Explore the vast range of titles available.

Peripheral neuropathy is one of the most common side effects of chemotherapy, affecting up to 60% of all cancer patients receiving chemotherapy. Moreover, paclitaxel induces neuropathy in up to 97% of all gynecological and urological cancer patients. In cancer cells, paclitaxel induces cell death via microtubule stabilization interrupting cell mitosis. However, paclitaxel also affects cells of the central and peripheral nervous system. The main symptoms are pain and numbness in hands and feet due to paclitaxel accumulation in the dorsal root ganglia. This review describes in detail the pathomechanisms of paclitaxel in the peripheral nervous system. Symptoms occur due to a length-dependent axonal sensory neuropathy, where axons are symmetrically damaged and die back. Due to microtubule stabilization, axonal transport is disrupted, leading to ATP undersupply and oxidative stress. Moreover, mitochondria morphology is altered during paclitaxel treatment. A key player in pain sensation and axonal damage is the paclitaxel-induced inflammation in the spinal cord as well as the dorsal root ganglia. An increased expression of chemokines and cytokines such as IL-1β, IL-8, and TNF-α, but also CXCR4, RAGE, CXCL1, CXCL12, CX3CL1, and C3 promote glial activation and accumulation, and pain sensation. These findings are further elucidated in this review.

Paclitaxel (PTX) is a commonly used chemotherapeutic agent for treating various solid tumors; however, it often leads to a severe side effect known as paclitaxel‐induced peripheral neuropathy (PIPN), for which effective treatments are limited. Although mRNA therapies have shown promise in addressing central nervous system (CNS) disorders, the successful delivery of mRNA therapeutics to the nervous system is still hindered by many biological barriers. In this study, it is demonstrated that, compared with commercial MC3 lipid nanoparticles (MC3 LNPs), mRNA‐loaded P6CIT‐derived lipopolymer nanoparticles (P6CIT LPNPs), which are delivered via intrathecal injection, achieve effective penetration through the pia mater. More importantly, this P6CIT LPNP demonstrates the ability to achieve highly targeted mRNA transfection in gliocytes within the spinal cord and dorsal root ganglia (DRG), which is essential for the regulation of neuroinflammation. Furthermore, two intrathecal injections of P6CIT LPNPs encapsulating mIL‐10 (P6CIT/mIL‐10) significantly alleviate PIPN by reducing proinflammatory cytokine production, gliocyte activation, and presynaptic NMDA receptor hyperactivity in both male and female mice. This study presents a promising and clinically translatable platform for using mRNA‐loaded LPNPs to treat PIPN. The P6CIT lipopolymer demonstrates superior transfection efficacy in the spinal cord and DRG, as well as enhanced penetration of the pia mater compared to the MC3 ionizable lipid. Intrathecal delivery of P6CIT LPNPs enables effective transfection in the gliocytes in the spinal cord and DRG. Notably, intrathecal administration of P6CIT/mIL‐10 significantly alleviates allodynia in paclitaxel‐induced peripheral neuropathy mice.

Abstract Background: Peripheral neuropathy is damage to the peripheral nerve. The most common cause of neuropathy is paclitaxel. Several avenues have been explored to ameliorate the neurotoxicity associated with paclitaxel. Clinical studies have assessed the efficacy of glutamine with different doses and schedules to prevent gastrointestinal toxicity (mucositis, diarrhea) and peripheral neuropathy in patients receiving a variety of chemotherapy agents or radiation therapy and found that glutamine can prevent paclitaxel-induced peripheral neuropathy. Methods: Total of 50 patients, aged 30 or more with diagnosis of cancer and fulfilling the inclusion and exclusion criteria, formed the study population. We assigned 25 patients to the glutamine group and 25 patients to no glutamine group. All patients received weekly paclitaxel. Results: : The incidence of neuropathy of all grades at 3 months was 78% and at 6 months was 80%.In this study, most common symptom reported was numbness in toes (74%). In this study, Grade 1 was the most common grade of symptom reported by the patient (40%–50%). 2nd, 3rd, and 4th most common grade of symptom reported by the patient was Grade 0, Grade 2, and Grade 3, respectively. There was no Grade 4 symptom reported by any patient. All the symptoms were statistically comparable in both groups (Myalgias: P = 0.066, Arthralgia: P = 0.93, Dysesthesia: P = 0.82, Paresthesia: P = 0.92, Numbness fingers: P = 0.97, Numbness toes: P = 0.60). In our study, there was no incidence of cranial nerve weakness or any incidence of the postural drop. The electrophysiological study is the best tool available and can detect neuropathy at the very earlier stage even when the clinical exam is negative. Apart from that nature of neuropathy can be determined but grading is not possible which makes very difficult to decide on follow-up examinations when the physician should intervene. Moreover, there are fluctuations in SNAP and CMAP, and these fluctuations are most probably related to the innate variability of serial nerve conduction study parameters, particularly motor and sensory amplitude. Glutamine did not prevent neurotoxicity induced by weekly paclitaxel.

Paclitaxel-induced peripheral neuropathy is a frequent chemotherapy complication that causes nerve damage and profoundly reduces patients' quality of life. Despite extensive preclinical evidence supporting the neuroprotective potential of trimetazidine against peripheral neuropathy, its clinical efficacy remains unexplored. This proof-of-concept randomized controlled trial aimed to investigate the effect of trimetazidine administered during the early phase of treatment on the incidence of paclitaxel-induced peripheral neuropathy in patients with non-metastatic breast cancer. This parallel randomized placebo-controlled blinded endpoint trial was conducted at the Oncology Center, Minia University, Egypt, involving 60 breast cancer patients scheduled to receive weekly paclitaxel 90 mg/m . Patients were randomized to receive either trimetazidine 35 mg once daily or placebo alongside standard care. Measurements included the incidence of paclitaxel-induced neuropathy assessed by the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, patient quality of life via the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx) subscale, and exploratory serum biomarkers, specifically nerve growth factor (NGF) levels. Neuropathy and biomarkers were evaluated over an 8-week period. The incidence of grade 2 and 3 peripheral neuropathies was significantly lower in the trimetazidine group compared to controls, with notable reductions in paresthesia (p = 0.037), peripheral motor neuropathy (p = 0.004), and dysesthesia (p = 0.045), except for peripheral sensory neuropathy (p = 0.152). Clinically significant worsening in neuropathy-related quality of life was more frequent in the control group compared to the trimetazidine group (p = 0.001). Additionally, the trimetazidine group exhibited a significantly greater percentage increase in serum nerve growth factor from baseline (p = 0.003). Trimetazidine offers a safe and effective option for mitigating early paclitaxel-induced peripheral neuropathy in breast cancer patients. Further large-scale studies with longer follow-up are warranted to confirm these findings and explore effects across different chemotherapy regimens. https://clinicaltrials.gov/study/NCT06459193, identifier NCT06459193.

Paclitaxel is an effective and widely used chemotherapeutic, but also causes debilitating peripheral sensory neuropathy. Due to its influence on microtubule stability, we and others have hypothesized that paclitaxel alters neuromechanical properties. A prior study suggested that paclitaxel increases the tensile moduli of rat sensory nerves. However, the effects of paclitaxel on tissue level viscoelasticity have not been tested. In this study, sural branches of C57BL/6J mouse sciatic nerves were bilaterally excised. One nerve was treated with Ringer’s solution containing paclitaxel, and the contralateral nerve with Ringer’s alone. Nerves were then subject to a passive loading protocol in which peak stress, relaxed stress, and stress-relaxation dynamics were monitored at increasing strain. Elastic and tangent tensile moduli were calculated from both peak and relaxed stress-strain curves as well as failure stress were significantly elevated in paclitaxel-treated nerves compared to controls. Double-exponential fits (with τm and τn indicating fast and slow time constants, respectively) were successfully applied to model stress-relaxation. Though no significant differences in the τm and τn were found between groups, paclitaxel treatment significantly increased the variability of τm, suggesting heterogeneous effects on nerve biomechanical properties. Our data establish that paclitaxel effects at the cellular level influence tensile viscoelastic properties of nerves at the tissue level. These results have implications for understanding biomechanical influences on the progression and physical rehabilitation of paclitaxel-induced neuropathy.

Paclitaxel (PTX) serves as a primary chemotherapy agent against diverse solid tumors including breast cancer, lung cancer, head and neck cancer and ovarian cancer, having severe adverse effects including PTX-induced peripheral neuropathy (PIPN) and hypersensitivity reactions (HSR). A recommended anti-allergic agent diphenhydramine (DIP) has been used to alleviate PTX-induced HSR. Desloratadine (DLT) is a third generation of histamine H 1 receptor antagonist, but also acted as a selective antagonist of 5HTR 2A . In this study we investigated whether DLT ameliorated PIPN-like symptoms in mice and the underlying mechanisms. PIPN was induced in male mice by injection of PTX (4 mg/kg, i.p.) every other day for 4 times. The mice exhibited 50% reduction in mechanical threshold, paw thermal response latency and paw cold response latency compared with control mice. PIPN mice were treated with DLT (10, 20 mg/kg, i.p.) 30 min before each PTX administration in the phase of establishing PIPN mice model and then administered daily for 4 weeks after the model was established. We showed that DLT administration dose-dependently elevated the mechanical, thermal and cold pain thresholds in PIPN mice, whereas administration of DIP (10 mg/kg, i.p.) had no ameliorative effects on PIPN-like symptoms. We found that the expression of 5HTR 2A was selectively elevated in the activated spinal astrocytes of PIPN mice. Spinal cord-specific 5HTR 2A knockdown by intrathecal injection of AAV9 -5Htr2a-shRNA significantly alleviated the mechanical hyperalgesia, thermal and cold hypersensitivity in PIPN mice, while administration of DLT (20 mg/kg) did not further ameliorate PIPN-like symptoms. We demonstrated that DLT administration alleviated dorsal root ganglion neuronal damage and suppressed sciatic nerve destruction, spinal neuron apoptosis and neuroinflammation in the spinal cord of PIPN mice. Furthermore, we revealed that DLT administration suppressed astrocytic neuroinflammation via the 5HTR 2A /c-Fos/NLRP3 pathway and blocked astrocyte-neuron crosstalk by targeting 5HTR 2A . We conclude that spinal 5HTR 2A inhibition holds promise as a therapeutic approach for PIPN and we emphasize the potential of DLT as a dual-functional agent in ameliorating PTX-induced both PIPN and HSR in chemotherapy. In summary, we determined that spinal 5HTR 2A was selectively activated in PIPN mice and DLT could ameliorate the PTX-induced both PIPN- and HSR-like pathologies in mice. DLT alleviated the damages of DRG neurons and sciatic nerves, while restrained spinal neuronal apoptosis and CGRP release in PIPN mice. The underlying mechanisms were intensively investigated by assay against the PIPN mice with 5HTR 2A -specific knockdown in the spinal cord by injection of adeno-associated virus 9 (AAV9) -5Htr2a-shRNA . DLT inhibited astrocytic NLRP3 inflammasome activation-mediated spinal neuronal damage through 5HTR 2A /c-FOS pathway. Our findings have supported that spinal 5HTR 2A inhibition shows promise as a therapeutic strategy for PIPN and highlighted the potential advantage of DLT as a dual-functional agent in preventing against PTX-induced both PIPN and HSR effects in anticancer chemotherapy.

Purpose To assess the safety, dosing, and preventive effects of cannabidiol (CBD) on chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving oxaliplatin- or paclitaxel-based chemotherapy. Methods Patients with cancer scheduled to undergo treatment with carboplatin and paclitaxel (Carbo-Tax) or capecitabine and oxaliplatin (CAPOX) received 150 mg CBD oil twice daily (300 mg/daily) for 8 days beginning 1 day before initiation of chemotherapy. Ten CIPN-specific patient-reported outcome (PRO) measures were captured at baseline and each day after the first cycle of chemotherapy for 8 days. Multi-frequency vibrometry (MF-V) was captured at baseline and day 4 ± 1 after initiation of chemotherapy. Controls were obtained from a similar patient cohort that did not receive CBD. Adverse events were captured using the CTCAE ver. 4.03. Results From March to December 2021, 54 patients were recruited. CBD-treated patients were significantly older ( p  = 0.013/0.037, CAPOX/Carbo-Tax) compared to controls. Patients receiving CBD and CAPOX or Carbo-Tax showed significantly lower (better) change in Z -scores in high-frequency MF-V (125 and 250 Hz) compared to controls. This difference was most pronounced for patients receiving Carbo-Tax (− 1.76, CI-95 = [− 2.52; − 1.02] at 250 Hz). CAPOX patients treated with CBD had significantly lower peak baseline-adjusted difference in three PRO items on cold sensitivity to touch, discomfort swallowing cold liquids, and throat discomfort (− 2.08, − 2.06, and − 1.81, CI-95 = [− 3.89; − 0.12], NRS 0–10). No significant differences in PRO items were found for patients receiving Carbo-Tax. Possible side effects included stomach pain (grades 1–2) for patients receiving CAPOX. Conclusion CBD attenuated early symptoms of CIPN with no major safety concerns. Long-term follow-up is ongoing. Results should be confirmed in a larger, randomized study. Trial registration number NCT 04,167,319 (U.S National Library of Medicine; ClinicalTrials.gov). Date of registration: November 18, 2019.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common side-effect of anti-cancer therapy. To date, there are no clinically effective analgesics that could prevent and treat CIPN. However, the exact pathogenesis of CIPN is still unclear. In the present study, we use the paclitaxel-induced peripheral neuropathy (PIPN) model, aiming to better understand the transcriptomic level of the Dorsal root ganglia (DRG) neurons in rats with PIPN. mRNA from each DRG sample was reverse transcribed to cDNA and sequenced using next-generation high throughput sequencing technology. Quantitative RT-PCR verification was used to confirm the identified Differentially expressed genes (DEGs) in the DRG of PIPN rats. RNAseq results have identified 384 DEGs (adjusted P-value < 0.05; fold change ≥ 2) in the DRG of rats 14 days after paclitaxel injection in total, including 97 up-regulated genes, and 287 down-regulated genes. GO analysis revealed that these DEGs were majorly involved in neuropeptide activity, chemokine receptor activity, defense response, and inflammatory response. Kyoto Encyclopedia of Gene and Genomes analysis showed that neuroactive ligand-receptor interaction and cytokine-cytokine receptor interaction were involved in sensory neurons of rats with PIPN. Besides, comparison analysis identified that 11 DEGs in the PIPN model are shared with either inflammatory pain (Ces1d, Cfd, Retn, and Fam150b) or neuropathic pain (Atf3, Csrp3, Ecel1, Gal, Sprr1a, Tgm1, and Vip). Quantitative RT-PCR results also confirmed the validation of the RNAseq data. These results suggested that neuroactive ligand-receptor interaction and cytokine-cytokine receptor interaction are majorly involved in sensory neurons of rats with PIPN. Immune, inflammatory responses and neuron functional changes are the major pathogenesis of PIPN. Paclitaxel-induced peripheral neuropathy has shared characteristics with both inflammatory pain and neuropathic pain.

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

Neuropathic pain triggered by chemotherapy poses a significant clinical challenge. Investigating cell type-specific alterations through single-cell transcriptome analysis holds promise in understanding symptom development and pathogenesis. In this study, we performed single nuclei RNA (snRNA) sequencing of dorsal root ganglions (DRG) to explore the molecular mechanism underlying paclitaxel-induced neuropathic pain. Mouse exposed to repeated paclitaxel doses developed persistent pain hypersensitivity lasting at least 21 days. The snRNA sequencing unveiled seven major cell types within DRGs, with neurons further subdivided into 12 distinct subclusters using known markers. Notably, type C low-threshold mechanoreceptors (C_LTMR) exhibited the most pronounced transcriptomic changes post-paclitaxel administration. Differential gene expression and Gene Ontology (GO) analysis highlighted suppressed potassium-related currents, microtubule transport, and mitochondrial functions in C_LTMR following paclitaxel treatment. Pseudo-time analysis uncovered nine distinct states (state 1 to 9) of C_LTMR. State 1 exhibits higher prevalence in paclitaxel-treated mice and altered neurotransmission properties, likely contributing to paclitaxel-induced pain hypersensitivity. Additionally, Camk1d is involved in temperature hyperalgesia in CIPN, a key clinical symptom observed in human patients with CIPN. This comprehensive exploration sheds light on the molecular mechanisms driving paclitaxel-induced neuropathic pain, offering potential avenues for therapeutic intervention.