Huangqi Guizhi Wuwu Decoction Improves Inflammatory Factor Levels in Chemotherapy-induced Peripheral Neuropathy by Regulating the Arachidonic Acid Metabolic Pathway.

BACKGROUND: Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common complication that arises from the use of anticancer drugs. Huangqi Guizhi Wuwu Decoction (HGWWD) is an effective classic prescription for treating CIPN however, the mechanism of the activity is not entirely understood. OBJECTIVE: This study aimed to investigate the remedial effects and mechanisms of HGWWD on CIPN. METHODS: Changes in behavioral biochemical histopathological and biomarker indices were used to evaluate the efficacy of HGWWD treatment. Ultra-high-performance liquid chromatography/mass spectrometry combined with the pattern recognition method was used to screen biomarkers and metabolic pathways related to CIPN. The results of pathway analyses were verified by protein blotting experiments. RESULTS: A total of 29 potential biomarkers were identified and 13 metabolic pathways were found to be involved in CIPN. In addition HGWWD reversed the levels of 19 biomarkers. Prostaglandin H2 and 17α 21-dihydroxypregnenolone were targeted as core biomarkers. CONCLUSION: This study provides scientific evidence to support the finding that HGWWD mainly inhibits the inflammatory response during CIPN by regulating arachidonic acid metabolism.

FTY720/Fingolimod mitigates paclitaxel-induced Sparcl1-driven neuropathic pain and breast cancer progression.

Paclitaxel is among the most active chemotherapy drugs for the aggressive triple negative breast cancer (TNBC). Unfortunately, it often induces painful peripheral neuropathy (CIPN), a major debilitating side effect. Here we demonstrate that in naive and breast tumor-bearing immunocompetent mice, a clinically relevant dose of FTY720/Fingolimod that targets sphingosine-1-phosphate receptor 1 (S1PR1), alleviated paclitaxel-induced neuropathic pain. FTY720 also significantly attenuated paclitaxel-stimulated glial fibrillary acidic protein (GFAP), a marker for activated astrocytes, and expression of the astrocyte-secreted synaptogenic protein Sparcl1/Hevin, a key regulator of synapse formation. Notably, the formation of excitatory synapses containing VGluT2 in the spinal cord dorsal horn induced by paclitaxel was also inhibited by FTY720 treatment, supporting the involvement of astrocytes and Sparcl1 in CIPN. Furthermore, in this TNBC mouse model that mimics human breast cancer, FTY720 administration also enhanced the anti-tumor effects of paclitaxel, leading to reduced tumor progression and lung metastasis. Taken together, our findings suggest that targeting the S1P/S1PR1 axis with FTY720 is a multipronged approach that holds promise as a therapeutic strategy for alleviating both CIPN and enhancing the efficacy of chemotherapy in TNBC treatment.

The mechanism of Taohong Siwu decoction in treating chemotherapy-induced peripheral neuropathy: a network pharmacology and molecular docking study.

Background: Taohong Siwu decoction (THSWD) is a classic traditional Chinese medicine (TCM) formula known for its effects in promoting blood circulation, removing blood stasis, and rejuvenating energy. There have been clinical reports of THSWD treating chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel. We conducted a network pharmacology and molecular docking analysis to further clarify the molecular mechanisms by which THSWD exerts its protective effects against CIPN. Methods: Chemical components of THSWD and their corresponding targets were obtained through the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP), and related targets of CIPN were searched in disease databases including Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), GeneCards, and DrugBank. Common targets between THSWD and CIPN were identified using Venn diagrams. A protein-protein interaction (PPI) network was constructed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), which was followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. AutoDock and PyMOL were used for the molecular docking validation of the key components of THSWD with core targets. Results: At total of 69 chemical components of THSWD were identified, corresponding to 856 targets; 2,297 targets were associated with CIPN, with an intersection of 105 common targets. PPI analysis identified eight core targets: MYC, TNF, MAPK14, AKT1, ESR1, RELA, TP53, and HSP90AA1; KEGG enrichment analysis implicated signaling pathways such as PI3K-Akt, NF-κB, and HIF-1, etc. Molecular docking results indicated that the selected active components and their corresponding target proteins have good binding activity. Conclusions: Through network pharmacology, this study found that THSWD has significant advantages in treating CIPN. By analyzing potential core targets, biological functions, and involved signaling pathways, we clarified the potential molecular biological mechanisms involved in THSWD's treatment effect. This study provides a theoretical basis for the clinical application of THSWD in treating CIPN.

Promising Roles of Phytocompounds and Nutrients in Interventions to Mitigate Chemotherapy-Induced Peripheral Neuropathy.

OBJECTIVES: Provide an overview of scientific reports and literature related to the role(s) of phytocompounds and nutrients in neuroprotection. Discuss how these properties may inform nutrition- and dietary interventions to mitigate chemotherapy-induced peripheral neuropathy (CIPN), for which there are no effective treatments. METHODS: A literature search (2010-2023) was conducted in PubMed and Google Scholar where search terms-diet, nutrition, neuroprotection, neurodegenerative diseases, and social determinants of health-were used to narrow articles. From this search, manuscripts were reviewed to provide an overview of the neuroprotective properties of various phytocompounds and nutrients and their observed effects in neurodegenerative conditions and CIPN. Social determinant of health factors (SDOH) related to economic stability and access to nutritious foods were also reviewed as potential barriers to dietary interventions. RESULTS: Twenty-eight publications were included in this literature review. Phytocompounds found in green tea (EGCG), turmeric (curcumin), cruciferous vegetables (sulforaphane), as well as certain vitamins, are promising, targeted interventions to mitigate CIPN. SDOH factors such as economic instability and limited access to nutritious foods may act as barriers to dietary interventions and limit their generalizability. CONCLUSION: Dietary interventions focused on the use of phytocompounds and vitamins with known antioxidant, anti-inflammatory, and neuroprotective properties, hold promise and may provide patients with natural, non-pharmacological therapeutics for the management and/or prevention of CIPN. However, rigorous clinical trial research is needed to explore these effects in humans. IMPLICATIONS FOR NURSING PRACTICE: Nurses support cancer survivors at the point-of-care, particularly during and after neurotoxic chemotherapy treatments. If future research supports dietary interventions to mitigate CIPN, nurses will ultimately be positioned to help translate this knowledge into clinical practice through educating patients on how to infuse nutrient-rich foods into their diets. Further, nurses will need to be conscious of SDOH factors that may impede access to these foods.

Corrigendum: Exercise for reducing chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis of randomized controlled trials.

[This corrects the article DOI: 10.3389/fneur.2023.1252259.].

Targeting metabolic pathways alleviates bortezomib-induced neuropathic pain without compromising anticancer efficacy in a sex-specific manner.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of cancer treatment that significantly impacts patients' quality of life. This study investigated the effects of targeting metabolic pathways on bortezomib-induced neuropathic pain and tumor growth using a Lewis lung carcinoma (LLC) mouse model, while exploring potential sex differences. Methods: Male and female C57BL/6J mice were implanted with LLC cells and treated with bortezomib alone or in combination with metformin, dichloroacetate (DCA), or oxamate. Tactile allodynia was assessed using von Frey filaments. Tumor volume and weight were measured to evaluate tumor growth. Results: Metformin, DCA, and oxamate effectively attenuated bortezomib-induced neuropathic pain without compromising the anticancer efficacy of bortezomib in both male and female mice. The LLC model exhibited a paraneoplastic neuropathy-like phenotype. Significant sex differences were observed, with male mice exhibiting larger tumors compared to females. Oxamate was more effective in alleviating allodynia in males, while metformin and DCA showed greater efficacy in reducing tumor growth in females. Discussion: Targeting metabolic pathways can alleviate CIPN without interfering with bortezomib's anticancer effects. The LLC model may serve as a tool for studying paraneoplastic neuropathy. Sex differences in tumor growth and response to metabolic interventions highlight the importance of considering sex as a biological variable in preclinical and clinical studies investigating cancer biology, CIPN, and potential therapeutic interventions.

Smell and Taste Alterations in Patients Receiving Curative or Palliative Chemotherapy-The CONKO 021-ChemTox Trial.

Previous data regarding chemotherapy-induced olfactory and gustatory dysfunction (CIOGD) are heterogeneous due to inconsistent study designs and small numbers of patients. To provide consistent, reliable data, we conducted a cohort study using standardized testing. Patients diagnosed with lymphoma, leukemia, or gastrointestinal malignancies were examined up to five times (T1 to T5), beginning prior to chemotherapy. We examined patients receiving temporary treatment up to 12 months post-therapy. Clinical assessment included extensive questionnaires, psychophysical tests of olfactory and gustatory function, and measurement of peripheral neuropathy. Statistical analysis included non-parametric tests to evaluate the longitudinal development of CIOGD. Our data (n = 108) showed a significant decline in olfactory and gustatory testing during chemotherapy (p-values < 0.001). CIOGD appeared stronger among patients above 60 years, while sex did not matter significantly. However, we identified distinct associations between CIOGD and reported anorexia as well as with higher neuropathy scores. Self-assessment appeared less sensitive to chemosensory dysfunction than psychophysical testing. Post-therapy, olfactory and gustatory function regenerated, though baseline levels were not attained within 6 to 12 months. In conclusion, our data highlight the wide prevalence and slow recovery of CIOGD. Understanding CIOGD as a potential neurotoxic effect may disclose new therapeutic prospects.

Chuna Manual Therapy or Electroacupuncture with Pregabalin for Chemotherapy-Induced Peripheral Neuropathy: A Randomized Controlled Pilot Study.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common side effects of chemotherapy, and effective treatments for CIPN are still lacking. For this reason, there is a growing interest in complementary and alternative medicine as a potential source of nonsurgical treatments for CIPN symptoms alongside pregabalin. One such option being explored is Chuna manual therapy (CMT), a traditional Korean manual therapy. Methods: This study compares the effectiveness and safety of using only pregabalin (PG) as a conventional method of treating breast and colorectal cancer patients with CIPN symptoms with a combination of both PG and electroacupuncture (EA) or CMT, while also assessing the feasibility of future large-scale clinical studies. Due to the COVID-19 pandemic, only 74 CIPN patients were recruited to this study. Twenty-five were assigned to the PG group, 26 to the PG + EA group, and 22 to the PG + CMT group for a five-week treatment and a four-week follow-up study. Results: For the primary outcome, we evaluated the mean differences in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) compared to the baseline at week 5 (visit 4). Although we found that the PG + CMT group showed the biggest difference (-16.64 [95% CI: -25.16, -8.11]) compared to the PG group (-8.60 [95% CI: -14.93, -2.27]) and the PG + EA group (-6.73 [95% CI: -12.34, -1.13]), this finding lacked statistical significance (p = 0.2075). In terms of safety, two patients in the PG + CMT group reported side effects: one bruise and one headache. Conclusions: The low attrition and high adherence rates of all the groups, and the similar rates of side effects among them, support the feasibility of larger-scale follow-up studies.

Identification of Matrine as a Kirsten rats Arcomaviral oncogene homolog inhibitor alleviating chemotherapy-induced neuropathic pain.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) represents a prevailing and severe clinical concern, characterized by limited availability of clinically effective treatment strategies. Current evidence endorses matrine's potential as a neuroprotective and analgesic agent for CIPN. Nevertheless, the precise targets and mechanisms of action of matrine remain insufficiently explored, impeding comprehensive pharmacological investigation and clinical application. OBJECTIVE: This study endeavors to elucidate the analgesic and neuroprotective effects of matrine in mice with vincristine-induced neuropathic pain. A focal point is the identification of matrine's specific target and the underlying molecular mechanisms governing its analgesic and neuroprotective actions. METHODS: To discern matrine's analgesic effects in CIPN mice, we conducted behavioral experiments encompassing the Von Frey filament test and Hargreaves Test. Furthermore, we conducted electrophysiological and histopathological assessments involving HE staining, Nissl staining, and Fluoro-Jade B staining to evaluate matrine's effects on neuroprotection within dorsal root ganglia and the spinal cord of CIPN mice. Sequentially, thermal shift assay, GTP hydrolysis assay, and nucleotide exchange assay were executed to validate matrine's inhibitory effects on KRAS. Molecular docking and site-directed mutagenesis experiments were implemented to identify the precise binding pocket of matrine on KRAS. Lastly, matrine's inhibitory effects on downstream signaling pathways of KRAS were confirmed through experiments conducted at animal model. RESULTS: Matrine exhibited a notable increase in mechanical withdrawal threshold and thermal withdrawal latency in vincristine-treated mice. This compound substantially ameliorated the neurofunctional blockade associated with sensory and motor functions induced by vincristine. Moreover, matrine mitigated pathological damage within DRG and the L4-L5 spinal cord regions. The study's MST experiments indicated matrine's substantial elevation of KRAS's melting temperature. The GTP hydrolysis and nucleotide exchange assays revealed concentration-dependent inhibition of KRAS activity by matrine. Molecular docking provided insight into the binding mode of matrine with KRAS, while site-directed mutagenesis verified the specific binding site of matrine on KRAS. Lastly, matrine's inhibition of downstream Raf/Erk1/2 and PI3K/Akt/mTOR signaling pathways of KRAS was confirmed in VCR mice. CONCLUSION: Compared to previous studies, our research has identified matrine as a natural inhibitor of the elusive protein KRAS, often considered "undruggable." Furthermore, this study has revealed that matrine exerts its therapeutic effects on chemotherapy-induced peripheral neuropathy (CIPN) by inhibiting KRAS activation, subsequently suppressing downstream signaling pathways such as Raf/Erk1/2 and PI3K/Akt/mTOR. This investigation signifies the discovery of a novel target for matrine, thus expanding the potential scope of its involvement in KRAS-related biological functions and diseases. These findings hold the promise of providing a crucial experimental foundation for forthcoming drug development initiatives centered around matrine, thereby advancing the field of pharmaceutical research.

Fall Risk Associated with Taxanes: Focus on Chemotherapy-Induced Peripheral Neuropathy.

OBJECTIVES: Chemotherapy-induced peripheral neuropathy (CIPN) remains a significant toxicity for women with breast cancer receiving taxane-based treatment. This analysis has been done within the context of an ongoing 16-week randomized clinical trial consisting of a gait, balance, and strength training exercise intervention for the lower extremities in women with persistent CIPN who received taxane-based chemotherapy for breast cancer. The aim of this analysis is to determine the baseline fall risk among 62 study participants with persistent taxane-induced CIPN assigned to the control group. METHODS: This analysis used the baseline demographic, medical data, nerve conduction, gait, balance, and muscle strength variables of participants prior to randomization to develop an explanatory model of fall risk. The analytic approach utilized generalized linear modeling with Lasso to select baseline risk factors for future falls. RESULTS: Characteristics of the study sample by intervention and control group revealed no significant differences between the groups at baseline. The only baseline risk factors that were significantly associated with future falls were near falls within the last month (ß = 0.90, P = .056) with an odds ratio = 2.46, 95% confidence interval 0.31 to 17, and right ankle plantar flexion torque. (ß = 0. 05, P = .006) with an odds ratio = 1.05, 95% confidence interval 1.01 to 1.10. Demographic and medical data, nerve conduction parameters, gait, balance, or muscle strength variables did not significantly influence fall risk in this population. CONCLUSIONS: The potential for injury and disability from falls is a considerable concern among oncology clinicians and women with breast cancer and persistent CIPN. While falls and fall risk have been previously examined in other studies of breast cancer survivors, the majority of studies fail to capture the occurrence of "near falls" a significant predictor of fall risk. In addition, it is possible that ankle strength may prove to be a potential target for fall prevention in this population. Evidence-based interventions focused on improving neuropathic symptoms, physical function, and quality of life in persons with CIPN are still needed. IMPLICATION FOR NURSING PRACTICE: Oncology nurses and nurse practitioners should query patients who received taxane-based chemotherapy for not only the incidence and frequency of falls but the occurrence of near falls. A prompt referral to physical therapy may be useful in strengthening the lower extremities to improve balance and prevent falls.

The role of the gut microbiome in neuroinflammation and chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most debilitating adverse effects caused by chemotherapy drugs such as paclitaxel, oxaliplatin and vincristine. It is untreatable and often leads to the discontinuation of cancer therapy and a decrease in the quality of life of cancer patients. It is well-established that neuroinflammation and the activation of immune and glial cells are among the major drivers of CIPN. However, these processes are still poorly understood, and while many chemotherapy drugs alone can drive the activation of these cells and consequent neuroinflammation, it remains elusive to what extent the gut microbiome influences these processes. In this review, we focus on the peripheral mechanisms driving CIPN, and we address the bidirectional pathways by which the gut microbiome communicates with the immune and nervous systems. Additionally, we critically evaluate literature addressing how chemotherapy-induced dysbiosis and the consequent imbalance in bacterial products may contribute to the activation of immune and glial cells, both of which drive neuroinflammation and possibly CIPN development, and how we could use this knowledge for the development of effective treatment strategies.

Prevention of taxane chemotherapy-induced nail changes and peripheral neuropathy by application of extremity cooling: a prospective single-centre study with intrapatient comparison.

PURPOSE: Common side effects of taxane chemotherapy are nail toxicity and peripheral neuropathy (CIPN) causing severe impact on the quality of life. Different methods of cryotherapy to prevent these side effects have been tested. We investigated the use of machine-controlled cooling of hands and feet to reduce nail toxicity and CIPN in patients receiving taxane chemotherapy. METHODS: Patients receiving Docetaxel (planned dose ≥ 300 mg/m2) or Paclitaxel (planned dose ≥ 720 mg/m2 - ) in the adjuvant or palliative setting of different cancers were included. The dominant hand and foot were cooled to approximately 10 °C using the Hilotherapy machine. The contralateral hand and foot were used as intrapatient comparison. The primary endpoint was the occurrence of any CIPN due to paclitaxel or nail toxicity due to Docetaxel. Both the intention to treat population (ITT) and the per protocol population (PPP) were analyzed. RESULTS: A total of 69 patients, 21 treated with Docetaxel and 48 with Paclitaxel, were included at our centre between 08/2020 and 08/2022. Nail toxicity due to Docetaxel was overall not significantly improved by cooling in the ITT or PPP but a significant benefit across visits was found for the ITT. CIPN due to Paclitaxel was numerically better in the ITT and significantly better in the PPP. A significant benefit of cooling on CIPN occurrence across visits was found for the ITT and the PPP. Cooling was very well tolerated. CONCLUSION: Cooling of hands and feet has a clinically meaningful impact on reducing occurrence of CIPN and nail toxicity on treatment with taxanes. Effects are more significant over time and are dose dependent. TRIAL REGISTRATION NUMBER: 2020-00381. Date of registration. 24th February 2020.

Efficacy of Mirogabalin for Taxane-associated Chemotherapy-induced Peripheral Neuropathy in Perioperative Chemotherapy for Early Breast Cancer.

BACKGROUND/AIM: Treatment with taxanes can result in chemotherapy-induced peripheral neuropathy (CIPN). We investigated the efficacy and safety of mirogabalin for the treatment of CIPN in patients who had been administered perioperative chemotherapy including taxane-based agents for breast cancer. PATIENTS AND METHODS: We retrospectively analyzed the case of 43 patients with early breast cancer who received a taxane as perioperative chemotherapy and were administered mirogabalin at the diagnosis of CIPN. RESULTS: Thirty-six patients (83.7%) had grade 1 CIPN and the other seven patients (16.3%) had grade 2 CIPN. The median mirogabalin dose was 10 mg (5-30 mg). CIPN improved from grade 1 to 0 in 12 patients (27.9%) and from grade 2 to 1 in one patient (2.3%); 13 (30.2%) patients thus had an objective therapeutic response. There were no cases in which chemotherapy was reduced or discontinued due to CIPN. Adverse events were evaluated by Common Terminology Criteria for Adverse Events and included five cases of dizziness (11.7%), three of somnolence (7.0%), and two of nausea (4.7%), all of which were grade ≤2. There were no cases of serious (grade ≥3) adverse effects. CONCLUSION: Mirogabalin may be effective and safe for treating CIPN of patients who receive a taxane in a perioperative breast cancer setting.

Effect of frozen gloves on chemotherapy-induced neurotoxicity in breast cancer patients: a systematic review and meta-analysis.

Background: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a dose-limiting side effect observed in breast cancer patients. Its primary clinical manifestations include limb numbness, tingling sensations, hypoesthesia, or paresthesia. In severe instances, some patients may also encounter muscle cramps, weakness, and pain, leading to potential paralysis. The onset of CIPN significantly impacts the quality of life for cancer patients. Hence, it is imperative to explore preventive strategies for managing CIPN. Methods: We searched for relevant randomized controlled trials (RCTs) and non-randomized controlled trials (non-RCTs) in several databases. The primary outcome measures encompassed the Patient Neurotoxicity Questionnaire (PNQ), the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), and the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Secondary outcomes aimed to evaluate the quality of life and the tolerability of ice gloves. Meta-analysis was conducted using RevMan 5.3 software to determine the relative risk ratio (RR) and 95% confidence interval (CI). Results: We conducted an analysis involving 372 patients across seven trials. In our meta-analysis, the use of ice gloves demonstrated non-significant results in reducing the incidence of both motor and sensory neuropathy, as assessed through CTCAE (sensory: RR: 0.94; 95% CI: 0.85 to 1.02; P = 0.15; motor: RR: 1.04; 95% CI: 0.88 to 1.22; P = 0.64). Similarly, when evaluated using the PNQ, there was no significant reduction observed in the incidence of sensory and motor neuropathy (sensory: RR: 0.49; 95% CI: 0.20 to 1.20; P = 0.12; motor: RR: 0.71; 95% CI: 0.26 to 1.99; P = 0.52). Consistently, our conclusions remained unchanged when employing the FACT-Taxane assessment. Regarding the evaluation of the quality of life, our observations suggested a potential improvement with the use of ice gloves, and participants exhibited moderate tolerance towards them. Conclusion: Ice gloves are a reasonable option for the treatment of CIPN in patients undergoing chemotherapy for breast cancer. However, the effectiveness of ice gloves in combating CIPN remains inconclusive at this time due to the low quality and limited number of clinical trials on this topic. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023457045, identifier CRD42023457045.

Single and Combined Effects of Cannabigerol (CBG) and Cannabidiol (CBD) in Mouse Models of Oxaliplatin-Associated Mechanical Sensitivity, Opioid Antinociception, and Naloxone-Precipitated Opioid Withdrawal.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients, with estimates of at least 30% of patients experiencing persistent neuropathy for months or years after treatment cessation. An emerging potential intervention for the treatment of CIPN is cannabinoid-based pharmacotherapies. We have previously demonstrated that treatment with the psychoactive CB1/CB2 cannabinoid receptor agonist Δ9-tetrahydrocannabinol (Δ9-THC) or the non-psychoactive, minor phytocannabinoid cannabidiol (CBD) can attenuate paclitaxel-induced mechanical sensitivity in a mouse model of CIPN. We then showed that the two compounds acted synergically when co-administered in the model, giving credence to the so-called entourage effect. We and others have also demonstrated that CBD can attenuate several opioid-associated behaviors. Most recently, it was reported that another minor cannabinoid, cannabigerol (CBG), attenuated cisplatin-associated mechanical sensitivity in mice. Therefore, the goals of the present set of experiments were to determine the single and combined effects of cannabigerol (CBG) and cannabidiol (CBD) in oxaliplatin-associated mechanical sensitivity, naloxone-precipitated morphine withdrawal, and acute morphine antinociception in male C57BL/6 mice. Results demonstrated that CBG reversed oxaliplatin-associated mechanical sensitivity only under select dosing conditions, and interactive effects with CBD were sub-additive or synergistic depending upon dosing conditions too. Pretreatment with a selective α2-adrenergic, CB1, or CB2 receptor selective antagonist significantly attenuated the effect of CBG. CBG and CBD decreased naloxone-precipitated jumping behavior alone and acted synergistically in combination, while CBG attenuated the acute antinociceptive effects of morphine and CBD. Taken together, CBG may have therapeutic effects like CBD as demonstrated in rodent models, and its interactive effects with opioids or other phytocannabinoids should continue to be characterized.

Targeting TRPV4 Channels for Cancer Pain Relief.

Despite the unique and complex nature of cancer pain, the activation of different ion channels can be related to the initiation and maintenance of pain. The transient receptor potential vanilloid 4 (TRPV4) is a cation channel broadly expressed in sensory afferent neurons. This channel is activated by multiple stimuli to mediate pain perception associated with inflammatory and neuropathic pain. Here, we focused on summarizing the role of TRPV4 in cancer etiology and cancer-induced pain mechanisms. Many studies revealed that the administration of a TRPV4 antagonist and TRPV4 knockdown diminishes nociception in chemotherapy-induced peripheral neuropathy (CIPN). Although the evidence on TRPV4 channels' involvement in cancer pain is scarce, the expression of these receptors was reportedly enhanced in cancer-induced bone pain (CIBP), perineural, and orofacial cancer models following the inoculation of tumor cells to the bone marrow cavity, sciatic nerve, and tongue, respectively. Effective pain management is a continuous problem for patients diagnosed with cancer, and current guidelines fail to address a mechanism-based treatment. Therefore, examining new molecules with potential antinociceptive properties targeting TRPV4 modulation would be interesting. Identifying such agents could lead to the development of treatment strategies with improved pain-relieving effects and fewer adverse effects than the currently available analgesics.

Exploring microRNA patterns as biomarkers of FOLFOX chemotherapy-induced peripheral neuropathy in patients with colorectal cancer.

FOLFOX is a combination of chemotherapeutic agents (5-fluorouracil, leucovorin, and oxaliplatin) and is used to treat advanced colorectal cancer (CRC) but induces various side effects. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most critical side effects that compromise the quality of life of patients with CRC undergoing FOLFOX chemotherapy. This study aimed to evaluate circulating miRNA, cortisol and catecholamine as potential biomarkers that can predict FOLFOX-CIPN symptoms. High-throughput microRNA (miRNA) sequencing was performed on the RNA circulating in the plasma of eight patients with CRC who underwent FOLFOX chemotherapy. miRNA expression profiles were evaluated according to two groups: those who underwent ≤3 cycles and those who underwent ≥6 cycles of FOLFOX chemotherapy. The identified miRNAs were validated in 27 patients with CRC who underwent FOLFOX chemotherapy using quantitative reverse transcription polymerase chain reaction. Target genes were predicted using bioinformatics and functional analyses. Cortisol and catecholamine concentrations in peripheral plasma were measured using an enzyme-linked immunosorbent assay. miR-3184-5p was differentially expressed when miRNA expression was compared between the groups that underwent ≤3 and ≥6 cycles of FOLFOX chemotherapy. Cortisol levels were significantly higher in the group that underwent ≥6 cycles of FOLFOX chemotherapy than in the group that underwent ≤3 cycles. This study suggests that miR-3184-5p may be a potential marker for predicting CIPN.

Naringenin relieves paclitaxel-induced pain by suppressing calcitonin gene-related peptide signalling and enhances the anti-tumour action of paclitaxel.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) commonly causes neuropathic pain, but its pathogenesis remains unclear, and effective therapies are lacking. Naringenin, a natural dihydroflavonoid compound, has anti-inflammatory, anti-nociceptive and anti-tumour activities. However, the effects of naringenin on chemotherapy-induced pain and chemotherapy effectiveness remain unexplored. EXPERIMENTAL APPROACH: Female and male mouse models of chemotherapy-induced pain were established using paclitaxel. Effects of naringenin were assessed on pain induced by paclitaxel or calcitonin gene-related peptide (CGRP) and on CGRP expression in dorsal root ganglia (DRG) and spinal cord tissue. Additionally, we examined peripheral macrophage infiltration, glial activation, c-fos expression, DRG neuron excitability, microglial M1/M2 polarization, and phosphorylation of spinal NF-κB. Furthermore, we investigated the synergic effect and related mechanisms of naringenin and paclitaxel on cell survival of cancer cells in vitro. KEY RESULTS: Systemic administration of naringenin attenuated paclitaxel-induced pain in both sexes. Naringenin reduced paclitaxel-enhanced CGRP expression in DRGs and the spinal cord, and alleviated CGRP-induced pain in naïve mice of both sexes. Naringenin mitigated macrophage infiltration and reversed paclitaxel-elevated c-fos expression and DRG neuron excitability. Naringenin decreased spinal glial activation and NF-κB phosphorylation in both sexes but influenced microglial M1/M2 polarization only in females. Co-administration of naringenin with paclitaxel enhanced paclitaxel's anti-tumour effect, impeded by an apoptosis inhibitor. CONCLUSION AND IMPLICATIONS: Naringenin's anti-nociceptive mechanism involves CGRP signalling and neuroimmunoregulation. Furthermore, naringenin facilitates paclitaxel's anti-tumour action, possibly involving apoptosis. This study demonstrates naringenin's potential as a supplementary treatment in cancer therapy by mitigating side effects and potentiating efficacy of chemotherapy.

Pilot trial testing the effects of exercise on chemotherapy-induced peripheral neurotoxicity (CIPN) and the interoceptive brain system.

Purpose: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a prevalent, dose-limiting, tough-to-treat toxicity involving numbness, tingling, and pain in the extremities with enigmatic pathophysiology. This randomized controlled pilot study explored the feasibility and preliminary efficacy of exercise during chemotherapy on CIPN and the role of the interoceptive brain system, which processes bodily sensations. Methods: Nineteen patients (65±11 years old, 52% women; cancer type: breast, gastrointestinal, multiple myeloma) starting neurotoxic chemotherapy were randomized to 12 weeks of exercise (home-based, individually tailored, moderate intensity, progressive walking and resistance training) or active control (nutrition education). At pre-, mid-, and post-intervention, we assessed CIPN symptoms (primary clinical outcome: CIPN-20), CIPN signs (tactile sensitivity using monofilaments), and physical function (leg strength). At pre- and post-intervention, we used task-free ("resting") fMRI to assess functional connectivity in the interoceptive brain system, involving the salience and default mode networks. Results: The study was feasible (74-89% complete data across measures) and acceptable (95% retention). We observed moderate/large beneficial effects of exercise on CIPN symptoms (CIPN-20, 0-100 scale: -7.9±5.7, effect size [ES]=-0.9 at mid-intervention; -4.8±7.3, -ES=0.5 at post-intervention), CIPN signs (ES=-1.0 and -0.1), and physical function (ES=0.4 and 0.3). Patients with worse CIPN after neurotoxic chemotherapy had lower functional connectivity within the default mode network (R2=40-60%) and higher functional connectivity within the salience network (R2=20-40%). Exercise tended to increase hypoconnectivity and decrease hyperconnectivity seen in CIPN (R2 = 12%). Conclusion: Exercise during neurotoxic chemotherapy is feasible and may attenuate CIPN symptoms and signs, perhaps via changes in interoceptive brain circuitry. Future work should test for replication with larger samples. ClinicalTrials.gov identifier NCT03021174.

Manganese- and Platinum-Driven Oxidative and Nitrosative Stress in Oxaliplatin-Associated CIPN with Special Reference to Ca4Mn(DPDP)5, MnDPDP and DPDP.

Platinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy induced by oxidative-nitrosative-stress-mediated chain reactions is most disturbing. Recently, hope has been raised regarding the catalytic antioxidants mangafodipir (MnDPDP) and calmangafodipir [Ca4Mn(DPDP)5; PledOx®], which by mimicking mitochondrial manganese superoxide dismutase (MnSOD) may be expected to overcome oxaliplatin-associated chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, two recent phase III studies (POLAR A and M trials) applying Ca4Mn(DPDP)5 in colorectal cancer (CRC) patients receiving multiple cycles of FOLFOX6 (5-FU + oxaliplatin) failed to demonstrate efficacy. Instead of an anticipated 50% reduction in the incidence of CIPN in patients co-treated with Ca4Mn(DPDP)5, a statistically significant increase of about 50% was seen. The current article deals with confusing differences between early and positive findings with MnDPDP in comparison to the recent findings with Ca4Mn(DPDP)5. The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca4Mn(DPDP)5 may be explained by redox interactions between Pt2+ and Mn2+ and subtle oxidative-nitrosative chain reactions. In peripheral sensory nerves, Pt2+ presumably leads to oxidation of the Mn2+ from Ca4Mn(DPDP)5 as well as from Mn2+ in MnSOD and other endogenous sources. Thereafter, Mn3+ may be oxidized by peroxynitrite (ONOO-) into Mn4+, which drives site-specific nitration of tyrosine (Tyr) 34 in the MnSOD enzyme. Conformational changes of MnSOD then lead to the closure of the superoxide (O2•-) access channel. A similar metal-driven nitration of Tyr74 in cytochrome c will cause an irreversible disruption of electron transport. Altogether, these events may uncover important steps in the mechanism behind Pt2+-associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca4Mn(DPDP)5 mainly depends on their MnSOD-mimetic activity when it comes to their potential use as rescue medicines during, e.g., acute myocardial infarction. However, pharmacokinetic considerations suggest that the efficacy of MnDPDP on Pt2+-associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt2+ outcompetes Mn2+ and endogenous Zn2+ in binding to fodipir (DPDP), hence suggesting that the previously reported protective efficacy of MnDPDP against CIPN is a result of chelation and elimination of Pt2+ by DPDP, which in turn suggests that Mn2+ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN.