds for neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve in rats. We also compared the antinociceptive effect of the extract (500 mg/kg, i.g.) with that induced by gabapentin (50 mg/kg, i.g.), a first-line clinical treatment for neuropathic pain. The effect of co-administration of extract (500 mg/kg, i.g.) and low-dose gabapentin (30 mg/kg, i.g.) was also assessed. In addition, the effect of the extract on body weight, and blood and hepatic parameters were investigated to reveal possible side effects of treatment. RESULTS: The extract showed high content of total phenol; good reducing capacity for DPPH, ABTS●+ and ORAC assays; presence of vitexin; and a high capacity to inhibit strand breaking of supercoiled DNA. The predominant sugar was sucrose, followed by glucose and fructose. Total protein was greater than triacylglycerides, with the latter being present in a trace amount in the extract. The extract increased the thermal and mechanical thresholds, which was reduced by CCI. The antinociceptive effect was comparable to gabapentin and was also found after co-administration of extract and low-dose gabapentin. No significant change was found in body weight and blood and hepatic indicators after extract treatment. CONCLUSIONS: Aqueous extract from L. divaricata leaves was as effective as gabapentin at attenuating CCI-induced neuropathic pain, indicating for first time the therapeutic potential of this species for this type of pain.

Antinociceptive and Anti-Inflammatory Effects of Nypa fruticans Wurmb by Suppressing TRPV1 in the Sciatic Neuropathies.

Neuropathic pain is generally characterized by sensory abnormalities such as sensory disorders, hyperalgesia, and allodynia. Recent studies have reported that TRPV1 activation is essential for establishing of inflammation in the neuropathy pain models, showing that the expression of this receptor is increased, and contributing to enhanced thermal sensitivity. Nypa fruticans Wurmb (NF), which was used as a folk remedy, is a plant that is gaining attention due to its various effects. In this study, we investigated the antinociceptive and anti-inflammatory effects of NFE (Nypa fruticans Wurmb extracts) by controlling the neurological function of TRPV1. In sciatic crush injury rat models, a significant level of antinociceptive effect was observed in the thermal hyperalgesia test in which NF extracts (NFE 500 mg/kg) were orally administered, daily. Protein quantification of the sciatic nerve and the of the L4-L6 spinal cord showed a decrease of the TRPV1 expression, the inflammatory expression factor, COX2, and proinflammatory factors in the NFE treated groups. Our results indicate that NFE affects antinociceptive and anti-inflammatory by controlling TRPV1 in sciatic neuropathic pain models.

Neuroprotective Effects of Ozone Therapy After Sciatic Nerve Cut Injury.

A number of antioxidants have been used to treat peripheral nerve injury. However, there are few definitive experimental studies of ozone therapy for peripheral nerve cut injury. We aimed to examine the effects of mild level ozone therapy on sciatic nerve regeneration. One hundred adult male Wistar albino rats were randomly divided into four groups: group 1 (n=20) no cut injury or therapy; group 2 (n=20) sham; group 3 (n=30) nerve cut injury, no therapy; group 4 (n=30) nerve cut injury and ozone therapy. Sciatic functional index (SFI) and withdrawal reflex (WDR) were measured for all groups before nerve cut, at postoperative day 1, and at weeks 2, 4, 6 and 8. More myelinated (M) nerve fibers were observed after nerve cut injury in the ozone-therapy group. Significant differences were seen in plasma SOD (superoxide dismutase), CAT (catalase) and GPx (glutathione peroxidase) activities (p<0.05), and significant functional improvement was observed at postoperative weeks 2 and 4 (p<0.05) after ozone treatment. This is the first study conducted for the purpose of examining the effects of ozone therapy on sciatic nerve cut injury.

Bromelain reversed electrolyte imbalance in the chronically constricted sciatic nerve of Wistar rats.

Derangement of electrolyte in the sensory nervous system has been attributed to the development and maintenance of hyperalgesic and allodynic symptoms in painful neuropathy. This study investigated the effect of bromelain on electrolyte imbalance in chronically constricted sciatic nerve of rats (a model of neuropathic pain). Forty Wistar rats, divided into five groups of eight animals each were used for this study. von Frey filaments, tail immersion and acetone spray tests were used to assessed allodynic and thermal hyperalgesic symptoms in the Wistar rats. Sodium ion (Na+), potassium ion (K+), calcium ion (Ca2+) and chloride ion (Cl-) concentrations as well as sodium-potassium and calcium electrogenic pump (Na-K ATPase and Ca ATPase, respectively) activities were estimated using spectrophotometry techniques. Bromelain significantly (p < 0.05) reversed elevation of Na+ and Ca2+ concentration compared with sciatic nerve chronic constriction injury (snCCI) group (35.68 ± 1.71 vs 44.46 ± 1.24 mg/ml/mg protein and 1.06 ± 0.19 vs 6.66 ± 0.03 mg/ml/mg protein, respectively). There were also significant (p < 0.05) increases in the level of K+ (0.84 ± 0.02 vs 0.36 ± 0.05 mg/ml/mg protein) and Cl- (18.51 ± 0.29 vs 15.82 ± 0.21 mg/ml/mg protein). Bromelain reduced the activities of Ca2+ electrogenic pumps significantly compared with snCCI. This study therefore suggests that bromelain mitigated electrolyte imbalance in chronic constricted injury of the sciatic nerve implying that this may be an important mechanism for the anti-nociceptive effect of bromelain.

Neurada procumbens promotes functions regain in a mouse model of mechanically induced sciatic nerve injury.

Peripheral nerve injury is a complex condition which results in restricted physical activity. Despite the tremendous efforts to figure out effective remedies, the complete functional retrieval is still a goal to be achieved. So, the need of hour is the exploration of potential natural compounds to recover this functional loss. Here, we have investigated the role of a local plant "Neurada procumbens" in ameliorating the functional recovery after an induced nerve compression injury in a mouse model. A dose of N. procumbens (50mg/kg of body weight) was administered orally from the day of injury to onwards. The motor functional recovery was assessed by evaluating muscle grip strength and sciatic functional index; while the sensory functions were gauged by the hotplate test. The serological parameters were carried out to analyze the effect of N. procumbens on oxidative stress level. The recovery of sensory and motor functions was significantly improved and perceived earlier in the treatment group. Moreover, the elevated antioxidant level was statistically significant in the treatment group. These results indicate that the supplementation of N. procumbens accelerates functional recovery after sciatic nerve crush injury.

Foeniculum vulgare (Fennel) promotes functional recovery and ameliorates oxidative stress following a lesion to the sciatic nerve in mouse model.

Peripheral nerve injury is one of the major health concerns of the present era which can lead to the long-lasting disability and even demise. Currently, no effective and side effect free remedy exists and exploration of effective therapeutic strategies to regain functional outcome is a need of hour. In the present study, we used BALB/c mice (N = 14 age, 10-12 weeks & weight 32-34 g) that were divided into two groups: Normal chow (n = 7) and Fennel chow (n = 7) group. Here, we have explored the role of crude Foeniculum vulgare mill seeds in promoting functional recovery following a mechanical insult to the sciatic nerve by an oral administration of a crude dose of 500 mg/kg BW. The recovery of both sensory and motor functions was significantly (p > .05) accelerated in the treatment group, assessed by behavioral analyses alongside total antioxidant capacity increase. Conclusively, F. vulgare can be a potential therapeutic candidate for accelerating functional recovery after peripheral nerve injury. PRACTICAL APPLICATIONS: The outcomes of study have vital practical application both for scientists and consumers. The therapeutic role of phytochemicals on functional recovery has not been explored yet. This study will help figure out plant based regimen as booster for brain health and intervention against traumatic nerve injuries. Moreover, it may also attract the food and pharmaceutical industries to formulate cost effective therapeutic products. Likewise, it can prove instrumental for scientists for advance research on this aspect with more mechanistic targets.

Anti-hyperalgesic effect of (-)-α-bisabolol and (-)-α-bisabolol/ß-Cyclodextrin complex in a chronic inflammatory pain model is associated with reduced reactive gliosis and cytokine modulation.

Chronic pain is a continuous or recurring pain which exceeds the normal course of recovery to an injury or disease. According to the origin of the chronic pain, it can be classified as inflammatory or neuropathic. This study aimed to evaluate the antinociceptive and anti-inflammatory effect of (-)-α-bisabolol (BIS) alone and complexed with ß-cyclodextrin (ßCD) in preclinical models of chronic pain. Chronic pain was induced by Freund's Complete Adjuvant (FCA) or partial lesion of the sciatic nerve (PLSN). Swiss mice were treated with BIS, BIS-ßCD (50 mg/kg, p.o) or vehicle (control) and mechanical hyperalgesia, thermal hyperalgesia, muscle strength and motor coordination were evaluated. In addition, levels of TNF-α and IL-10 and expression of the ionized calcium-binding adapter protein (IBA-1) were assessed in the spinal cord of the mice. The complexation efficiency of BIS in ßCD was evaluated by High-Performance Liquid Chromatography. BIS and BIS-ßCD reduced (p < 0.001) mechanical and thermal hyperalgesia. No alterations were found in force and motor coordination. In addition, BIS and BIS-ßCD inhibited (p < 0.05) TNF-α production in the spinal cord and stimulated (p < 0.05) the release of IL-10 in the spinal cord in PLSN-mice. Further, BIS and BIS-ßCD reduced IBA-1 immunostaining. Therefore, BIS and BIS-ßCD attenuated hyperalgesia, deregulated cytokine release and inhibited IBA-1 expression in the spinal cord in the PLSN model. Moreover, our results show that the complexation of BIS in ßCD reduced the therapeutic dose of BIS. We conclude that BIS is a promising molecule for the treatment of chronic pain.