Ursolic acid alleviates paclitaxel-induced peripheral neuropathy through PPARγ activation.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) reduces the overall quality of life and leads to interruption of chemotherapy. Ursolic acid, a triterpenoid naturally which presents in fruit peels and in many herbs and spices, can function as a peroxisome proliferator-activated receptor γ (PPARγ) agonist, and has been widely used as an herbal medicine with a wide spectrum of pharmacological activities, including anti-cancer, anti-inflammatory and neuroprotective effect. METHODS: We used a phenotypic drug screening approach to identify ursolic acid as a potential neuroprotective drug in vitro and in vivo and carried out additional biochemical experiments to identify its mechanism of action. RESULTS: Our study demonstrated that ursolic acid reduced neurotoxicity and cell apoptosis induced by pacilitaxel, resulting in an improvement of CIPN. Moreover, we explored the potential mechanisms of ursolic acid on CIPN. As a result, ursolic acid inhibited CHOP (C/EBP Homologous Protein) expression, indicating the endoplasmic reticulum (ER) stress suppression, and regulating CHOP related apoptosis regulator (the Bcl2 family) to reverse pacilitaxel induced apoptosis. Moreover, we showed that the therapeutic effect of ursolic acid on the pacilitaxel-induced peripheral neuropathy is PPARγ dependent. CONCLUSIONS: Taken together, the present study suggests ursolic acid has potential as a new PPARγ agonist targeting ER stress-related apoptotic pathways to ameliorate pacilitaxel-induced peripheral neuropathic pain and nerve injury, providing new clinical therapeutic method for CIPN.

The Serotonin-Mediated Anti-Allodynic Effect of Yokukansan on Paclitaxel-Induced Neuropathic Pain.

Refractory peripheral neuropathy can occur as a side effect in 60-70% of patients receiving Paclitaxel (PTX). Yokukansan (YKS) is a Japanese herbal medicine reported to have analgesic properties for entrapment nerve injuries. Therefore, we investigated the anti-allodynic effect of Yokukansan on Paclitaxel-induced neuropathic pain. All experiments used 6-week-old male Sprague Dawley rats. Mechanical allodynia was evaluated using a dynamic plantar aesthesiometer. A mobile touch-stimulator unit applied progressively increasing force to the mid-plantar region of the hind paw in a vertical direction until the animal withdrew its paw. This was carried out before the Paclitaxel administration and during the first, second, third, and fourth weeks. Using a rat model of PTX-induced neuropathic pain (PTX rat), we injected PTX (intraperitoneally, 2 mg/kg) five times every 2 days. Using the dynamic plantar test, we evaluated the anti-allodynic effect of YKS (orally administered, 1 g/kg). YKS administration on a daily basis significantly enhanced the withdrawal threshold in PTX rats and reduced the expression level of activated microglia immunostaining with Iba1, a specific marker for microglia. The intrathecal administration of WAY-100635 (5-hydroxytryptamine [5-HT]1A receptor antagonist) and Ketanserin (5-HT2A/2C receptor antagonist) inhibited the protective effects of YKS. YKS exhibited an anti-allodynic effect in a rodent model of PTX-induced neuropathic pain by reducing the sensitivity to pain stimuli. These results suggest that Yokukansan may activate 5-HT receptors in the spinal cord, mediating Paclitaxel-induced neuropathic pain.

Neuropathic Pain Affects Quality of Life in Breast Cancer Survivors with Chemotherapy-Induced Peripheral Neuropathy.

BACKGROUND: Despite the significant impact of chemotherapy-induced peripheral neuropathy on the quality of life for breast cancer survivors, there is a notable lack of comprehensive research. Therefore, a crucial need exists for further systematic investigation and inquiry into this matter. AIMS: This study examined predictors of quality of life in breast cancer survivors with chemotherapy-induced peripheral neuropathy. DESIGN: A cross-sectional, correlational design. SETTINGS: This study was conducted at a medical center in northern Taiwan and a teaching hospital in northeastern Taiwan. PARTICIPANTS/SUBJECTS: One hundred and thirty adult women with breast cancer, who have undergone chemotherapy and obtained a Total Neuropathy Scale-Clinical Version score>0, were enrolled. METHODS: Neuropathic pain, sleep disturbances, depression, and quality of life were evaluated using multiple regression analysis to identify quality of life predictors. Clinical importance was established using the minimally important difference of Functional Assessment of Cancer Therapy-Breast. RESULTS: The study indicated that improving depression (B = -10.87, p < .001) and neuropathic pain (B = -8.33, p = .004) may enhance the quality of life of breast cancer survivors with chemotherapy-induced peripheral neuropathy. Moreover, the individual's marital status and family history of breast cancer were identified as predictive factors. CONCLUSIONS: This study illuminates quality of life determinants for breast cancer survivors with chemotherapy-induced peripheral neuropathy, advocating comprehensive care and addressing depression and neuropathic pain for better outcomes.

Yoga as a non-pharmacologic therapy to reduce dinutuximab-induced pain in patients with neuroblastoma.

BACKGROUND: Anti-GD2 antibodies are key components of treatment for high-risk neuroblastoma; however, they cause neuropathic pain. Yoga therapy may help reduce pain and distress associated with anti-GD2 therapy. PROCEDURE: Children 3 years of age or older with neuroblastoma participated in individualized yoga therapy while receiving the anti-GD2 antibody dinutuximab (DIN). Yoga therapy was deemed feasible if patients participated during 60% or more of DIN admissions. Patients and caregivers assessed pain/distress before and after yoga therapy with a distress thermometer (DT) and Wong-Baker FACES pain rating scale and completed questionnaires regarding satisfaction with yoga therapy. Therapy was deemed efficacious if there was a ≥1 point pain score change and reduction in distress after yoga. RESULTS: Eighteen patients were enrolled; 52 encounters (admissions for DIN) were evaluable. Ten of 18 were female, three of 18 were Hispanic, and 10/18 were White. Median age at enrollment was 5.5 years (range: 3-11). Yoga therapy was feasible in 39/52 (75%) encounters. Significant reductions in caregiver-reported pain and distress and reductions in patient-reported pain and distress after yoga therapy were reported. Twelve of 18 caregivers completed questionnaires: seven agreed/strongly agreed that yoga was valuable, and nine agreed/strongly agreed to continued participation in yoga. Thirty-four of 36 clinicians reported that they would recommend yoga therapy for other patients receiving DIN. CONCLUSIONS: Yoga therapy was feasible during DIN therapy and may be effective in reducing DIN-associated pain and distress. Future studies are needed to evaluate changes in opioid usage with the addition of yoga therapy during anti-GD2 antibody therapy.

Tinospora cordifolia ameliorates paclitaxel-induced neuropathic pain in albino rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Tinospora cordifolia (T. cordifolia) (Willd.) Miers, a member of the Menispermaceae, family documented in the ancient textbooks of the Ayurveda System of Medicine, has been used in the management of sciatica pain and diabetic neuropathy. AIM: The study has been designed to evaluate the antinociceptive potential of various extracts of T. cordifolia stem in Paclitaxel (PT)-generated neuropathic pain model in albino rats and explore its possible mechanism employing molecular docking studies. METHODS: Stems of T. cordifolia were shade dried, grinded in fine powder, and extracted separately with different solvents viz. ethanol, water & hydro-alcoholic and characterized using LCMS/MS. The antinociceptive property of T. cordifolia stem (200 and 400 mg/kg) was examined in albino rats using a PT-induced neuropathic pain model. Further, the effect of these extracts was also observed using different behavioral assays viz. cold allodynia, mechanical hyperalgesia (pin-prick test), locomotor activity test, walking track test, and Sciatic Functional Index (SFI) in rats. Tissue lysate of the sciatic nerve was used to determine various biochemical markers such as GSH, SOD, TBARS, tissue protein, and nitrite. Further to explore the possible mechanism of action, the most abundant and therapeutically active compounds available in aqueous extract were analyzed for binding affinity towards soluble epoxide hydrolase (sEH) enzyme (PDB ID: 3wk4) employing molecular docking studies. RESULTS: The results of the LCMS/MS study of different extracts of T. cordifolia indicated presence of alkaloids, glycosides, terpenoids, sterols and sugars such as amritoside A, tinocordin, magnoflorine, N-methylcoclaurine, coridine, 20ß-hydroxyecdysone and menaquinone-7 palmatin, cordifolioside A and tinosporine etc. Among all the three extracts, the hydroalcoholic extract (400 mg/kg) showed the highest response followed by aqueous and ethanolic extracts as evident in in vivo behavioral and biochemical evaluations. Furthermore, docking studies also exposed that these compounds viz. N-methylcoclaurine tinosporin, palmatine, tinocordin, 20ß-hydroxyecdysone, and coridine exhibited well to excellent affinity towards target sEH protein. CONCLUSION: T. cordifolia stem could alleviate neuropathic pain via soluble epoxide hydrolase inhibitory activity.

Metformin inhibits paclitaxel-induced mechanical allodynia by activating opioidergic pathways and reducing cytokines production in the dorsal root ganglia and thalamus.

It has been shown that AMP-activated protein kinase (AMPK) is involved in the nociceptive processing. This observation has prompted us to investigate the effects of the AMPK activator metformin on the paclitaxel-induced mechanical allodynia, a well-established model of neuropathic pain. Mechanical allodynia was induced by four intraperitoneal (i.p) injections of paclitaxel (2 mg/kg.day) in mice. Metformin was administered per os (p.o.). Naltrexoneandglibenclamide were used to investigate mechanisms mediating metformin activity. Concentrations of cytokines in the dorsal root ganglia (DRG) and thalamus were determined. After a single p.o. administration, the two highest doses of metformin (500 and 1000 mg/kg) attenuated the mechanical allodynia. This response was attenuated by all doses of metformin (250, 500 and 1000 mg/kg) when two administrations, 2 h apart, were carried out. Naltrexone (5 and 10 mg/kg, i.p.), but not glibenclamide (20 and 40 mg/kg, p.o.), attenuated metformin activity. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and CXCL-1 in the DRG were increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentrations of TNF-α, IL-1ß and CXCL-1 in the DRG. Concentration of IL-6, but not TNF-α, in the thalamus was increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentration of IL-6 in the thalamus. In summary, metformin exhibits activity in the model of neuropathic pain induced by paclitaxel. This activity may be mediated by activation of opioidergic pathways and reduced production of TNF-α, IL-1ß and CXCL-1 in the DRG and IL-6 in the thalamus.

Cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid mitragynine against neuropathic, but not inflammatory pain.

AIMS: Mitragynine (MG) is an alkaloid found in Mitragyna speciosa (kratom), a plant used to self-treat symptoms of opioid withdrawal and pain. Kratom products are commonly used in combination with cannabis, with the self-treatment of pain being a primary motivator of use. Both cannabinoids and kratom alkaloids have been characterized to alleviate symptoms in preclinical models of neuropathic pain such as chemotherapy-induced peripheral neuropathy (CIPN). However, the potential involvement of cannabinoid mechanisms in MG's efficacy in a rodent model of CIPN have yet to be explored. MAIN METHODS: Prevention of oxaliplatin-induced mechanical hypersensitivity and formalin-induced nociception were assessed following intraperitoneal administration of MG and CB1, CB2, or TRPV1 antagonists in wildtype and cannabinoid receptor knockout mice. The effects of oxaliplatin and MG exposure on the spinal cord endocannabinoid lipidome was assessed by HPLC-MS/MS. KEY FINDINGS: The efficacy of MG on oxaliplatin-induced mechanical hypersensitivity was partially attenuated upon genetic deletion of cannabinoid receptors, and completely blocked upon pharmacological inhibition of CB1, CB2, and TRPV1 channels. This cannabinoid involvement was found to be selective to a model of neuropathic pain, with minimal effects on MG-induced antinociception in a model of formalin-induced pain. Oxaliplatin was found to selectively disrupt the endocannabinoid lipidome in the spinal cord, which was prevented by repeated MG exposure. SIGNIFICANCE: Our findings suggest that cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid MG in a model of CIPN, which may result in increased therapeutic efficacy when co-administered with cannabinoids.

Parthenolide as a potential analgesic in the treatment of paclitaxel-induced neuropathic pain: the rat modeling.

In this study, we determined the therapeutic effect of parthenolide (PTL), the active component of Tanacetum parthenium, on neuropathic pain caused by paclitaxel (PTX), a chemotherapeutic drug frequently used in cancer treatment, at the gene and protein levels. To this end, 6 groups were formed: control, PTX, sham, 1 mg/PTL, 2 mg/kg PTL, and 4 mg/kg PTL. Pain formation was tested by Randall-Selitto analgesiometry and locomotor activity behavioral analysis. Then, PTL treatment was performed for 14 days. After the last dose of PTL was taken, Hcn2, Trpa1, Scn9a, and Kcns1 gene expressions were measured in rat brain (cerebral cortex/CTX) tissues. In addition, changes in the levels of SCN9A and KCNS1 proteins were determined by immunohistochemical analysis. Histopathological hematoxylin-eosin staining was also performed to investigate the effect of PTL in treating tissue damage on neuropathic pain caused by PTX treatment. When the obtained data were analyzed, pain threshold and locomotor activity decreased in PTX and sham groups and increased with PTL treatment. In addition, it was observed that the expression of the Hcn2, Trpa1, and Scn9a genes decreased while the Kcns1 gene expression increased. When protein levels were examined, it was determined that SCN9A protein expression decreased and the KCNS1 protein level increased. It was determined that PTL treatment also improved PTX-induced tissue damage. The results of this study demonstrate that non-opioid PTL is an effective therapeutic agent in the treatment of chemotherapy-induced neuropathic pain, especially when used at a dose of 4 mg/kg acting on sodium and potassium channels.

KATP Channel Prodrugs Reduce Inflammatory and Neuropathic Hypersensitivity, Morphine-Induced Hypersensitivity, and Precipitated Withdrawal in Mice.

Previous studies show ATP-sensitive potassium (KATP) channel openers can reduce hypersensitivity associated with chronic pain models in rodents, and reduce morphine tolerance. Many agonists of KATP channels are not soluble in physiologically relevant vehicles, requiring adaptation for clinical use. This study compared the antinociceptive activity of novel KATP channel targeting prodrugs, CKLP1, CKLP2, and CF3-CKLP. These prodrugs are activated by endogenous alkaline phosphatase enzymes present in the peripheral and central nervous systems. Analgesic capabilities of intrathecally injected prodrugs were tested in rodent models of spinal nerve ligation (SNL) and complete Freund's adjuvant (CFA) as models for neuropathic and inflammatory pain, respectively. CKLP1 and CKLP2 significantly increased mechanical paw withdrawal thresholds 1-2 hours after intrathecal administration in the SNL model, but all three prodrugs were able to attenuate hypersensitivity up to 7 days after CFA treatment. The reduction of opioid tolerance and opioid-induced hypersensitivity in mice treated chronically with morphine was significantly reduced in CKLP1 and CKLP2 treated animals. Prodrug cleavage was confirmed in mouse spinal cords using liquid chromatography. These studies may aid in the further development of KATP channel prodrugs for use in treatments of chronic pain, opioid tolerance, and withdrawal. SIGNIFICANCE STATEMENT: The cromakalim prodrugs, CKLP1, CKLP2, and CF3-CKLP1 reduced hypersensitivity in inflammatory and neuropathic pain models in male and female mice. CKLP1 and CKLP2 also reduced morphine-induced hypersensitivity in a mouse model of chronic morphine exposure. CKLP2 reduced jumping and rearing behaviors after naloxone-induced precipitated morphine withdrawal. Taken together, CKLP2 demonstrates the potential for development as a non-opioid analgesic drug.

Capsaicin treatment in neuropathic pain: axon reflex vasodilatation after 4 weeks correlates with pain reduction.

ABSTRACT: Capsaicin, an agonist at the transient receptor potential vanilloid 1, is used for the topical treatment of peripheral neuropathic pain. Reversible receptor defunctionalization and degeneration and subsequent regeneration of cutaneous nociceptors are discussed as its mechanism of action. Here, we hypothesize an accelerated functional recovery of a subclass of nociceptive afferents, the peptidergic vasoactive nociceptors, as the potential cause of capsaicin analgesia. In this noninterventional exploratory trial, 23 patients with peripheral neuropathic pain were treated with one topical high-concentration capsaicin application. Baseline pain ratings, comorbidities, and quality of life were assessed. Functional laser speckle contrast analysis (heat-evoked neurogenic vasodilatation to assess functional properties of peptidergic nociceptors) and quantitative sensory testing were performed in the affected skin. Four weeks after treatment, functional laser speckle contrast analysis and questionnaires were repeated. Telephone interviews were conducted at weeks 2, 10, and 12. Topical capsaicin treatment induced a significant reduction in pain intensity with a maximum at 4 weeks. At the same time, heat-evoked neurogenic vasodilatation was on average similar to pretreatment values. Half of the patients not only showed a functional recovery but also an improvement in vasodilatation, indicating regeneration of nerve fibers. Patients with improved heat-evoked neurogenic vasodilatation at week 4 showed a greater pain reduction than those with deterioration. The degree of vasodilatation significantly correlated with pain reduction. These findings suggest that (1) regeneration of peptidergic nociceptors may be the mechanism behind capsaicin-induced analgesia and (2) that a disease-modifying effect of capsaicin on these fibers already occurs 4 weeks after application.

Using Network Pharmacology and Animal Experiment to Investigate the Therapeutic Mechanisms of Polydatin against Vincristine-Induced Neuropathic Pain.

Background: Polydatin (PD) is the primary active compound in Polygonum cuspidatum Sieb and has been demonstrated to exert anti-inflammatory and neuroprotective activities. In the present study, we aimed to explore the therapeutic mechanisms of PD against chemotherapy-induced neuropathic pain. Methods: The putative targets of PD were obtained from the CTD and SwissTargetPrediction databases. Neuropathic pain- and VIN-related targets were collected from the CTD and GeneCards databases. Subsequently, the intersection targets were obtained using the Venn tool, and the protein-protein interaction (PPI) was constructed by the STRING database. GO and KEGG enrichment analyses were performed to investigate the biological functions of the intersection targets. Further, a rat model of VIN-induced neuropathic pain was established to confirm the reliability of the network pharmacology findings. Results: A total of 46 intersection targets were identified as potential therapeutic targets, mainly related to neuroinflammation. KEGG pathway analysis indicated that the IL-17 signaling pathway was involved in the mechanism of the antinociceptive effect of PD. PPI network analysis indicated that RELA, IL-6, TP53, MAPK3, and MAPK1 were located at crucial nodes in the network. Additionally, PD exerted an antinociceptive effect by increasing the nociceptive threshold. The results of qRT-PCR, western blot, and immunohisochemistry indicated that PD inhibited the IL-6, TP53, and MAPK1 levels in VIN-induced neuropathic pain rats. Conclusions: Overall, this research provided evidence that suppressing inflammatory signaling pathways might be a potential mechanism action of PD's antinociceptive effect against VIN-induced neuropathic pain.

Therapeutic Efficacy of Traditional Chinese Medicine Syndrome-Based Formulae to Neuropathic Pain Caused by Chemotherapy.

OBJECTIVE: Chemotherapy-induced neuropathic pain (CINP) is a troublesome complication of anti-cancer treatment. The aim of this retrospective study was to investigate the effectiveness of classic Chinese herbal formulae (CHF) Huang Qi Gui Zhi Wu Wu Tang (HQGZWWT) and Dang Gui Si Ni Tang (DGSNT) in the treatment of CINP. MATERIALS AND METHODS: Douleur Neuropathique 4 (DN4) and Functional Assessment of Cancer Therapy-General (FACT-G) questionnaires were rated at baseline and after 3-monthly CHF treatment. RESULTS: By searching through our medical records of all the CIPN patients from 2018 to 2019, we identified and enrolled 37 patients with Deficiency-Cold syndrome in the study, for whom the treatment of neuropathic pain by regular pharmacotherapies had failed or intolerable. At the third month evaluation with the DN4 questionnaire, 13 patients had symptomatic remission, 15 patients remained stable, and 9 patients had no response to CHF. The 3-month mean DN4 score was significantly higher than that at the baseline (P < .001). After CHF treatment, significant differences in quality of life were noted in the physical, social, emotional, and functional well-being subscales, and in the total score, of the FACT-G (P < .001). No adverse events or instances of disease progression were observed. CONCLUSIONS: The results of our small study are the first in the literature to show the clinical effectiveness of CHF for CINP. Combination of HQGZWWT and DGSNT is well tolerated and may offer the possibility to ameliorate CINP more than conventional care can. It merits further investigation.

Capsaicin 8% for Peripheral Neuropathic Pain Treatment: A Retrospective Cohort Study.

BACKGROUND: Chronic neuropathic pain is a disabling condition that affects quality of life. Despite recommendations and guidelines, treatment remains suboptimal as it often does not result in significant symptom relief. Capsaicin 8% patch has been used for the treatment of several peripheral neuropathic pain etiologies with encouraging results. OBJECTIVES: To assess the results of capsaicin 8% patch on neuropathic pain by evaluating pain intensity and the painful treatment area. STUDY DESIGN: Observational retrospective cohort study. SETTING: All patients submitted to capsaicin treatment at the Chronic Pain Unit of the Hospital Centre of Tondela Viseu, from 2011 through 2019. METHODS: Records of capsaicin treatments were reviewed, and the data collected. The primary outcome was pain intensity and painful treatment area reduction between the first and last treatment. Also, the number of treatments performed, neuropathic pain duration, anatomic location, pain etiology, and concomitant oral pain medication at baseline and upon treatment conclusion was also listed. RESULTS: Postsurgical neuropathic pain was the most common etiology (49%), followed by postherpetic (28%). The median (interquartile range [IQR]) baseline pain intensity assessed by the Numeric Rating Scale (NRS-11) was 6 (5-8) and the median (IQR) final NRS-11 was 3 (1-5), with a median (IQR) relative difference of -0.5 (-0.85-0.17) with statistically significant differences (P < 0.001) between baseline and last pain intensity, regarding all groups. Also, there was a reduction in the painful treatment area between baseline and the last evaluation, with a median (IQR) relative difference of -0.4 (-0.625-0.167). LIMITATIONS: A relatively small sample and occasional different timing for pain intensity and pain treatment area assessment due to logistical difficulties. CONCLUSIONS: Capsaicin 8% patch is a valuable option for the treatment of peripheral neuropathic pain, providing a significant reduction in pain intensity and painful area. It is well tolerated and has a high treatment compliance.Ethics Committee Reference Number: 16/16//04/2021.

The Role of Saponins in the Treatment of Neuropathic Pain.

Neuropathic pain is a chronic pain caused by tissue injury or disease involving the somatosensory nervous system, which seriously affects the patient's body function and quality of life. At present, most clinical medications for the treatment of neuropathic pain, including antidepressants, antiepileptic drugs, or analgesics, often have limited efficacy and non-negligible side effects. As a bioactive and therapeutic component extracted from Chinese herbal medicine, the role of the effective compounds in the prevention and treatment of neuropathic pain have gradually become a research focus to explore new analgesics. Notably, saponins have shown analgesic effects in a large number of animal models. In this review, we summarized the most updated information of saponins, related to their analgesic effects in neuropathic pain, and the recent progress on the research of therapeutic targets and the potential mechanisms. Furthermore, we put up with some perspectives on future investigation to reveal the precise role of saponins in neuropathic pain.

Huangqi Guizhi Wuwu Decoction can prevent and treat oxaliplatin-induced neuropathic pain by TNFα/IL-1ß/IL-6/MAPK/NF-kB pathway.

OBJECTIVE: This study explored the effects and mechanisms of Huangqi Guizhi Wuwu Decoction on chemotherapy-induced neuropathic pain (CINP). METHODS: Bodyweight and related behavioral testing of the rat model were utilized to investigate the effects of Huangqi Guizhi Wuwu Decoction on CINP. ELISA was used to measure the levels of TNF-α, IL-1ß, and IL-6, in the serum of chronic CINP rats. Immunohistochemistry and Western blot analysis were performed to detect the expression of MAPK pathway related-proteins namely ERK1/2, p38, and JNK, and the expression of downstream essential proteins such as c-Fos, CREB, and NF-κB. RESULTS: Body weight and related behavioral testing of the rat model suggests that Huangqi Guizhi Wuwu Decoction can improve the slow weight gain of oxaliplatin-induced chronic CINP model rats and effectively prevent and treat oxaliplatin-induced regular CIPN rat model of hyperalgesia. It can also oppress the mechanical pain threshold, cold pain threshold, and heat pain threshold decreased. Furthermore, by ELISA, immunohistochemistry, and western blot analysis, we found that Huangqi Guizhi Wuwu Decoction can down-regulate the levels of TNF-α, IL-1ß, and IL-6 in the serum of chronic CINP rats induced by oxaliplatin. It also suppresses the expression of MAPK pathway related-proteins ERK1/2, p38, and JNK. This results in a decrease in the expression of downstream essential proteins, c-Fos, CREB, and Nf-κB. CONCLUSIONS: In conclusion, we found that Huangqi Guizhi Wuwu Decoction can combat nerve cell injury, reduce pain sensitization, and prevent and repair the damage of nerve cells in the oxaliplatin CINP model rats via TNFα/IL-1ß/IL-6/MAPK/NF-kB pathway.

Investigation of the key targets and pharmacological mechanisms of rhamnocitrin against oxaliplatin-induced neuropathic pain based on network pharmacology approach and experimental validation.

Rhamnocitrin (RH) is a bioactive flavonoid of Astragali Radix, which exerts a wide variety of pharmacological effects. However, there are no reports focusing on the therapeutical effects and mechanisms of RH against neuropathic pain (NP). In this study, systematic pharmacology and in vivo experimental approaches were employed to identify the potential targets of RH for treating oxaliplatin-induced NP. Our findings indicated that the therapeutical effect of RH might be closely associated with key genes, including MAPK3, MAPK1, SRC, PTGS2, EGFR, MMP9, and MMP2, as well as potential signaling pathways such as PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance, and Rap1 signaling pathway. The in vivo experimental findings demonstrated that RH could suppress oxidative stress, inflammatory response, and down-regulate MMP2 and MMP9 expressions to exert its therapeutic effects against NP. This study used network pharmacology and experimental validation to elucidate the potential targets and underlying mechanisms by which RH improves oxaliplatin-induced NP and offer new insight on drug development for NP.

Involvement of spinal cannabinoid receptor type 2 in the analgesia effect of hyperbaric oxygen treatment on paclitaxel-induced neuropathic pain.

BACKGROUND: Chemotherapy-induced neuropathic pain (CINP) is intractable, and spinal cannabinoid receptors (CBRs) are potential therapeutic targets for CINP. Previous studies demonstrated that hyperbaric oxygen (HBO2) may contribute in alleviating specific peripheral neuropathic pain. However, neither CINP nor CBR have been clarified. We hypothesized that HBO2 is capable of alleviating CINP, and the effect could be explained by the activation of spinal CBRs. METHODS: A series of paclitaxel-induced CINP models were established on male Sprague-Dawley rats. Then HBO2 treatment was administered for seven consecutive days at 2.5 atmospheres absolute. Two groups were treated with AM251 (an antagonist of CBR type-1, CBR1) or AM630 (an antagonist of CBR type-2, CBR2) respectively 30 minutes before each HBO2 treatment. The mechanical withdrawal threshold was assessed before, during and at two weeks after HBO2 treatment. Lumbar spinal cords were collected for Western blot analysis of CBR1, CBR2, GFAP and CD11b, and ELISA analysis of proinflammatory cytokines IL-1ß and TNF-α. RESULTS: A mechanical allodynia was successfully exhibited and the spinal GFAP, CD11b, IL-1ß and TNF-α significantly increased after the modeling, and these effects could be further reversed by HBO2 treatment, which could be blocked by AM630, other than AM251. CONCLUSION: HBO2 treatment can alleviate paclitaxel-induced neuropathic pain, and be mediated by CBR2. Spinal glial cells and proinflammatory cytokines are involved in this process.

Punicalagin and ellagic acid containing Punica granatum L. fruit rind extract prevents vincristine-induced neuropathic pain in rats: an in silico and in vivo evidence of GABAergic action and cytokine inhibition.

Objectives: We aimed to investigate the protective potential of Punica granatum L. fruit rind extract (PFE) containing punicalagin (10.3% W/W), ellagic acid (EA) (2.7%W/W) in vincristine (75 µg/kg i.p.)- induced neuropathic pain in Wistar rats.Methods: Docking simulation studies were done on the three-dimensional (3D) structure of the GABAA and PPAR γ receptor for the binding of EA as well as punicalagin docking studies on TNF-α, and IL-6. The Present Study conceptualized a test battery to evaluate the behavioral, biochemical and histological changes.Results: Vincristine -induced significant cold allodynia, mechanical hyperalgesia, and functional deficit on 12th and 21st days. It also increased in the levels of TNF-α (Tumor necrosis factor-α), IL-6 (Interleukin-6), and MPO (Myeloperoxidase). Administration of PFE (100 and 300 mg/kg, p.o.), EA (50 mg/kg), and gabapentin (100 mg/kg) attenuated Vincristine-induced behavioral and biochemical changes significantly (P < .05). PFE showed better antinociceptive activity to EA. The histopathological evaluation also revealed the protective effects of PFE. Pretreatment of bicuculline (selective antagonist of GABAA receptors) reversed antinociceptive action of PFE, but administration of γ aminobutyric acid potentiated the action of PFE. PPAR-γ antagonist BADGE did not modify the effect of PFE. Docking results revealed that EA properly positioned into GABA and PPARγ binding site and acts as a partial agonist. Docking score of Punicalagin found to be - 9.02 kcal/mol and - 8.32 kcal/mol on IL-6 and TNFα respectively.Discussion: Conclusively, the attenuating effect of PFE may be attributed to the GABAergic system, cytokine inhibition, and anti-inflammatory activities.

Mechanisms, Characteristics, and Treatment of Neuropathic Pain and Peripheral Neuropathy Associated with Dinutuximab in Neuroblastoma Patients.

Prognosis of metastatic neuroblastoma is very poor. Its treatment includes induction chemotherapy, surgery, high-dose chemotherapy, radiotherapy, and maintenance with retinoic acid, associated with the anti-GD2 monoclonal antibody (ch14.18) dinutuximab. Immunotherapy determined a significant improvement in survival rate and is also utilized in relapsed and resistant neuroblastoma patients. Five courses of dinutuximab 100 mg/m2 are usually administered as a 10-day continuous infusion or over 5 consecutive days every 5 weeks. Dinutuximab targets the disialoganglioside GD2, which is highly expressed on neuroblastoma cells and minimally present on the surface of normal human neurons, peripheral pain fibers, and skin melanocytes. Anti GD2 antibodies bind to surface GD2 and determine the lysis of neuroblastoma cells induced by immune response via the antibody-dependent cellular cytotoxicity and the complement-dependent cytotoxicity. Dinutuximab has significant side effects, including neuropathic pain, peripheral neuropathy, hypersensitivity reactions, capillary leak syndrome, photophobia, and hypotension. The most important side effect is neuropathic pain, which is triggered by the same antibody-antigen immune response, but generates ectopic activity in axons, which results in hyperalgesia and spontaneous pain. Pain can be severe especially in the first courses of dinutuximab infusion, and requires the administration of gabapentin and continuous morphine infusion. This paper will focus on the incidence, mechanisms, characteristics, and treatment of neuropathic pain and peripheral neuropathy due to dinutuximab administration in neuroblastoma patients.

Neuroprotective properties of ethanolic extract of Citrus unshiu Markovich peel through NADPH oxidase 2 inhibition in chemotherapy-induced neuropathic pain animal model.

The present study aimed to determine the antioxidant effect of Citrus unshiu Markovich (CUM) extract in neuronal cell lines under oxidative stress and to investigate the effect of chemotherapy-induced peripheral neuropathy (CIPN) on the nociceptive response in a preclinical mice model. We tested the inhibition of H2 O2 in Neuro2A cells treated with CUM. Experimental animals were treated with oxaliplatin to induce CINP, and then administered oral CUM for 4 weeks in order to observe the effect of CUM. Animals were evaluated weekly for thermal hyperalgesia and digital motor nerve conduction velocity (NCV). Lumbar dorsal root ganglia (DRG) isolated from each animal were evaluated through immunochemical and western blot analysis for nerve damage, inflammatory response, and expression of redox signaling factors. The main mechanisms were determined to be decreased inducible nitric oxide synthase (iNOS) production due to the inhibition of NADPH oxidase 2 (NOX2). To determine the functional role of NOX2 in CINP, we administrated CUM into NOX2-deficient mice with neuropathic pain. Therefore, we suggest that CUM controls the expression levels of inflammatory factors in CINP via NOX2 inactivation. This study demonstrated that a complementary medicine such as CUM might be a potential novel therapeutic agent for the treatment of CINP.