Oxaliplatin-induced Peripheral Neuropathy Research Articles

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.

The therapeutic effects of Hexuetongbi formula to combat the oxaliplatin-induced peripheral neuropathy using network pharmacological methods in rat model

The therapeutic effects of Hexuetongbi formula to combat the oxaliplatin-induced peripheral neuropathy using network pharmacological methods in rat model

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.

Effect of Fenofibrate as PPARα Agonist in Suppressing the Development of Oxaliplatin-Induced Peripheral Neuropathy via TRPA1 Modulation

Background: CIPN (Chemotherapy-induced Peripheral Neuropathy) primarily affects the sensory system and is accompanied by pain, autonomic dysfunction, and motor impairments. Alterations of intracellular second messengers at the supraspinal level in CIPN needed to be explored more. In addition, there is a lack of evidence regarding implications for the supraspinal area through the propagation of pain via the ascending pathway. Objective: In this study, we evaluated the effect of fenofibrate as a PPARα agonist in suppressing the development of CIPN. Methods: Twenty-four mice were distributed to the normal control group, neuropathy group, and neuropathy with the treatment of fenofibrate 75 and 150 mg/kg groups, resulting in 6 animals per group. Oxaliplatin was injected on days 0, 2, 4, and 6. The hot plate test was performed before the oxaliplatin administration and then continued on the 7th, 14th, and 21st days. Thalamus tissues were collected to measure the TRPA1 mRNA expression using qPCR. Results: Fenofibrate 75 mg/kg co-treatment with oxaliplatin tended to prevent the enhancement of oxaliplatin-induced thermal hyperalgesia in hind-paw withdrawal and rubbing responses. Furthermore, fenofibrate 75 and 150 mg/kg co-treatment with oxaliplatin significantly reduced the relative TRPA1 mRNA expression but did not modulate the relative BDNF mRNA expression in the thalamus. Conclusion: PPARα agonist has a potential effect in suppressing the development of CIPN. However, given the various perspectives on the role of neurotrophins in CIPN, additional non-clinical investigations, are needed to provide more insight into other mechanisms of CIPN and the role of PPAR agonists.

The association between sociodemographic, clinical, and potentially preventive therapies with oxaliplatin-induced peripheral neuropathy in colorectal cancer patients.

The purpose of this retrospective cohort study was to evaluate whether several potentially preventive therapies reduced the rate of oxaliplatin-induced peripheral neuropathy (OIPN) in colorectal cancer patients and to assess the relationship of sociodemographic/clinical factors with OIPN diagnosis. Data were obtained from the Surveillance, Epidemiology, and End Results database combined with Medicare claims. Eligible patients were diagnosed with colorectal cancer between 2007 and 2015, ≥ 66years of age, and treated with oxaliplatin. Two definitions were used to denote diagnosis of OIPN based on diagnosis codes: OIPN 1 (specific definition, drug-induced polyneuropathy) and OIPN 2 (broader definition, additional codes for peripheral neuropathy). Cox regression was used to obtain hazard ratios (HR) with 95% confidence intervals (CI) for the relative rate of OIPN within 2years of oxaliplatin initiation. There were 4792 subjects available for analysis. At 2years, the unadjusted cumulative incidence of OIPN 1 was 13.1% and 27.1% for OIPN 2. For both outcomes, no therapies reduced the rate of OIPN diagnosis. The anticonvulsants gabapentin and oxcarbazepine/carbamazepine were associated with an increased rate of OIPN (both definitions) as were increasing cycles of oxaliplatin. Compared to younger patients, those 75-84years of age experienced a 15% decreased rate of OIPN. For OIPN 2, prior peripheral neuropathy and moderate/severe liver disease were also associated with an increased hazard rate. For OIPN 1, state buy-in health insurance coverage was associated with a decreased hazard rate. Additional studies are needed to identify preventive therapeutics for OIPN in cancer patients treated with oxaliplatin.

TRPM3 as a novel target to alleviate acute oxaliplatin-induced peripheral neuropathic pain.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is an adverse effect observed in up to 80% of patients of cancer on treatment with cytostatic drugs including paclitaxel and oxaliplatin. Chemotherapy-induced peripheral neuropathic pain can be so severe that it limits dose and choice of chemotherapy and has significant negative consequences on the quality of life of survivors. Current treatment options for CIPNP are limited and unsatisfactory. TRPM3 is a calcium-permeable ion channel functionally expressed in peripheral sensory neurons involved in the detection of thermal stimuli. Here, we focus on the possible involvement of TRPM3 in acute oxaliplatin-induced mechanical allodynia and cold hypersensitivity. In vitro calcium microfluorimetry and whole-cell patch-clamp experiments showed that TRPM3 is functionally upregulated in both heterologous and homologous expression systems after acute (24 hours) oxaliplatin treatment, whereas the direct application of oxaliplatin was without effect. In vivo behavioral studies using an acute oxaliplatin model for CIPNP showed the development of cold and mechano hypersensitivity in control mice, which was lacking in TRPM3 deficient mice. In addition, the levels of protein ERK, a marker for neuronal activity, were significantly reduced in dorsal root ganglion neurons derived from TRPM3 deficient mice compared with control after oxaliplatin administration. Moreover, intraperitoneal injection of a TRPM3 antagonist, isosakuranetin, effectively reduced the oxaliplatin-induced pain behavior in response to cold and mechanical stimulation in mice with an acute form of oxaliplatin-induced peripheral neuropathy. In summary, TRPM3 represents a potential new target for the treatment of neuropathic pain in patients undergoing chemotherapy.

A randomized controlled trial of hand/foot-cooling by hilotherapy to prevent oxaliplatin-related peripheral neuropathy in patients with malignancies of the digestive system

Both acute and chronic symptoms of oxaliplatin-induced peripheral neuropathy (OIPN) affect patients' treatment dose and duration as well as quality-of-life. Hand/foot-cooling has been shown to reduce taxane-induced peripheral neuropathy but there is unclear evidence in the setting of oxaliplatin. In a monocentric, open-label phase II trial, patients with malignancies of the digestive system receiving oxaliplatin-based chemotherapy were randomly assigned to receive either continuous cooling of hands and feet using hilotherapy at 11°C during oxaliplatin infusion compared with usual care (no cooling). The primary endpoint was grade ≥2 neuropathy-free rate in 12 weeks after initiation of chemotherapy. Secondary endpoints included OIPN-related treatment alterations, acute OIPN symptoms and perceived comfort of the intervention. The intention-to-treat population included 39 patients in the hilotherapy group and 38 in the control group. The grade ≥2 neuropathy-free rate at 12 weeks was 100% in the experimental group versus 80.5% in the control group (P= 0.006). This effect was persistent at 24 weeks (66.0% versus 49.2%, respectively) (P= 0.039). Next, treatment alterations-free rate at week 12 was 93.5% in the hilotherapy group compared with 83.3% in the control group (P= 0.131). Patients in the hilotherapy group experienced significantly less acute OIPN symptoms of numbness or tingling [odds ratio (OR) 0.05, 95% confidence interval (CI) 0.02-0.11, P < 0.0001], pain (OR 0.06, 95% CI 0.02-0.15, P < 0.0001) and/or cold sensitivity (OR 0.02, 95% CI 0.01-0.05, P < 0.0001) in fingers or toes as well as less pharyngeal cold sensitivity (OR 0.14, 95% CI 0.05-0.42, P= 0.0005). The majority of patients in the hilotherapy group rated the intervention as neutral, rather comfortable or very comfortable. In this first study on hand/foot-cooling in oxaliplatin alone, hilotherapy significantly reduced the incidence of grade ≥2 OIPN at 12 and 24 weeks. Hilotherapy also reduced acute OIPN symptoms and was generally well tolerated.

Comparative Transcriptome of Dorsal Root Ganglia Reveals Distinct Etiologies of Paclitaxel- and Oxaliplatin-induced Peripheral Neuropathy in Rats.

Chemotherapy-induced peripheral neuropathy is one of the most common side effects of anticancer therapy. It is anticipated that chemotherapies with different mechanisms of action may affect somatosensory neurons differently. This study aimed to explore similar and differential etiologies of oxaliplatin- and paclitaxel-induced neuropathy by comparing the transcriptomes of dorsal root ganglia (DRGs). We retrieved our previously published transcriptome data of DRGs extracted from vehicle-, oxaliplatin- and paclitaxel-treated rats (GSE160543), to analyze in parallel the differentially expressed genes (DEGs) and Gene ontology (GO) terms enrichment. We found that both oxaliplatin and paclitaxel treatments consistently produced mechanical allodynia, thermal hyperalgesia, and cold hyperalgesia in rats. Compared to vehicle, 320 and 150 DEGs were identified after oxaliplatin and paclitaxel treatment, respectively. Only 17 DEGs were commonly dysregulated by the two reagents. Activating transcription factor 3 (Atf3), a marker of nerve injury, was elevated only after paclitaxel treatment. GO analysis suggested that paclitaxel treatment was associated with neuronal changes characterized by numerous terms that are related to synaptic transmission, while oxaliplatin was more likely to affect dividing cells (e.g., the glia) and neuroinflammation. Notably, 29 biological processes GO terms were commonly enriched in response to both drugs. However, 28 out of 29 terms were oppositely modulated. This study suggests that distinct mechanisms underly paclitaxel- and oxaliplatin-induced neuropathy. Paclitaxel might directly affect somatosensory neurons while oxaliplatin primarily targets dividing cells and immune cells.

The neuroprotective effect of pterostilbene on oxaliplatin-induced peripheral neuropathy via its anti-inflammatory, anti-oxidative and anti-apoptotic effects: Comparative study with celecoxib

BackgroundOxaliplatin is one of the first-line drugs in solid tumors treatment. However, neuropathy is a devastating side effect leading to poor compliance and treatment cessation. AimThe current study explored pterostilbene plausible neuroprotective effects aiming to ascertain the potential mechanisms involved in relieving oxaliplatin-induced peripheral neuropathy (OIPN) and investigating whether pterostilbene and celecoxib combination could show better relief. Main methodsRats were divided into six groups; control, pterostilbene (40 mg/kg/day, p.o. for 5 weeks), oxaliplatin (4 mg/kg, i.p. twice per week for 4.5 weeks), celecoxib (30 mg/kg/day, p.o. for 5 weeks) and combination of pterostilbene and celecoxib. Behavioral tests and histopathological analysis of sciatic nerves were done. MAPKs, cytokines, COX-2, and PGE2 gene and protein expressions were estimated using qRT-PCR, western, and ELISA techniques. Malondialdehyde (MDA) and total antioxidant capacity (TAC) were assessed by colorimetric assay while apoptotic markers by immunohistochemical analysis and qRT-PCR. Key findingsThe study revealed that pterostilbene and celecoxib averted oxaliplatin-induced behavioral and motor impairments along with restoration of histopathological changes. Moreover, pterostilbene and celecoxib have significantly attenuated sciatic nerve: p38 MAPK, JNK, ERK1/2, NF-κB, COX-2, PGE2, TNF-α, and interleukins levels. Pterostilbene and celecoxib have reduced caspase-3, Bax, and MDA while increasing Bcl-2 level and TAC. SignificanceAltogether, Pterostilbene mitigates OIPN by interrupting the vicious cycle of inflammation, oxidation, and apoptosis. Furthermore, pterostilbene and celecoxib show comparable attenuation on MAPKs cascades, inflammatory cytokines, oxidative and apoptotic markers. Likewise, co-administration of pterostilbene and celecoxib shows further relief of neuropathic pain.

Animal models of chemotherapy-induced peripheral neuropathy for hematological malignancies: A review.

Chemotherapy is one of the main treatments for hematologic malignancies. However, chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common long-term toxic reactions in chemotherapy, and the occurrence of CIPN affects patients' quality of life and can cause interruption of chemotherapy in severe cases, thus reducing the efficacy of chemotherapy. We currently summarize the existing CIPN animal models, including the characteristics of several common animal models such as bortezomib-induced peripheral neuropathy, vincristine-induced peripheral neuropathy, and oxaliplatin-induced peripheral neuropathy. It was found that CIPN may lead to behavioral, histopathological, and neurophysiological changes inducing peripheral neuropathy. However, the mechanism of CIPN has not been fully elucidated, especially the prevention and treatment protocols need to be improved. Therefore, this review article summarizes the progress of research on CIPN animal models and the possible mechanisms and treatment of CIPN.

Syringaresinol Alleviates Oxaliplatin-Induced Neuropathic Pain Symptoms by Inhibiting the Inflammatory Responses of Spinal Microglia

Oxaliplatin-induced peripheral neuropathy (OIPN) is a serious side effect that impairs the quality of life of patients treated with the chemotherapeutic agent, oxaliplatin. The underlying pathophysiology of OIPN remains unclear, and there are no effective therapeutics. This study aimed to investigate the causal relationship between spinal microglial activation and OIPN and explore the analgesic effects of syringaresinol, a phytochemical from the bark of Cinnamomum cassia, on OIPN symptoms. The causality between microglial activation and OIPN was investigated by assessing cold and mechanical allodynia in mice after intrathecal injection of the serum supernatant from a BV-2 microglial cell line treated with oxaliplatin. The microglial inflammatory response was measured based on inducible nitric oxide synthase (iNOS), phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated nuclear factor-kappa B (p-NF-κB) expression in the spinal dorsal horn. The effects of syringaresinol were tested using behavioral and immunohistochemical assays. We found that oxaliplatin treatment activated the microglia to increase inflammatory responses, leading to the induction of pain. Syringaresinol treatment significantly ameliorated oxaliplatin-induced pain and suppressed microglial expression of inflammatory signaling molecules. Thus, we concluded that the analgesic effects of syringaresinol on OIPN were achieved via the modulation of spinal microglial inflammatory responses.

Potential Mediators of Oxaliplatin-Induced Peripheral Neuropathy From Adjuvant Therapy in Stage III Colon Cancer: Findings From CALGB (Alliance)/SWOG 80702.

We sought to evaluate the independent and interactive associations of planned treatment duration, celecoxib use, physical activity, body mass index (BMI), diabetes mellitus, and vitamin B6 with oxaliplatin-induced peripheral neuropathy (OIPN) among patients with stage III colon cancer enrolled in a clinical trial. We conducted a prospective, observational study of 2,450 patients with stage III colon cancer enrolled in the CALGB/SWOG 80702 trial, randomly assigned to 6 versus 12 cycles of adjuvant fluorouracil, leucovorin, and oxaliplatin chemotherapy with or without 3 years of celecoxib. OIPN was reported using the Common Terminology Criteria for Adverse Events (CTCAE) during and following completion of chemotherapy and the FACT/GOG-NTX-13 15-17 months after random assignment. Multivariate analyses were adjusted for baseline sociodemographic and clinical factors. Patients assigned to 12 treatment cycles, relative to 6, were significantly more likely to experience higher-grade CTCAE- and FACT/GOG-NTX-13-reported neuropathy and longer times to resolution, while neither celecoxib nor vitamin B6 intake attenuated OIPN. Exercising ≥ 9 MET-hours per week after treatment relative to < 9 was associated with improvements in FACT/GOG-NTX-13-reported OIPN (adjusted difference in means, 1.47; 95% CI, 0.49 to 2.45; P = .003). Compared with patients with baseline BMIs < 25, those with BMIs ≥ 25 were at significantly greater risk of developing higher-grade CTCAE-reported OIPN during (adjusted odds ratio, 1.18; 95% CI, 1.00 to 1.40; P = .05) and following completion (adjusted odds ratio, 1.23; 95% CI, 1.01 to 1.50; P = .04) of oxaliplatin treatment. Patients with diabetes were significantly more likely to experience worse FACT/GOG-NTX-13-reported neuropathy relative to those without (adjusted difference in means, -2.0; 95% CI, -3.3 to -0.73; P = .002). There were no significant interactions between oxaliplatin treatment duration and any of these potentially modifiable exposures. Lower physical activity, higher BMI, diabetes, and longer planned treatment duration, but not celecoxib use or vitamin B6 intake, may be associated with significantly increased OIPN severity.