Paclitaxel-induced Peripheral Neuropathy Research Articles

Neuroprotective effect of chelidonic acid through oxidative stress reduction in paclitaxel-induced peripheral neuropathy in rats.

The present study evaluated the effect of chelidonic acid on paclitaxel-induced neuropathy in male Wistar rats. Neuropathy was induced by administering paclitaxel (2mg/kg, i.p.) on 0, 2, 4, and 6days of the protocol. Chelidonic acid treatment (at doses of 10, 20, and 40mg/kg orally, for 21days) was initiated simultaneously with paclitaxel administration. After completion of the protocol, mechanical allodynia, hyperalgesia, and thermal hyperalgesia were measured. Additionally, nerve conduction velocity was assessed. The study investigated inflammatory cytokines, oxidative stress, and histological changes in the sciatic nerve. Furthermore, the Nrf2 was measured, and the protein expression of pAMPK and HIF-1α was assessed using western blotting. The results showed that chelidonic acid significantly normalized mechanical allodynia, hyperalgesia, and thermal hyperalgesia. It also led to a significant improvement in motor and sensory nerve conduction velocity and reduced oxidative stress compared with paclitaxel alone. Inflammatory markers such as TNF-alpha, IL-6, and IL-1β concentrations, as well as nitric oxide and C-reactive protein, were significantly decreased in the chelidonic acid-treated group. Histopathological examination revealed reduced neuronal damage, demyelination, and leukocyte infiltration with chelidonic acid treatment. Chelidonic acid treatment also resulted in a considerable rise in Nrf2 levels (p < 0.001) and increased protein expression of pAMPK in the sciatic nerve. Conversely, HIF-1α expression was significantly declined in the chelidonic acid treatment. Overall, the findings suggest that chelidonic acid treatment attenuates paclitaxel-induced neuropathic pain.

Prophylactic role of pentoxifylline against paclitaxel-induced neuropathy among patients with breast cancer: a randomized-controlled trial.

Paclitaxel-induced peripheral neuropathy (PN) is a significant clinical concern for which no approved treatment is currently available. The purpose of this trial was to investigate the neuro-prophylactic impact of pentoxifylline against paclitaxel-induced PN in patients diagnosed with breast cancer (BC). BC patients who were assigned to paclitaxel chemotherapy were randomly allocated to pentoxifylline or a control group for 12 weeks. The main outcomes included the assessment of PN incidence according to the defined Common Terminology Criteria for Adverse Events, quality of life (QoL) using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTx) scale, and neuropathic pain using the scale of self-reported Leeds Assessment for Neuropathic Symptoms and Signs (s-LANSS). The code of the clinical trial registration is NCT06562998. The current study included a total of 72 patients allocated into pentoxifylline arm (n = 35) and placebo arm (n = 37). By the 12th week, the prevalence of PN (grade 2 or 3) was significantly lower in the pentoxifylline arm 10/35 (28.6%) compared to 24/37 (64.9%) of the controls (P value = 0.016). The total FACT/GOG-NTx score indicated a considerably worse QoL in the control group [98.18 (10.2) vs. 81.43 (14.8) for pentoxifylline and the control group, respectively, P < 0.001] with a mean difference of -16.75 [95% confidence interval (CI): -23.97 to -9.53]. S-LANSS scale showed significantly higher scores after 6 weeks [13.72 (5.86) vs. 17.52 (3.16), P = 0.002] and 12 weeks [17.84 (4.25) vs. 23.80 (1.00), P < 0.001] for pentoxifylline and control group, respectively. In conclusion, the use of pentoxifylline showed a significant reduction in paclitaxel-induced PN, which improved their QoL.

Electroacupuncture with different frequencies for paclitaxel-induced peripheral neuropathy: a randomized controlled trial

To observe the clinical efficacy of electroacupuncture (EA) at frequencies of 2 Hz, 100 Hz, and 2 Hz/100 Hz for chemotherapy-induced peripheral neuropathy (CIPN). One hundred and sixty female breast cancer patients with CIPN induced by paclitaxel were randomly divided into a 2 Hz EA group (40 cases, 1 case dropped out), a 100 Hz EA group (40 cases, 2 cases dropped out), a 2 Hz/100 Hz EA group (40 cases, 3 cases dropped out), and a medication group (40 cases, 2 cases dropped out). The three EA groups received acupuncture at bilateral Quchi (LI 11), Waiguan (TE 5), Hegu (LI 4), Zusanli (ST 36), and Yanglingquan (GB 34). Electrodes of the HANS-200E acupoint nerve stimulator were connected to the same side Hegu (LI 4) and Waiguan (TE 5), and Zusanli (ST 36) and Sanyinjiao (SP 6), with EA stimulation frequencies of 2 Hz, 100 Hz, and 2 Hz/100 Hz, respectively. Each session lasted 30 min, once every other day, three times a week. The medication group received oral mecobalamin tablets, 0.5 mg per dose, three times a day. All groups were treated for four weeks. The functional assessment of cancer therapy/gynaecologic oncology group-neurotoxicity (FACT/GOG-Ntx), peripheral neurotoxicity grading based on the National Cancer Institute-common terminology criteria for adverse events Version 5.0 (NCI-CTCAE V5.0), and peripheral neuropathy pain visual analogue scale (VAS) scores were observed before and after treatment, and at follow-up after 4 weeks of treatment completion, and clinical efficacy was evaluated after theatment. Compared before treatment, FACT/GOG-Ntx scores in all groups were decreased after treatment and during follow-up (P<0.01). The score reduction between before and after treatment in the three EA groups was greater than the medication group (P<0.01, P<0.05), with the 2 Hz and 2 Hz/100 Hz EA groups showing a greater reduction than the 100 Hz EA group (P<0.05). The reduction of FACT/GOG-Ntx score between before treatment and follow-up in the 2 Hz and 2 Hz/100 Hz EA groups was greater than the medication group (P<0.01). Peripheral neurotoxicity grading in the three EA groups were improved after treatment (P<0.01). Compared before treatment, the peripheral neurotoxicity grading in the 2 Hz and 2 Hz/100 Hz EA groups was improved at follow-up (P<0.01, P<0.05). The VAS scores for peripheral neuropathy pain in the three EA groups were decreased after treatment (P<0.01, P<0.05). At follow-up, VAS scores in the 2 Hz, 2 Hz/100 Hz, and medication groups were decreased (P<0.01, P<0.05), with a greater reduction in the 2 Hz/100 Hz EA group than the medication group after treatment and follow-up (P<0.01, P<0.05). The overall effective rates for the 2 Hz, 100 Hz, 2 Hz/100 Hz, and medication groups were 79.5% (31/39), 68.4% (26/38), 81.1% (30/37), and 47.4% (18/38), respectively, with the 2 Hz and 2 Hz/100 Hz groups showing higher effective rates than the medication group (P<0.05). EA is effective in treating paclitaxel-induced CIPN. While there is no overall difference in efficacy among the different frequencies, 2 Hz and 2 Hz/100 Hz EA showing potential advantages. For patients with concurrent peripheral neuropathy pain, 2 Hz/100 Hz electroacupuncture is recommended.

Attenuation of p38 MAPK/NF-κB/TRPV1/CGRP is involved in the antinociceptive effect of hesperidin methyl chalcone and taxifolin in paclitaxel-induced peripheral neuropathy.

Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is a disabling side effect of PTX, which adversely affects the life quality of cancer patients. Flavonoids such as hesperidin methyl chalcone (HMC) and taxifolin (TAX) can alleviate neuropathic pain via their anti-inflammatory, antioxidant, neuroprotective, and antinociceptive properties. The current study aimed to assess the efficacy of HMC and TAX in preventing PIPN individually or in combination. Pretreatment with HMC and TAX mitigated PTX-induced mechanical allodynia and hyperalgesia, cold allodynia, and thermal hyperalgesia as well as restorethe normal histological architecture. Remarkably, neuropathic pain was relieved by suppression of nerve growth factor (NGF), p38 mitogen-activated protein kinase (p38 MAPK), and transient receptor potential vanilloid type-1 (TRPV1), which ultimately lead to reduced calcitonin gene-related peptide (CGRP). Furthermore, both HMC or TAX enhanced nuclear factor erythroid 2-related factor 2 (Nrf2), leading to elevated glutathione (GSH) and total antioxidant capacity (TAC) along with lowered malondialdehyde (MDA), which in turn, downregulated nuclear factor kappa B P65 (NF-κB P65) and its phosphorylated form and eventually reduced tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) then lowered the apoptotic indices. Promisingly, the combination of both agents was superior to each drug alone through targeting more diverse signaling pathways and achieving synergistic and comprehensive therapeutic effects. In conclusion, pretreatment with HMC and TAX separately or in combination alleviated PIPN via modulating NGF/p38 MAPK/NF-κB P65/TRPV1/CGRP pathway.

Automated System to Capture Patient Symptoms From Multitype Japanese Clinical Texts: Retrospective Study.

Natural language processing (NLP) techniques can be used to analyze large amounts of electronic health record texts, which encompasses various types of patient information such as quality of life, effectiveness of treatments, and adverse drug event (ADE) signals. As different aspects of a patient's status are stored in different types of documents, we propose an NLP system capable of processing 6 types of documents: physician progress notes, discharge summaries, radiology reports, radioisotope reports, nursing records, and pharmacist progress notes. This study aimed to investigate the system's performance in detecting ADEs by evaluating the results from multitype texts. The main objective is to detect adverse events accurately using an NLP system. We used data written in Japanese from 2289 patients with breast cancer, including medication data, physician progress notes, discharge summaries, radiology reports, radioisotope reports, nursing records, and pharmacist progress notes. Our system performs 3 processes: named entity recognition, normalization of symptoms, and aggregation of multiple types of documents from multiple patients. Among all patients with breast cancer, 103 and 112 with peripheral neuropathy (PN) received paclitaxel or docetaxel, respectively. We evaluate the utility of using multiple types of documents by correlation coefficient and regression analysis to compare their performance with each single type of document. All evaluations of detection rates with our system are performed 30 days after drug administration. Our system underestimates by 13.3 percentage points (74.0%-60.7%), as the incidence of paclitaxel-induced PN was 60.7%, compared with 74.0% in the previous research based on manual extraction. The Pearson correlation coefficient between the manual extraction and system results was 0.87 Although the pharmacist progress notes had the highest detection rate among each type of document, the rate did not match the performance using all documents. The estimated median duration of PN with paclitaxel was 92 days, whereas the previously reported median duration of PN with paclitaxel was 727 days. The number of events detected in each document was highest in the physician's progress notes, followed by the pharmacist's and nursing records. Considering the inherent cost that requires constant monitoring of the patient's condition, such as the treatment of PN, our system has a significant advantage in that it can immediately estimate the treatment duration without fine-tuning a new NLP model. Leveraging multitype documents is better than using single-type documents to improve detection performance. Although the onset time estimation was relatively accurate, the duration might have been influenced by the length of the data follow-up period. The results suggest that our method using various types of data can detect more ADEs from clinical documents.

ART26.12, a novel fatty acid-binding protein 5 inhibitor, shows efficacy in multiple preclinical neuropathy models.

Painful neuropathy is a pathological condition caused by numerous factors including diabetes, chemotherapy or cancer. ART26.12 is a novel fatty acid-binding protein 5 inhibitor, which our group showed could prevent and treat persistent pain in a preclinical model of oxaliplatin-induced peripheral neuropathy. In the current study, the efficacy of orally dosed ART26.12 was tested in multiple neuropathy models of different aetiology. Paw withdrawal threshold to von Frey monofilaments and latency to escape a cold plate were used as measurements of mechanical and cold sensitivity. ART26.12 (25 and 50 mg/kg BID), dosed prior to the induction of paclitaxel-induced peripheral neuropathy (PIPN), reversed mechanical allodynia induced by paclitaxel in both male and female rats, and ART26.12 (50 mg/kg BID) prevented the induction of PIPN in female rats. ART26.12 (50 mg/kg BID) also had a protective effect on body weight in the PIPN model. ART26.12 (25 and 100 mg/kg BID) reversed mechanical allodynia when treating established streptozotocin-induced diabetic neuropathy in male rats. In a model of breast cancer-induced bone pain in female rats, ART26.12 (100 mg/kg BID) reversed mechanical allodynia within 1 h of dosing. In the same model, ART26.12 (25 mg/kg BID) reversed mechanical allodynia from day 4 of treatment. Overall, these preclinical data suggest that ART26.12 is a safe and efficacious therapeutic drug for continued development towards the prevention and treatment of peripheral neuropathy. This work now shows that ART26.12, a novel and selective inhibitor of FABP5, can prevent and treat multiple preclinical models of peripheral neuropathy. Given its excellent safety profile, further work is warranted to develop ART26.12 as a potential therapeutic tool for pain management.

Nicotinamide riboside activates SIRT3 to prevent paclitaxel-induced peripheral neuropathy

Paclitaxel (PTX) is a microtubule stabilizer that disrupts the normal cycle of microtubule depolymerization and repolymerization, leading to cell cycle arrest and cancer cell death. It is commonly used as a first-line chemotherapeutics for various malignancies, such as breast cancer, non-small cell lung cancer, and ovarian cancer. However, PTX chemotherapy is associated with common and serious side effects, including chemotherapy-induced peripheral neuropathy (CIPN). As cancer treatment advances and survival rates increase, the impact of CIPN on patients' quality of life has become more significant. To date, there is no effective treatment strategy for CIPN. Surtuin3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+) dependent protein deacetylase located on mitochondria. It transfers the acetyl group of the lysine side chain of acetylated substrate proteins to NAD+, producing deacetylated proteins to regulate mitochondrial energy metabolic processes. SIRT3 has been found to play an important role in various diseases, including aging, neurodegenerative diseases, cancer, heart disease, metabolic diseases, etc. However, the role of SIRT3 in CIPN is still unknown. This study found for the first time that activating SIRT3 helps to improve paclitaxel-induced CIPN. Nicotinamide riboside (NR) can protect dorsal root ganglion (DRG) mitochondria against oxidative damage caused by paclitaxel through activating SIRT3-MnSOD2 and SIRT3-Nrf2 pathway. Moreover, NR can enhance the anticancer activity of paclitaxel. Together, our research provides new strategy and candidate drug for the treatment of CIPN.

Pre-treatment amino acids and risk of paclitaxel-induced peripheral neuropathy in SWOG S0221.

Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting and debilitating neurotoxicity of many commonly used anti-cancer agents, including paclitaxel. The objective of this study was to confirm the previously found inverse association between pre-treatment blood concentrations of histidine and CIPN occurrence and examine relationships of other amino acids with CIPN severity. Pre-treatment serum concentrations of 20 amino acids were measured in the SWOG S0221 (NCT00070564) trial of patients with early-stage breast cancer receiving paclitaxel. The associations between amino acids and CIPN severity were tested in regression analysis adjusted for paclitaxel schedule, age, self-reported race, and body mass index with Bonferroni correction. The network of metabolic pathways of amino acids was analyzed using over-representation analysis. The partial correlation network of amino acids was evaluated using a debiased sparse partial correlation algorithm. In the primary analysis, histidine concentration was not associated with CIPN occurrence (odds ratio (OR) = 0.97 [0.83, 1.13], p = 0.72). In secondary analyses, higher concentrations of four amino acids, glutamate (β = 0.58 [0.23, 0.93], p = 0.001), phenylalanine (β = 0.54 [0.19, 0.89], p = 0.002), tyrosine (β = 0.57 [0.23, 0.91], p = 0.001), and valine (β = 0.58 [0.24, 0.92], p = 0.001) were associated with more severe CIPN, but none of these associations retained significance after adjustment. In the over-representation analysis, no amino acid metabolic pathways were significantly enriched (all FDR > 0.05). In the network of enriched pathways, glutamate metabolism had the highest centrality. This analysis showed that pre-treatment serum amino acid concentrations are not strongly predictive of CIPN severity. Prospectively designed studies that assess non-amino acid metabolomics predictors are encouraged.

Sex differences in PD-L1-induced analgesia in paclitaxel-induced peripheral neuropathy mice depend onTRPV1-based inhibition of CGRP.

Paclitaxel (PTX) is extensively utilized in the management of diverse solid tumors, frequently resulting in paclitaxel-induced peripheral neuropathy (PIPN). The present study aimed to investigate sex differences in the behavioral manifestations and underlying pathogenesis of PIPN and search for clinically efficacious interventions. Male and female C57BL/6 mice (5-6 weeks and 12 months, weighing 18-30 g) were intraperitoneally (i.p.) administered paclitaxel diluted in saline (NaCl 0.9%) at a dose of 2 mg/kg every other day for a total of 4 injections. Von Frey and hot plate tests were performed before and after administration to confirm the successful establishment of the PIPN model and also to evaluate the pain of PIPN and the analgesic effect of PD-L1. On day 14 after PTX administration, PD-L1 protein (10 ng/pc) was injected into the PIPN via the intrathecal (i.t.) route. To knock down TRPV1 in the spinal cord, adeno-associated virus 9 (AAV9)-Trpv1-RNAi (5 μL, 1 × 1013 vg/mL) was slowly injected via the i.t. route. Four weeks after AAV9 delivery, the downregulation of TRPV1 expression was verified by immunofluorescence staining and Western blotting. The levels of PD-L1, TRPV1 and CGRP were measured via Western blotting, RT-PCR, and immunofluorescence staining. The levels of TNF-α and IL-1β were measured via RT-PCR. TRPV1 and CGRP protein and mRNA levels were higher in the spinal cords of control female mice than in those of control male mice. PTX-induced nociceptive behaviors in female PIPN mice were greater than those in male PIPN mice, as indicated by increased expression of TRPV1 and CGRP. The analgesic effects of PD-L1 on mechanical hyperalgesia and thermal sensitivity were significantly greater in female mice than in male mice, with calculated relative therapeutic levels increasing by approximately 2.717-fold and 2.303-fold, respectively. PD-L1 and CGRP were partly co-localized with TRPV1 in the dorsal horn of the mouse spinal cord. The analgesic effect of PD-L1 in PIPN mice was observed to be mediated through the downregulation of TRPV1 and CGRP expression following AAV9-mediated spinal cord specific decreased TRPV1 expression. PTX-induced nociceptive behaviors and the analgesic effect of PD-L1 in PIPN mice were sexually dimorphic, highlighting the significance of incorporating sex as a crucial biological factor in forthcoming mechanistic studies of PIPN and providing insights for potential sex-specific therapeutic approaches.

A novel marine-derived mitophagy inducer ameliorates mitochondrial dysfunction and thermal hypersensitivity in paclitaxel-induced peripheral neuropathy.

Mitochondrial dysfunction contributes to the pathogenesis and maintenance of chemotherapy-induced peripheral neuropathy (CIPN), a significant limitation of cancer chemotherapy. Recently, the stimulation of mitophagy, a pivotal process for mitochondrial homeostasis, has emerged as a promising treatment strategy for neurodegenerative diseases, but its therapeutic effect on CIPN has not been explored. Here, we assessed the mitophagy-inducing activity of 3,5-dibromo-2-(2',4'-dibromophenoxy)-phenol (PDE701), a diphenyl ether derivative isolated from the marine sponge Dysidea sp., and investigated its therapeutic effect on a CIPN model. Mitophagy activity was determined by a previously established mitophagy assay using mitochondrial Keima (mt-Keima). Mitophagy induction was further verified by western blotting, immunofluorescence, and electron microscopy. Mitochondrial dysfunction was analysed by measuring mitochondrial superoxide levels in SH-SY5Y cells and Drosophila larvae. A thermal nociception assay was used to evaluate the therapeutic effect of PDE701 on the paclitaxel-induced thermal hyperalgesia phenotype in Drosophila larvae. PDE701 specifically induced mitophagy but was not toxic to mitochondria. PDE701 ameliorated paclitaxel-induced mitochondrial dysfunction in both SH-SY5Y cells and Drosophila larvae. Importantly, PDE701 also significantly ameliorated paclitaxel-induced thermal hyperalgesia in Drosophila larvae. Knockdown of ATG5 or ATG7 abolished the effect of PDE701 on thermal hyperalgesia, suggesting that PDE701 exerts its therapeutic effect through mitophagy induction. This study identified PDE701 as a novel mitophagy inducer and a potential therapeutic compound for CIPN. Our results suggest that mitophagy stimulation is a promising strategy for the treatment of CIPN and that marine organisms are a potential source of mitophagy-inducing compounds.

Proteomic Analysis of Dorsal Root Ganglia in a Mouse Model of Paclitaxel-Induced Neuropathic Pain.

Paclitaxel is a chemotherapy drug widely used for the treatment of various cancers based on its ability to potently stabilize cellular microtubules and block division in cancer cells. Paclitaxel-based treatment, however, accumulates in peripheral system sensory neurons and leads to a high incidence rate (over 60%) of chemotherapy induced peripheral neuropathy. Using an established preclinical model of paclitaxel-induced peripheral neuropathy (PIPN), we examined proteomic changes in dorsal root ganglia (DRG) of adult male mice that were treated with paclitaxel (8 mg/kg, at 4 injections every other day) relative to vehicle-treated mice. High throughput proteomics based on liquid chromatography electrospray ionization mass spectrometry identified 165 significantly altered proteins in lumbar DRG. Gene ontology enrichment and bioinformatic analysis revealed an effect of paclitaxel on pathways for mitochondrial regulation, axonal function, and inflammatory purinergic signaling as well as microtubule activity. These findings provide insight into molecular mechanisms that can contribute to PIPN in patients.

The potential neuroprotective effects of cannabinoids against paclitaxel-induced peripheral neuropathy: in vitro study on neurite outgrowth.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a shared burden for 68.1% of oncological patients undergoing chemotherapy with Paclitaxel (PTX). The symptoms are intense and troublesome, patients reporting paresthesia, loss of sensation, and dysesthetic pain. While current medications focus on decreasing the symptom intensity, often ineffective, no medication is yet recommended by the guidelines for the prevention of CIPN. Cannabinoids are an attractive option, as their neuroprotective features have already been demonstrated in neuropathies with other etiologies, by offering the peripheral neurons protection against toxic effects, which promotes analgesia. Methods: We aim to screen several new cannabinoids for their potential use as neuroprotective agents for CIPN by investigating the cellular toxicity profile and by assessing the potential neuroprotective features against PTX using a primary dorsal root ganglion neuronal culture. Results: Our study showed that synthetic cannabinoids JWH-007, AM-694 and MAB-CHMINACA and phytocannabinoids Cannabixir® Medium dried flowers (NC1) and Cannabixir® THC full extract (NC2) preserve the viability of fibroblasts and primary cultured neurons, in most of the tested dosages and time-points. The combination between the cannabinoids and PTX conducted to a cell viability of 70%-89% compared to 40% when PTX was administered alone for 48h. When assessing the efficacy for neuroprotection, the combination between cannabinoids and PTX led to better preservation of neurite length at all tested time-points compared to controls, highly drug and exposure-time dependent. By comparison, the combination of the cannabinoids and PTX administered for 24h conducted to axonal shortening between 23% and 44%, as opposed to PTX only, which shortened the axons by 63% compared to their baseline values. Discussion and Conclusion: Cannabinoids could be potential new candidates for the treatment of paclitaxel-induced peripheral neuropathy; however, our findings need to be followed by additional tests to understand the exact mechanism of action, which would support the translation of the cannabinoids in the oncological clinical practice.

CORRECTION OF PATHOLOGICAL CHANGES IN SALIVARY GLANDS OF ANIMALS WITH PACLITAXEL-INDUCED NEUROPATHY

Background. Paclitaxel is a highly effective chemotherapeutic agent used to treat breast, ovarian, and other cancers. At the same time, paclitaxel causes peripheral neuropathy as a side effect in 45%—70% of patients. Aim. The aim of the study was to investigate the effect of paclitaxel-induced peripheral neuropathy on the development of pathological changes in the salivary glands of animals and to explore the possibility of correction of the identified changes with vitamin B/ATP complex. Materials and Methods. To simulate toxic neuropathy, animals were injected i/p with paclitaxel 2 mg/kg for 4 days. In order to correct the identified changes, rats were injected i/m with vitamin B/ATP complex (1 mg/ kg) for 9 days. In the homogenate of the submandibular salivary glands, α-amylase activity, total proteolytic activity, total antitryptic activity, the content of medium mass molecules, thiobarbituric acid reactive substances (TBARS), oxidatively modified proteins, and catalase activity were determined. Results. A significant increase in the content of oxidatively modified proteins, medium mass molecules, and the content of TBARS and significant decrease in the activity of catalase and amylase were determined in the salivary glands of animals with toxic neuropathy compared to these parameters in intact animals. Administration of vitamin B/ATP complex for 9 days against the background of paclitaxel-induced neuropathy led to normalization of antitryptic activity and amylase activity, a significant decrease in the content of oxidatively modified proteins, medium mass molecules, and TBARS along with a significant increase in catalase activity in the salivary glands of animals compared to the untreated rats with neuropathy. Conclusion. Paclitaxel-induced neuropathy caused the development of pathological changes in the salivary glands of rats, which was evidenced by a carbonyl- oxidative stress and impaired protein synthetic function. The correction with vitamin B/ATP complex restored the protein-synthetic function and the proteinase-inhibitor balance, suppressed the oxidative stress and normalized free radical processes in the salivary glands of rats.

Desloratadine ameliorates paclitaxel-induced peripheral neuropathy and hypersensitivity reactions in mice.

Paclitaxel (PTX) serves as a primary chemotherapy agent against diverse solid tumors including breast cancer, lung cancer, head and neck cancer and ovarian cancer, having severe adverse effects including PTX-induced peripheral neuropathy (PIPN) and hypersensitivity reactions (HSR). A recommended anti-allergic agent diphenhydramine (DIP) has been used to alleviate PTX-induced HSR. Desloratadine (DLT) is a third generation of histamine H1 receptor antagonist, but also acted as a selective antagonist of 5HTR2A. In this study we investigated whether DLT ameliorated PIPN-like symptoms in mice and the underlying mechanisms. PIPN was induced in male mice by injection of PTX (4 mg/kg, i.p.) every other day for 4 times. The mice exhibited 50% reduction in mechanical threshold, paw thermal response latency and paw cold response latency compared with control mice. PIPN mice were treated with DLT (10, 20 mg/kg, i.p.) 30 min before each PTX administration in the phase of establishing PIPN mice model and then administered daily for 4 weeks after the model wasestablished. We showed that DLT administration dose-dependently elevated the mechanical, thermal and cold pain thresholds in PIPN mice, whereas administration of DIP (10 mg/kg, i.p.) had no ameliorative effects on PIPN-like symptoms. We found that the expression of 5HTR2A was selectively elevated in the activated spinal astrocytes of PIPN mice. Spinal cord-specific 5HTR2A knockdown by intrathecal injection of AAV9-5Htr2a-shRNA significantly alleviated the mechanical hyperalgesia, thermal and cold hypersensitivity in PIPN mice, while administration of DLT (20 mg/kg) did not further ameliorate PIPN-like symptoms. We demonstrated that DLT administration alleviated dorsal root ganglion neuronal damage and suppressed sciatic nerve destruction, spinal neuron apoptosis and neuroinflammation in the spinal cord of PIPN mice. Furthermore, we revealed that DLT administration suppressed astrocytic neuroinflammation via the 5HTR2A/c-Fos/NLRP3 pathway and blocked astrocyte-neuron crosstalk by targeting 5HTR2A. We conclude that spinal 5HTR2A inhibition holds promise as a therapeutic approach for PIPN and we emphasize the potential of DLT as a dual-functional agent in ameliorating PTX-induced both PIPN and HSR in chemotherapy. In summary, we determined that spinal 5HTR2A was selectively activated in PIPN mice and DLT could ameliorate the PTX-induced both PIPN- and HSR-like pathologies in mice. DLT alleviated the damages of DRG neurons and sciatic nerves, while restrained spinal neuronal apoptosis and CGRP release in PIPN mice. The underlying mechanisms were intensively investigated by assay against the PIPN mice with 5HTR2A-specific knockdown in the spinal cord by injection of adeno-associated virus 9 (AAV9)-5Htr2a-shRNA. DLT inhibited astrocytic NLRP3 inflammasome activation-mediated spinal neuronal damage through 5HTR2A/c-FOS pathway. Our findings have supported that spinal 5HTR2A inhibition shows promise as a therapeutic strategy for PIPN and highlighted the potential advantage of DLT as a dual-functional agent in preventing against PTX-induced both PIPN and HSR effects in anticancer chemotherapy.

The Potential Antinociceptive Effect and Mechanism of Cannabis sativa L. Extract on Paclitaxel-Induced Neuropathic Pain in Rats Uncovered by Multi-Omics Analysis.

Cannabis sativa L. (hemp) is a herbaceous plant rich in cannabinoids with a long history of use in pain treatment. The most well-characterized cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), garnered much attention in chemotherapy-induced peripheral neuropathy (CIPN) treatment. However, few studies have investigated the biological benefits and mechanism of hemp extract on CIPN. In the present study, hemp extract (JG) rich in cannabinoids was extracted by supercritical fluid carbon dioxide extraction (SFCE). The antinociceptive efficacy was evaluated using a paclitaxel-induced peripheral neuropathy (PIPN) rat model based on behavioral tests. Further omics-based approaches were applied to explore the potential mechanisms. The results showed that JG decreased mechanical allodynia, thermal hyperalgesia, and inflammatory cytokines in PIPN rats significantly. Transcriptome analysis identified seven key genes significantly regulated by JG in PIPN model rats, mainly related to the neuroactive ligand-receptor interaction pathway, PPAR signaling pathway, and cAMP signaling pathway. In metabolomic analysis, a total of 39 significantly altered metabolites were identified, mainly correlated with pentose and glucuronate interconversions and the glycerophospholipid metabolism pathway. Gut microbiota analysis suggested that increased community Lachnoclostridium and Lachnospiraceae_UCG-006 in PIPN rats can be reversed significantly by JG. In conclusion, hemp extract exhibited antinociceptive effects on PIPN. The analgesic mechanism was probably related to the regulation of inflammation, neuroactive ligand-receptor interaction pathway, sphingolipid metabolism, etc. This study provides novel insights into the functional interactions of Cannabis sativa L. extract on PIPN.

Relation between Vitamin D Level and Severity of Paclitaxel-Induced Peripheral Neuropathy in Breast Cancer Patients

Relation between Vitamin D Level and Severity of Paclitaxel-Induced Peripheral Neuropathy in Breast Cancer Patients

Risk factors of paclitaxel-induced peripheral neuropathy in patients with breast cancer: a prospective cohort study.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe adverse reaction in taxane-based chemotherapy. This study aimed to analyze the risk factors of peripheral neuropathy in patients with breast cancer receiving paclitaxel chemotherapy to provide a reference for the early prevention of CIPN. We included 350 patients with breast cancer who received chemotherapy for the first time at the Tangshan People's Hospital between August 2022 and June 2023 and were followed for at least 3 months after the end of chemotherapy. The incidence of CIPN in patients with breast cancer was calculated, and risk factors for CIPN were analyzed using logistic regression analysis. The incidence rate of CIPN was 79.1%. Multifactor logistic regression analysis indicated that age ≥45 years [odds ratio (OR)=5.119, 95% confidence interval (CI)=1.395-18.780] and ≥60 years (OR=9.366, 95% CI=1.228-71.421), history of hypertension (OR=3.475, 95% CI=1.073-11.250), cumulative dose of chemotherapy drugs >900 mg (OR=4.842, 95% CI=1.961-5.946), vitamin D deficiency (OR=6.214, 95% CI=2.308-16.729), abnormal alanine aminotransferase (OR=3.154, 95% CI=1.010-9.844), anemia before chemotherapy (OR=2.770, 95% CI=1.093-7.019), infusion duration of chemotherapy drugs >30min (OR=3.673, 95% CI=1.414-9.539), body mass index ≥24 kg/m2 (OR=8.139, 95% CI=1.157-57.240), mild depression (OR=4.546, 95% CI=1.358-15.223), and major depression (OR=4.455, 95% CI=1.237-16.037) increased the risk of CIPN. Having a regular caregiver (OR=0.223, 95% CI=0.087-0.573), high levels of physical activity (OR=0.071, 95% CI=0.008-0.647), and strong social support (OR=0.048, 95% CI=0.003-0.682) were protective factors against CIPN. Clinical attention should be paid to patients with these risk factors, and active and effective preventive measures should be taken to reduce the occurrence of CIPN and improve the quality of life.

Ursolic acid alleviates paclitaxel-induced peripheral neuropathy through PPARγ activation

BackgroundChemotherapy-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. MethodsWe 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. ResultsOur 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. ConclusionsTaken 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.

Protective Effects of Glatiramer Acetate Against Paclitaxel-Induced Peripheral Neuropathy in Rats: A Role for Inflammatory Cytokines and Oxidative Stress.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major challenge for cancer patients who undergo chemotherapy with paclitaxel. Therefore, finding effective therapies for CIPN is crucial. Glatiramer acetate is used to treat multiple sclerosis that exerts neuroprotective properties in various studies. We hypothesized that glatiramer acetate could also improve the paclitaxel-induced peripheral neuropathy.We used a rat model of paclitaxel (2mg/kg/every other day for 7 doses)-induced peripheral neuropathy. Rats were treated with either different doses of glatiramer acetate (1, 2, 4mg/kg/day) or its vehicle for 14 days in separate groups. The mechanical and thermal sensitivity of the rats by using the Von Frey test and the Hot Plate test, respectively, were assessed during the study. The levels of oxidative stress (malondialdehyde and superoxide dismutase), inflammatory markers (TNF-α, IL-10, NF-kB), and nerve damage (H&E and S100B staining) in the sciatic nerves of the rats were also measured at the end of study.Glatiramer acetate (2 and 4mg/kg) exerted beneficial effects on thermal and mechanical allodynia tests. It also modulated the inflammatory response by reducing TNF-α and NF-κB levels, enhancing IL-10 production, and improving the oxidative stress status by lowering malondialdehyde and increasing superoxide dismutase activity in the sciatic nerve of the rats. Furthermore, glatiramer acetate enhanced nerve conduction velocity in all treatment groups. Histological analysis revealed that glatiramer acetate (2 and 4mg/kg) prevented paclitaxel-induced damage to the nerve structure.These results suggest that glatiramer acetate can alleviate the peripheral neuropathy induced by paclitaxel.

Proteomic analysis of dorsal root ganglia in a mouse model of paclitaxel-induced neuropathic pain.

Paclitaxel is a chemotherapy drug widely used for the treatment of various cancers based on its ability to potently stabilize cellular microtubules and block division in cancer cells. Paclitaxel-based treatment, however, accumulates in peripheral system sensory neurons and leads to a high incidence rate (over 50%) of chemotherapy induced peripheral neuropathy in patients. Using an established preclinical model of paclitaxel-induced peripheral neuropathy (PIPN), we examined proteomic changes in dorsal root ganglia (DRG) of adult male mice that were treated with paclitaxel (8 mg/kg, at 4 injections every other day) relative to vehicle-treated mice. High throughput proteomics based on liquid chromatography electrospray ionization mass spectrometry identified 165 significantly altered proteins in lumbar DRG. Gene ontology enrichment and bioinformatic analysis revealed an effect of paclitaxel on pathways for mitochondrial regulation, axonal function, and inflammatory purinergic signaling as well as microtubule activity. These findings provide insight into molecular mechanisms that can contribute to PIPN in patients.