Oxaliplatin-induced Peripheral Neuropathy Research Articles

Danggui Sini decoction alleviates oxaliplatin-induced peripheral neuropathy by regulating gut microbiota and potentially relieving neuroinflammation related metabolic disorder.

Danggui Sini decoction (DSD), a traditional Chinese medicine formula, has the function of nourishing blood, warming meridians, and unblocking collaterals. Our clinical and animal studies had shown that DSD can effectively protect against oxaliplatin (OXA)-induced peripheral neuropathy (OIPN), but the detailed mechanisms remain uncertain. Multiple studies have confirmed that gut microbiota plays a crucial role in the development of OIPN. In this study, the potential mechanism of protective effect of DSD against OIPN by regulating gut microbiota was investigated. The neuroprotective effects of DSD against OIPN were examined on a rat model of OIPN by determining mechanical allodynia, biological features of dorsal root ganglia (DRG) as well as proinflammatory indicators. Gut microbiota dysbiosis was characterized using 16S rDNA gene sequencing and metabolism disorders were evaluated using untargeted and targeted metabolomics. Moreover the gut microbiota mediated mechanisms were validated by antibiotic intervention and fecal microbiota transplantation. DSD treatment significantly alleviated OIPN symptoms by relieving mechanical allodynia, preserving DRG integrity and reducing proinflammatory indicators lipopolysaccharide (LPS), IL-6 and TNF-α. Besides, DSD restored OXA induced intestinal barrier disruption, gut microbiota dysbiosis as well as systemic metabolic disorders. Correlation analysis revealed that DSD increased bacterial genera such as Faecalibaculum, Allobaculum, Dubosiella and Rhodospirillales_unclassified were closely associated with neuroinflammation related metabolites, including positively with short-chain fatty acids (SCFAs) and sphingomyelin (d18:1/16:0), and negatively with pi-methylimidazoleacetic acid, L-glutamine and homovanillic acid. Meanwhile, antibiotic intervention apparently relieved OIPN symptoms. Furthermore, fecal microbiota transplantation further confirmed the mediated effects of gut microbiota. DSD alleviates OIPN by regulating gut microbiota and potentially relieving neuroinflammation related metabolic disorder.

Paeoniflorin ameliorates oxaliplatin-induced peripheral neuropathy via inhibiting neuroinflammation through influence on gut microbiota

Oxaliplatin (OXA)-induced peripheral neuropathy (OIPN) is a severe side effect that greatly limits OXA clinical use and threatens patients' life and health. Paeoniflorin exhibits extensive anti-inflammatory and neuroprotective effects, but whether it can protect against OIPN and the underlying mechanisms remain unclear. This study aimed to investigate the effects of paeoniflorin on OIPN and probe into the underlying mechanisms. The OIPN model was established through oxaliplatin injection in rats. The ameliorative effects of paeoniflorin on OIPN was assessed by nociceptive hypersensitivities through pain behavioral methods. Neuroinflammation were examined by measuring the levels of inflammatory cytokines and immune cells infiltration. The signaling pathway of TLR4/MyD88/NF-κB was evaluated by Western blotting. Gut microbial changes were detected by 16S rDNA sequencing technology. In addition, antibiotics-induced microbiota eradication and fecal microbial transplantation (FMT) were applied for exploring the function of gut microbiota in the protective effects of paeoniflorin. The results revealed that paeoniflorin significantly alleviated mechanical and cold hypersensitivity, mitigated neuroinflammation and influenced gut microbial composition in OIPN rats. Fecal microbiota transplantation further verified that gut microbiota was required for paeoniflorin ameliorating OIPN and that the underlying mechanism involved downregulation of TLR4/MyD88/NF-κB signaling. Specifically, Akkermansia, Dubosiella and Corynebacterium might serve as crucial genera regulated by paeoniflorin in the treatment of OIPN. In summary, our investigations delineate paeoniflorin's ameliorative effects on OIPN by alleviating neuroinflammation through regulations of gut microbiota. This suggests that paeoniflorin may serve as a new potential strategy for treatment of OIPN in clinical practice.

Exploration for Blood Biomarkers of Human Long Non-coding RNAs Predicting Oxaliplatin-Induced Chronic Neuropathy Through iPS Cell-Derived Sensory Neuron Analysis.

Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes acute and chronic peripheral sensory neuropathy, for which no effective treatment has been established. In particular, chronic neuropathy can persist for years even after treatment completion, thus worsening patients' quality of life. To avoid the development of intractable adverse effects, a predictive biomarker early in treatment is awaited. In this study, we explored extracellular long non-coding RNAs (lncRNAs) released from primary sensory neurons as biomarker candidates for oxaliplatin-induced peripheral neuropathy. Because many human-specific lncRNA genes exist, we induced peripheral sensory neurons from human induced pluripotent stem cells. Oxaliplatin treatment changed the levels of many lncRNAs in extracellular vesicles (EVs) released from cultured primary sensory neurons. Among them, the levels of release of lncRNAs that were considered to be selectively expressed in dorsal root ganglia were correlated with those of lncRNAs in plasma EV obtained from healthy individuals. Several lncRNAs in plasma EVs early after the initiation of treatment showed greater changes in patients who did not develop chronic neuropathy that persisted for more than 1year than in those who did. Therefore, these extracellular lncRNAs in plasma EVs may represent predictive biomarkers for the development of chronic peripheral neuropathy induced by oxaliplatin.

Tetrandrine alleviates oxaliplatin-induced mechanical allodynia via modulation of inflammation-related genes.

Oxaliplatin, a platinum-based chemotherapy drug, causes neuropathic pain, yet effective pharmacological treatments are lacking. Previously, we showed that tetrandrine (TET), with anti-inflammatory properties, reduces mechanical allodynia in nerve-injured mice. This study explores the effect of TET on oxaliplatin-induced mechanical allodynia and gene changes in mice. Male C57BL/6J mice received oxaliplatin intraperitoneally to induce mechanical allodynia. Post-treatment with TET or vehicle, the mechanical withdrawal threshold (WMT) was assessed using von Frey filaments. TET alleviated oxaliplatin-induced mechanical allodynia. RNA sequencing identified 365 differentially expressed genes (DEGs) in the Control vs. Oxaliplatin group and 229 DEGs in the Oxaliplatin vs. TET group. Pearson correlation analysis of co-regulated DEGs and inflammation-related genes (IRGs) revealed 104 co-regulated inflammation-related genes (Co-IRGs) (|cor| > 0.8, P < 0.01). The top 30 genes in the PPI network were identified. Arg2, Cxcl12, H2-Q6, Kdr, and Nfkbia were highlighted based on ROC analysis. Subsequently, Arg2, Cxcl12, Kdr, and Nfkbia were further verified by qRCR. Immune infiltration analysis indicated increased follicular CD4 T cell infiltration in oxaliplatin-treated mice, reduced by TET. Molecular docking showed strong binding affinity between TET and proteins encoded by Arg2, Cxcl12, Kdr, and Nfkbia. In summary, TET may alleviate oxaliplatin-induced peripheral neuropathy in clinical conditions.

Incidence, Severity and Clinical Correlation of Oxaliplatin Induced Neuropathy in Patients with Colorectal Cancer: A Single Institutional Experience

Background: Colorectal cancer is the third most commonly diagnosed cancer worldwide, and its incidence is increasing in developing countries. Chemotherapy plays a significant role in the treatment of locally advanced and metastatic colorectal cancer. Oxaliplatin has remained the backbone of the treatment of colorectal carcinoma. The primary dose-limiting toxicity of oxaliplatin is neuropathy, which can reduce compliance during therapy and impair daily living activities. With limited data regarding the occurrence of oxaliplatin-induced peripheral neuropathy (OIPN) in the Indian population, we aimed to determine the incidence and severity of oxaliplatin-induced neurotoxicity and its clinical correlation with various clinical parameters in patients with colorectal carcinoma in a cancer care centre from North-East India. Material and Methods: A prospective observational analysis was performed on all histologically confirmed cases of colorectal adenocarcinoma who received oxaliplatin-based chemotherapy either in an adjuvant setting or first-line palliative setting at Dr. B. Borooah Cancer Institute between April 2019 to March 2020. Results: Our study evaluated 76 patients with colorectal carcinoma with a mean age of 54.07 ± 10 years. The majority (65.8%) of the patients had adenocarcinoma of the colon, and 34.2% had rectal adenocarcinoma. Twenty-three (30.3%) patients presented with metastatic disease. Oxaliplatin-based chemotherapy regimens were either CAPOX (72.4%) or FOLFOX (27.6%). Acute OIPN was observed in 59 patients (77.6%), and the most common symptom was cold-induced perioral paraesthesia. The most frequent grade for acute OIPN was grade II (30.3%). Chronic OIPN was seen in 47 (61.8%) patients, with the majority developing grade II neuropathy and was manifested mainly after 4th cycle of chemotherapy. The incidence of OIPN was higher in the patients aged ≥60 years, with a cumulative oxaliplatin dose of &gt; 1000 mg/m2 and baseline low serum magnesium or calcium level. Conclusion: Oxaliplatin is one of the essential chemotherapy drugs used in colorectal cancer with significant dose-limiting toxicity of peripheral neuropathy. Well-timed identification of neuropathic symptoms can increase treatment adherence and improve the patient’s quality of life.&#x0D;  

Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients – a randomized controlled trial. (OxaNeuro)

BackgroundOxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors’ quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN.MethodsThe OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months.The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy.DiscussionIf readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival.Trial registrationClinicalTrial.gov identifier: NCT05404230Protocol version: 1.2, April 25th. 2023

Pharmacokinetic-toxicodynamic Modeling to Elucidate the Involvement of Dorsal Root Ganglion Neuron in Oxaliplatin-induced Peripheral Neuropathy.

Oxaliplatin (L-OHP)-induced peripheral neuropathy (OIPN) limits L-OHP dosage due to nerve cell damage in the dorsal root ganglion (DRG) caused by platinum (Pt). Despite various recommended approaches for OIPN management, no effective approach has been established. The aim of this study was to evaluate Pt distribution into DRG after repeat administrations of L-OHP in rats and to develop a pharmacokinetic-toxicodynamic (PK-TD) model using Pt concentrations in DRG to predict neuropathy severity. Male Wistar rats were administered L-OHP (3, 5, or 8 mg/kg i.v.) once weekly. Blood and DRG samples were collected following L-OHP administration. For toxicodynamic (TD) study, OIPN was evaluated using the von Frey test. Plasma and DRG Pt concentrations and thresholds values in von Frey test were used for PK-TD modeling using Phoenix WinNonlin® version 8.3 software. Pt concentration in the DRG increased with repeated administration of L-OHP in a dose-dependent manner, indicating Pt accumulation in DRG following multiple administrations. The PK-TD model, consisting of an indirect response model and a transit compartment model with the DRG compartment, adequately described the temporal changes in OIPN with reliable TD parameters (≤36.4% with coefficient of variation). The maximum drug inhibition model could be employed to establish a quantitative correlation between the Pt content present in the DRG and the toxic potency resulting in OIPN. The utility of the PK-TD model for predicting neuropathy outcomes was established, suggesting that models composed of the DRG compartment contribute to determining an optimal dosing strategy for reducing OIPN.

Protective effect of alpha-lipoic acid and epalrestat on oxaliplatin-induced peripheral neuropathy in zebrafish.

Oxaliplatin is a platinum-based anti-cancer drug widely used in colorectal cancer patients, but it may cause peripheral neuropathy. As one of the main causes of oxaliplatin-induced peripheral neuropathy (OPN) is oxidative stress, which is also a key factor causing diabetic peripheral neuropathy (DPN), the aim of this study was to evaluate the preventive effects of alpha-lipoic acid (ALA) and epalrestat (EP), which are used for the treatment of DPN, in an OPN zebrafish model. Tg(nbt:dsred) transgenic zebrafish, with sensory nerves in the peripheral lateral line, were treated with oxaliplatin, oxaliplatin/EP, and oxaliplatin/ALA for 4 days. A confocal microscope was used to visualize and quantify the number of axon bifurcations in the distal nerve ending. To analyze the formation of synapses on sensory nerve terminals, quantification of membrane-associated guanylate kinase (MAGUK) puncta was performed using immunohistochemistry. The number of axon bifurcations and intensity of MAGUK puncta were significantly reduced in the oxaliplatin-treated group compared with those in the embryo medium-treated group. In both the oxaliplatin/EP and oxaliplatin/ALA-treated groups, the number of axon bifurcations and intensity of MAGUK puncta were greater than those in the oxaliplatin-treated group (p < .0001), and no significant difference was observed between larvae treated with oxaliplatin/ALA 1 μM and oxaliplatin/EP 1 μM (p = .4292). ALA and EP have protective effects against OPN in zebrafish. Our findings show that ALA and EP can facilitate more beneficial treatment for OPN.

The Effects of an App-Based Physical Activity Program on Colorectal Cancer Patients Undergoing Chemotherapy: A Randomized Controlled Trial.

Colorectal cancer is one of the most common malignancies worldwide. Oxaliplatin, which is used as adjuvant chemotherapy, affects quality of life by causing oxaliplatin-induced peripheral neuropathy in colorectal cancer patients. This study examined the effects of an application (app)-based physical activity program for alleviating peripheral neuropathy symptoms in colorectal cancer patients undergoing chemotherapy. This was a randomized controlled study that included 34 patients undergoing chemotherapy after being diagnosed with colorectal cancer. Outcomes were compared between patients who participated in a 6-week app-based physical activity program (experimental group; n = 17) and who received standard booklet education (control group; n = 17). Data were collected using questionnaires, and exercise time was recorded to evaluate intervention adherence. Significant differences were observed between the groups in peripheral neuropathy symptoms (F = 8.93, P = .002), interference with activities (Z = -2.55, P = .011), and quality of life (F = 7.65, P = .003). The experimental group showed significantly higher average exercise times at 1 to 4 weeks (Z = -2.10, P = .026), 5 to 6 weeks (Z = -4.02, P < .001), and 1 to 6 weeks (Z = -3.40, P = .001) than the control group. The app-based physical activity program had a positive effect on participants' exercise adherence and reduced peripheral neuropathy symptoms. Thus, we propose the adoption of a mobile health app that can be used at any time or place as an intervention for preventing or alleviating adverse effects during the treatment of cancer patients. An app-based physical activity program using the mobile health app can be used as a nursing intervention to manage symptoms and increase the health behavior adherence in cancer patients.

Discovery and Preclinical Evaluation of a Novel Inhibitor of FABP5, ART26.12, Effective in Oxaliplatin-Induced Peripheral Neuropathy

Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity characterised by mechanical allodynia and thermal hyperalgesia, without any licensed medications. ART26.12 is a fatty acid-binding protein (FABP) 5 inhibitor with antinociceptive properties, characterised here for the prevention and treatment of OIPN. ART26.12 binds selectively to FABP5 compared to FABP3, FABP4, and FABP7, with minimal off-target liabilities, high oral bioavailability, and a NOAEL of 1,000 mg/kg/day in rats and dogs. In an established preclinical OIPN model, acute oral dosing (25–100 mg/kg) showed a cannabinoid receptor type 1 (CB1)-dependent anti-allodynic effect lasting up to 8 hours (persisting longer than plasma exposure to ART26.12). Antagonists of cannabinoid receptor type 2 (CB2), peroxisome proliferator-activated receptor alpha, and transient receptor potential cation channel subfamily V member 1 (TRPV1) may have also been implicated. Twice daily oral dosing (25 mg/kg bis in die (BID) for 7 days) showed anti-allodynic effects in an established OIPN model without the development of tolerance. In a prevention paradigm, coadministration of ART26.12 (10 and 25 mg/kg BID for 15 days) with oxaliplatin prevented thermal hyperalgesia, mitigated mechanical allodynia, and attenuated OXA-induced weight loss. Multi-scale analyses revealed widespread lipid modulation, particularly among N-acyl amino acids in the spinal cord, including potential analgesic mediators. Additionally, ART26.12 administration led to upregulation of ion channels in the periaqueductal grey, and broad translational upregulation within the plasma proteome. These results show promise that ART26.12 is a safe and well-tolerated candidate for the treatment and prevention of OIPN through lipid modulation. PerspectiveInhibition of fatty acid-binding protein 5 (FABP5) is a novel target for reducing pain associated with chemotherapy. ART26.12 is a safe and well-tolerated small molecule FABP5 inhibitor effective at preventing and reducing pain induced with oxaliplatin through lipid modulation and activation of cannabinoid receptors.

Endothelial Glycocalyx in the Peripheral Capillaries is Injured Under Oxaliplatin-Induced Neuropathy

Oxaliplatin, a platinum-based anticancer drug, is associated with peripheral neuropathy (oxaliplatin-induced peripheral neuropathy, OIPN), which can lead to worsening of quality of life and treatment interruption. The endothelial glycocalyx, a fragile carbohydrate-rich layer covering the luminal surface of endothelial cells, acts as an endothelial gatekeeper and has been suggested to protect nerves, astrocytes, and other cells from toxins and substances released from the capillary vessels. Mechanisms underlying OIPN and the role of the glycocalyx remain unclear. This study aimed to define changes in the three-dimensional ultrastructure of capillary endothelial glycocalyx near nerve fibers in the hind paws of mice with OIPN. The mouse model of OPIN revealed disruption of the endothelial glycocalyx in the peripheral nerve compartment, accompanied by vascular permeability, edema, and damage to the peripheral nerves. To investigate the potential treatment interventions, nafamostat mesilate, a glycocalyx protective agent was used in tumor-bearing male mice. Nafamostat mesilate suppressed mechanical allodynia associated with neuropathy. It also prevented intra-epidermal nerve fiber loss and improved vascular permeability in the peripheral paws. The disruption of endothelial glycocalyx in the capillaries that lie within peripheral nerve bundles is a novel finding in OPIN. Furthermore, these findings point toward the potential of a new treatment strategy targeting endothelial glycocalyx to prevent vascular injury as an effective treatment of neuropathy as well as of many other diseases. PerspectiveOIPN damages the endothelial glycocalyx in the peripheral capillaries, increasing vascular permeability. In order to prevent OIPN, this work offers a novel therapy approach that targets endothelial glycocalyx.

Mitotherapy prevents peripheral neuropathy induced by oxaliplatin in mice

Oxaliplatin (OXA) is an antineoplastic agent used for the treatment of cisplatin-resistant tumours, presenting lower incidence of nephrotoxicity and myelotoxicity than other platinum-based drugs. However, OXA treatment is highly associated with painful peripheral neuropathy, a well-known and relevant side effect caused by mitochondrial dysfunction. The transfer of functional exogenous mitochondria (mitotherapy) is a promising therapeutic strategy for mitochondrial diseases. We investigated the effect of mitotherapy on oxaliplatin-induced painful peripheral neuropathy (OIPN) in male mice. OIPN was induced by i.p. injections of oxaliplatin (3 mg/kg) over 5 consecutive days. Mechanical (von Frey test) and cold (acetone drop test) allodynia were evaluated between 7 and 17 days after the first OXA treatment. Mitochondria was isolated from donor mouse livers and mitochondrial oxidative phosphorylation was assessed with high resolution respirometry. After confirming that the isolated mitochondria were functional, the organelles were administered at the dose of 0.5 mg/kg of mitochondrial protein on days 1, 3 and 5. Treatment with OXA caused both mechanical and cold allodynia in mice that were significant 7 days after the initial injection of OXA and persisted for up to 17 days. Mitotherapy significantly prevented the development of both sensory alterations, and attenuated body weight loss induced by OXA. Mitotherapy also prevented spinal cord ERK1/2 activation, microgliosis and the increase in TLR4 mRNA levels. Mitotherapy prevented OIPN by inhibiting neuroinflammation and the consequent cellular overactivity in the spinal cord, presenting a potential therapeutic strategy for pain management in oncologic patients undergoing OXA treatment.

Parkin-mediated mitophagy is a potential treatment for oxaliplatin-induced peripheral neuropathy.

Oxaliplatin-induced peripheral nerve pain (OIPNP) is a common chemotherapy-related complication, but the mechanism is complex. Mitochondria are vital for cellular homeostasis and regulating oxidative stress. Parkin-mediated mitophagy is a cellular process that removes damaged mitochondria, exhibiting a protective effect in various diseases; however, its role in OIPNP remains unclear. In this study, we found that Parkin-mediated mitophagy was decreased, and reactive oxygen species (ROS) was upregulated in OIPNP rat dorsal root ganglion (DRG) in vivo and in PC12 cells stimulated with oxaliplatin (OXA) in vitro. Overexpression of Parkin indicated that OXA might cause mitochondrial and cell damage by inhibiting mitophagy. We also showed that salidroside (SAL) upregulated Parkin-mediated mitophagy to eliminate damaged mitochondria and promote PC12 cell survival. Knockdown of Parkin indicated that mitophagy is crucial for apoptosis and mitochondrial homeostasis in PC12 cells. In vivo study also demonstrated that SAL enhances Parkin-mediated mitophagy in the DRG and alleviates peripheral nerve injury and pain. These results suggest that Parkin-mediated mitophagy is involved in the pathogenesis of OIPNP and may be a potential therapeutic target for OIPNP.NEW & NOTEWORTHY This article discusses the effects and mechanisms of Parkin-mediated mitophagy in oxaliplatin-induced peripheral nerve pain (OIPNP) from both in vivo and in vitro. We believe that our study makes a significant contribution to the literature because OIPNP has always been the focus of clinical medicine, and mitochondrial quality regulation mechanisms especially Parkin-mediated mitophagy, have been deeply studied in recent years. We use a variety of molecular biological techniques and animal experiments to support our argument.

Association of Genetic Polymorphism of ABCG2 Gene and the Occurrence of Oxaliplatin-Induced Peripheral Neuropathy in Patients with Colorectal Cancer

Association of Genetic Polymorphism of ABCG2 Gene and the Occurrence of Oxaliplatin-Induced Peripheral Neuropathy in Patients with Colorectal Cancer

Proton Pump Inhibitors Ameliorate Oxaliplatin-induced Peripheral Neuropathy: Retrospective Analysis of Two Real-world Clinical Databases.

Chemotherapy-induced peripheral neuropathy (CIPN) due to oxaliplatin (L-OHP) is a major clinical problem. Effective and safe preventive strategies for CIPN are urgently needed. Although proton pump inhibitors (PPIs) have various off-target effects, their clinical impact on L-OHP-induced CIPN remains unclear. In the present study, we investigated the effects of PPIs on L-OHP-induced CIPN in patients using two real-world clinical databases. We retrospectively analyzed the electronic medical records of Osaka University Hospital to examine the effect of PPIs on CIPN development in 217 patients who received XELOX (L-OHP plus capecitabine) therapy for colorectal cancer. In addition, the Japanese Adverse Drug Event Report (JADER) database was used to validate the effects of PPIs on L-OHP-induced CIPN. The incidences of CIPN (grade ≥2) and discontinuation of L-OHP were significantly lower in patients with PPIs than in those without PPIs. Multivariate analysis showed that concomitant PPIs use was an independent factor that significantly contributed to the prevention of grade ≥2 CIPN (odds ratio=0.054, p<0.001). Kaplan-Meier analysis showed that the time to onset of grade ≥2 CIPN was significantly prolonged in patients with PPIs without affecting the therapeutic efficacy of L-OHP (p=0.004). Moreover, JADER database analyses revealed that the reporting odds ratio of any PPI for L-OHP-induced CIPN was 0.485. Concomitant PPI use ameliorated L-OHP-induced CIPN in patients with colorectal cancer.

Renin-angiotensin-aldosterone system inhibitors are associated with improved paclitaxel-induced peripheral neuropathy in lung cancer: a study using administrative claims data.

Chemotherapy-induced peripheral neuropathy (CIPN) has been reported to reduce patients' quality of life and impair cancer treatment by causing anticancer drug withdrawal or interruption. However, there are currently no effective methods for the prevention of CIPN. Renin-angiotensin-aldosterone system (RAAS) inhibitors may be associated with a reduced risk of developing oxaliplatin-induced peripheral neuropathy, and it would be valuable to examine whether they have the same effect on CIPN caused by other anticancer drugs. Our study explored the potential preventive effects of RAAS inhibitors on preventing paclitaxel-induced peripheral neuropathy (PIPN). An exploratory cohort study was conducted using commercially available administrative claims data on lung cancer patients treated with paclitaxel-based chemotherapy. Cumulative paclitaxel doses, RAAS inhibitor prescriptions, and incidences of PIPN were identified using patient medical records. Fine-Gray analyses with death as a competing risk were performed. A propensity score approach was applied to address the problem of confounding. Patients with lung cancer who received paclitaxel-based chemotherapy were classified into users of RAAS inhibitor (n = 1320) and non-users of RAAS inhibitor (n = 4566). The doses of RAAS inhibitors in our study were similar to those commonly used to treat hypertension. The PIPN incidence was significantly lower in users of RAAS inhibitor than in the non-users of RAAS inhibitor (sub-distribution hazard ratio, 0.842; 95% confidence interval, 0.762-0.929). The result was consistent in various sensitivity analyses and important subgroup analyses. RAAS inhibitors at doses commonly used for hypertension were associated with a reduced incidence of PIPN in patients with lung cancer.

Effectiveness of Duloxetine on Oxaliplatin-induced Allodynia and Hyperalgesia in Rats.

Development of painful oxaliplatin-induced peripheral neuropathy (OIPN) is a major problem in people who receive oxaliplatin as part of cancer treatment. The pain experienced by those with OIPN can be seriously debilitating and lead to discontinuation of an otherwise successful treatment. Duloxetine is currently the only recommended treatment for established painful OIPN recommended by the American Society of Clinical Oncology, but its preventative ability is still not clear. This study examined the ability of duloxetine to prevent signs of chronic OIPN in female (n = 12) and male (n = 21) rats treated with the chemotherapeutic agent oxaliplatin. Using an established model of OIPN, rats were started on duloxetine (15mg) one week prior to oxaliplatin administration and continued duloxetine for 32 days. Behavioral testing for mechanical allodynia and mechanical hyperalgesia was done with selected von Frey filaments. Significant posttreatment differences were found for allodynia in female (p = .004), but not male rats. Duloxetine was associated with significant differences for hyperalgesia in both female (p < .001) and male (p < .001) rats. These findings provide preliminary evidence of the preventative effects of duloxetine on both oxaliplatin-induced allodynia and hyperalgesia in male and female rats, with a difference noted in response between the sexes.

Does statin suppress oxaliplatin-induced peripheral neuropathy in patients with colorectal cancer? A single-center observational study

BackgroundOxaliplatin-induced peripheral neuropathy (OIPN) is a common and dose-limiting toxicity that markedly limits the use of oxaliplatin and affects quality of life. Statins have been shown to exert neuroprotective effects in preclinical settings. The aim of the present study was to clarify whether statins prevented OIPN in patients with colorectal cancer (CRC) receiving adjuvant CAPOX therapy.MethodsWe examined 224 patients who received adjuvant CAPOX therapy for CRC between July 2010 and December 2021 at our hospital. Patients were divided into “Statin” and “Non-statin” groups based on statin use. Details on and the adverse events of adjuvant CAPOX therapy were examined in association with statin use.ResultsThirty-one patients (14%) were treated with statins. There were no intergroup differences in the relative dose intensity or number of CAPOX cycles between the Statin and Non-statin groups. In total, 94% of patients in the Statin group and 95% of those in the Non-statin group developed OIPN (p=0.67). The severity of OIPN was similar between the two groups (p=0.89). The frequency of treatment delays in CAPOX did not significantly differ between the Statin and Non-statin groups (16% vs. 11%, p=0.45).ConclusionsThe efficacy of statins to attenuate OIPN during adjuvant CAPOX therapy was not apparent in the current study. Further studies are needed to confirm the present results.

β-Caryophyllene Inhibits Oxaliplatin-Induced Peripheral Neuropathy in Mice: Role of Cannabinoid Type 2 Receptors, Oxidative Stress and Neuroinflammation.

Peripheral neuropathy is an important adverse effect caused by some chemotherapeutic agents, including oxaliplatin (OXA). OXA-induced peripheral neuropathy (OIPN) is a challenging condition due to diagnostic complexities and a lack of effective treatment. In this study, we investigated the antiallodynic effect of β-caryophyllene (BCP), a cannabinoid type 2 (CB2) receptor agonist, in a mouse model of OIPN. BCP treatment inhibited OXA-induced mechanical and cold allodynia in both preventive and therapeutic drug treatment regimens. Experiments with the CB2 receptor agonist GW405833 confirmed the role of CB2 receptors in OIPN. The CB2 antagonist SR144528 abrogated the anti-nociceptive effect of BCP on mechanical allodynia, without impacting OXA-induced sensitivity to cold. BCP decreased neuroinflammation, as inferred from TNF, IL-1β, IL-6, and IL-10 profiling, and also reduced ROS production, lipid peroxidation, and 4-hydroxynonenal protein adduct formation in the spinal cords of OXA-treated mice. BCP did not affect the antitumor response to OXA or its impact on blood cell counts, implying that the cytotoxicity of OXA was preserved. These results underscore BCP as a candidate drug for OIPN treatment via CB2 receptor-dependent mechanisms, and anti-inflammatory and antioxidant responses in the spinal cord.

Huangqi Guizhi Wuwu decoction alleviates oxaliplatin-induced peripheral neuropathy via the gut-peripheral nerve axis

BackgroundOxaliplatin-induced peripheral neurotoxicity (OIPN) limits the dose of chemotherapy and seriously affects the quality of life. Huangqi Guizhi Wuwu Decoction (HGWD) is a classical Traditional Chinese Medicine (TCM) formula for the prevention of OIPN. However, its specific pharmacological mechanism of action remains unknown. Our study found that HGWD can effectively alleviate chronic OIPN and regulate intestinal flora. Therefore, we explored the mechanism of action of HGWD in alleviating chronic OIPN from the perspective of intestinal flora.MethodsIn this study, we established an OIPN model in C57BL/6 mice treated with different concentrations of HGWD. Mechanical pain and cold pain were assessed at certain time points, and samples of mice colon, dorsal root ganglion (DRG), serum, and feces were collected. Associated inflammation levels in the colon and DRG were detected using immunohistochemical techniques; the serum lipopolysaccharide (LPS) levels and associated inflammation were assessed using the appropriate kits; and 16S rRNA sequencing was used to examine the dynamic changes in gut microorganisms. Finally, established fecal microbiota transplantation (FMT) and antibiotic (ABX) pretreatment models were used to validate flora’s role in HGWD for chronic OIPN by pain scoring and related pathological analysis.ResultsHGWD treatment significantly alleviated pain sensitivity in chronic OIPN mice. Pathological results showed that HGWD treatment improved intestinal ZO-1 expression and reduced serum LPS levels and associated inflammatory factors in the colon, serum, and DRG. The 16S rRNA results showed that HGWD restored the composition of the intestinal flora in a time-dependent manner to alleviate OIPN. FMT and ABX experiments demonstrated that HGWD can alleviate chronic OIPN by regulating intestinal flora homeostasis.ConclusionsHGWD prevents chronic OIPN by dynamically regulating intestinal flora homeostasis, thereby ameliorating intestinal barrier damage and reducing serum LPS and relevant inflammatory factor levels in the colon, serum, and DRG.