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Ther Adv Neurol Disord
Ther Adv Neurol Disord
TAN
sptan
Therapeutic Advances in Neurological Disorders
1756-2856
1756-2864
SAGE Publications Sage UK: London, England

10.1177/17562864241252718
10.1177_17562864241252718
Review
Targeting dorsal root ganglia for chemotherapy-induced peripheral neuropathy: from bench to bedside
https://orcid.org/0000-0003-4928-4051
Ege Eliana Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, TX, USA
Conceptualization Data curation Investigation Methodology Project administration Supervision Visualization Writing – original draft Writing – review & editing
Briggi Daniel Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, TX, USA
Data curation Investigation Methodology Writing – original draft
Vu Peter Department of Physical Medicine and Rehabilitation, University of Texas Health Science Center at Houston, Houston, TX, USA
Data curation Investigation Writing – original draft
Cheng Jianguo Department of Pain Management, Cleveland Clinic, Cleveland, OH, USA
Department of Neuroscience, Cleveland Clinic, Cleveland, OH, USA
Conceptualization Funding acquisition Investigation Resources Writing – review & editing
Lin Feng Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
Conceptualization Funding acquisition Investigation Resources Writing – review & editing
Xu Jijun Department of Pain Management and Inflammation and Immunity, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Conceptualization Data curation Funding acquisition Methodology Project administration Resources Supervision Writing – original draft Writing – review & editing
Xuj3@ccf.org
20 9 2024
2024
17 17562864241252718© The Author(s), 2024
2024
SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses
https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition affecting an increasing number of cancer survivors worldwide. However, insights into its pathophysiology and availability of effective therapies remain lacking. Dorsal root ganglia (DRG) have been studied as a key component of chemotherapeutic drug toxicity and a potential therapeutic target for CIPN treatment. This comprehensive review aims to synthesize, summarize, and correlate the results of both preclinical and clinical studies relevant to the pathophysiology and management of CIPN in relation to the DRG. Design: Review. A thorough literature search was conducted using the terms ‘dorsal root ganglion’ and ‘chemotherapy-induced peripheral neuropathy’, along with appropriate variations. Searched databases included PubMed, EMBASE, Medline, Cochrane Library, Wiley Library, and Web of Science. Inclusion criteria targeted all English language, peer-reviewed original research from the inception of these databases to the present year. Review articles, book chapters, and other nonoriginal publications were excluded. Of 134 relevant studies identified, the majority were preclinical studies elucidating how various chemotherapeutic agents, especially taxanes, disrupt neurotransmission, inflammatory processes, and apoptotic pathways within sensory neurons of DRG. Not only do these effects correlate with the presentation of CIPN, but their disruption has also been shown to reduce CIPN symptoms in preclinical models. However, clinical studies addressing DRG interventions are very limited in number and scope at this time. These results reveal various pathways within DRG that may be effective targets for CIPN treatment. While limited, clinical studies do offer promise in the utility of DRG neuromodulation in managing painful CIPN. In the future, clinical trials are needed to assess interventions aimed at these neuronal and nonneuronal pathological targets to better treat this complex condition.

chemotherapy
dorsal root ganglia
management
neuromodulation
neuropathy
pathophysiology
stimulation
National Institutes of Health https://doi.org/10.13039/100000002 CA228039 National Institutes of Health https://doi.org/10.13039/100000002 EY032458 National Institutes of Health https://doi.org/10.13039/100000002 NS127258 VeloSano at Cleveland Clinic Steve and Melody Golding Foundation cover-dateJanuary-December 2024
typesetterts1
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pmcIntroduction

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of antineoplastic treatment affecting more than half of the 28 million cancer survivors in the United States.1–3 Symptoms typically include sensory changes, impaired motor function, and neuropathic pain in the distal parts of the limbs. CIPN can occur in up to 80% of patients receiving chemotherapy. 4 Symptoms may persist in 60% of patients at 3 months after treatment and in 30% at 6 months and beyond. 5 These symptoms often limit the dose or even lead to discontinuation of chemotherapy, resulting in suboptimal cancer treatment. Long-term functional impairment from chemotherapy can also significantly reduce quality of life. 6 As the number of cancer survivors increases worldwide, understanding and mitigating these effects become increasingly critical.

Current therapeutic alternatives for the management of CIPN are far from satisfactory. There is a lack of evidence-based treatment and no Food and Drug Administration (FDA)-approved therapy for CIPN, in part due to the limited understanding of its pathophysiology. Numerous pathophysiological mechanisms have been proposed for commonly implicated chemotherapeutic agents, which include taxanes, platinum-based agents, alkylating agents, vinca alkaloids, proteasome inhibitors, and immunomodulators. 7 These agents interact with deoxyribonucleic acid (DNA), mitochondria, ion channels, and inflammatory pathways that induce axonal degeneration and peripheral neuropathy. 8 A common target of toxicity among these agents are the dorsal root ganglia (DRG), which are responsible for the transmission of sensory input and pain signals from the peripheral to the central nervous system (Figure 1). 9 Due to a lack of protection by the blood–brain barrier and the high permeability of surrounding capillaries, 10 DRG are particularly vulnerable to chemotherapy drug penetration and toxicity. Given that drug–ganglia interactions are central to CIPN, understanding them is essential in developing effective treatment options.

Figure 1. Chemotherapeutic insults affect sensory transmission through the dorsal root ganglia of the spinal cord through the involvement of microglia and immune cells, as well as the modification of various ion channels and inflammatory pathways. Neuronal damage is indicated by the red lightning strike. Proinflammatory processes are shown in red and anti-inflammatory processes are in green.

ROS, reactive oxygen species; TLR4, Toll-like receptor 4; TNF-α, tumor necrosis factor alpha.

Neuromodulation through electrical stimulation and targeted drug delivery has proven effective in a variety of neuropathic pain conditions.11–15 It has also been proposed as a treatment modality for CIPN.16,17 We have recently reported that dorsal root ganglion stimulation (DRG-S) could have potential for meaningful symptom relief in patients suffering from CIPN, 18 indicating that DRG could be a therapeutic target for CIPN. This review aims to synthesize, summarize, and interpret the results of preclinical and clinical research related to the role of DRG in CIPN as an effort to guide future research and management strategies for this debilitating pain syndrome.

Methods

A thorough literature search was conducted using the terms ‘dorsal root ganglion’ and ‘CIPN’, along with appropriate variations and corresponding Boolean operators. Searched databases included PubMed, EMBASE, Medline, Cochrane Library, Wiley Library, and Web of Science. Inclusion criteria targeted all English language, peer-reviewed abstracts, and original research from the inception of these databases to the present year (September 2023). Review articles, book chapters, and other nonoriginal publications were excluded. Multiple database queries and article back searches were conducted to identify relevant literature and experimental findings. All results and relevant references were reviewed by the authors and included as appropriate.

Results

Our literature search yielded 1159 articles, from which 134 relevant studies were identified (Figure 2). The majority (111) were preclinical studies related to the mechanisms and management of CIPN, while the rest consisted of clinical reports.

Figure 2. This flow diagram details our search strategy.

*Records were excluded if they were not in English, not peer-reviewed, not original research (e.g. reviews), or not focusing on DRG as a primary target of toxicity or treatment in the context of CIPN.

CIPN, chemotherapy-induced peripheral neuropathy; DRG, dorsal root ganglia.

Pathophysiology of CIPN

There is an increasing body of evidence supporting DRG as a critical pathophysiology hub and therapeutic target in animal models of CIPN. This evidence emerges from studies focusing on a variety of chemotherapeutic agent classes, particularly taxanes.

Taxane-induced CIPN

Taxanes are common first-line solid-tumor chemotherapies that inhibit microtubule–tubulin disassembly. 19 The two most widely used, and implicated in CIPN, are paclitaxel and docetaxel. 20 The prevalence of taxane-induced CIPN is as high as 90% in taxane-treated patients on standard chemotherapy doses (300 mg/m2 for paclitaxel and 100 mg/m2 for docetaxel) or accumulated doses (exceeding 1400 mg/m2).6,19 Taxane-induced neuropathy, particularly with paclitaxel, has been linked to pathological changes in ion channels, inflammatory responses, intracellular signaling, transcription factors, and mitochondrial oxidative stress within the DRG. 21

Neuronal damage and hypersensitivity

Treatment with taxanes can lead to direct damage to the primary sensory neurons in the DRG. DRG neurons show early signs of injury after paclitaxel treatment in rats. 22 The pathophysiological changes in the DRG include the upregulation of activating transcription factor 3 (ATF3, a marker of cell injury/regeneration), macrophage hyperplasia/hypertrophy, and satellite cell hypertrophy. 22 Paclitaxel’s toxic effects on DRG neurons result in the enlargement of neuronal cell bodies and a reduction in the neurite length,23,24 upregulation of pronociceptive ion channels, mitochondrial damage, and reactive oxygen species (ROS) formation.4,25

Paclitaxel treatment has been shown to upregulate transient receptor potential channels [TRPV1,26,27 TRPA1 (transient receptor potential ankyrin-1), and TRPV4 28 ] in DRG neurons, promoting the release of tumor necrosis factor-α (TNF-α) from immune cells and glial cells to mediate mechanical and cold allodynia in rats. Biochemical analyses of DRG showed that epigenetic modulation is involved in the paclitaxel-induced TRPV1 gene expression and neuropathic pain in rats. 29 Blocking TRPV1, TRPV4, or TNF-α signaling, in turn, reduces paclitaxel-induced pain. 30 Paclitaxel also increases the expression of voltage-gated sodium channels (Nav1.7) in rats and human DRG neurons. 31 Recent live imaging studies demonstrated that paclitaxel enhances vesicular trafficking and surface expression of Nav1.7 in the cell bodies of DRG neurons. 32 The upregulation of Nav1.7 in DRG neurons and its expression in the cell bodies contribute to ectopic spontaneous activity, which can be blocked by Pro-TX II, a selective Nav1.7 inhibitor. 31 In vitro treatment of paclitaxel on human DRG primary culture increased Nav1.7 expression, transient sodium currents, and action potential frequency in small DRG neurons. 33 Epigenetically, the repression of DRG Nav1.7 using the adeno-associated virus intrathecal delivery approach demonstrated effective and long-lasting reduction of tactile allodynia mediated by paclitaxel without changes in normal motor function in mice. 34 Paclitaxel-induced transcriptional downregulation of potassium channels in mouse DRG neurons also contribute to membrane depolarization and increased excitability of nociceptors, and consequently the development of pain. 35 Furthermore, the paclitaxel-induced increase in current in the calcium channels of DRG neurons may lead to increased pain in rat models of CIPN.36,37

In addition to these changes in ion channels, paclitaxel also induces swelling and vacuolation of sensory axonal mitochondria that are thought to contribute to CIPN. In a long-term longitudinal study in a rat model of paclitaxel CIPN, axonal degeneration or dysfunction of axonal microtubules was not observed. 38 Instead, the mitochondrial abnormality resulted in a chronic axonal energy deficiency that likely caused the CIPN symptoms.38,39 Oxidative stress from chemotherapy is known to induce mitochondrial damage, which in turn amplifies oxidative stress. 40 These damages may lead to neuronal apoptosis, neuroinflammation, and finally neurodegeneration. 40 Studies using DRG neuronal cell lines and a phenotypic drug screening approach have identified ethoxyquin and its novel derivatives as a potential neuroprotective therapy for CIPN in rodents without affecting paclitaxel’s antitumor effect. 41

Neuroimmune interactions

Neuroimmune interactions have also been identified as critical mechanisms for CIPN. 42 Paclitaxel binds to Toll-like receptor 4 (TLR4), 27 activating a proinflammatory intracellular signaling pathway via nuclear factor kappa B (NF-κB) and increasing inflammatory cytokine production. Blocking TLR4 signaling can reduce paclitaxel-induced CIPN. 43 We found that complement C3, a key component in innate immune response, is essential in paclitaxel-induced neuropathic pain. 44 We further demonstrated that blocking the anaphylatoxin C3a receptor (C3aR1) proinflammatory signaling could reduce CIPN by suppressing DRG neuronal hypersensitivity. 28 Paclitaxel-induced changes in inflammatory markers and mediators have also demonstrated influences on DRG-mediated mechanisms of CIPN. In mouse models, paclitaxel has been shown to promote CIPN via proinflammatory markers such as interleukin-1 beta (IL-1β), IL-6, and TNF-α, while suppressing anti-inflammatory factor IL-4 in DRG.45,46 Resveratrol improved the paclitaxel-induced pain symptoms in rats by increasing IL-10 and decreasing IL-1b. 47

Nonneuronal cells in the DRG also play an important role in CIPN. Satellite glial cells (SGCs) are glial cells that closely envelop sensory neurons, and represent the largest glial population in the DRG. 48 DRG SGCs play an important role in neuropathic pain by increasing gap junction coupling 49 between SGCs and by augmenting neuronal activity.50,51 Activation and gliosis of SGCs were reported in multiple studies of paclitaxel CIPN.22,49,52,53 A recent single-cell RNA sequencing study identified enriched expression of the tissue inhibitor metalloproteinase 3 (TIMP3) in SGCs, which was decreased after paclitaxel treatment. Intrathecal treatment with recombinant TIMP3 reversed mechanical allodynia in both Timp3 knockdown mice and in wild-type mice treated with paclitaxel. 54

Macrophage infiltration in the DRG is another key process in the development of CIPN.55,56 Upregulation of markers such as matrix metalloproteinase-3, which recruits and activates macrophages and ROS in DRG neurons, was noted in rat models with paclitaxel-induced neuropathy. 57 One particular role attributed to macrophages is the release of proinflammatory markers, sensitizing the DRG and invoking neuropathic pain. 58 In addition, macrophage infiltration has been implicated as an upstream mechanism in the necroptosis of DRG neurons, which has been linked with the development of paclitaxel-induced peripheral neuropathy. 59 Paclitaxel induced the release of high-mobility group box 1 (HMGB1) from macrophages to mediate CIPN through the ROS/p38 mitogen-activated protein kinases (MAPK)/NF-κB/histone acetyltransferases (HAT) pathway. 60 We found that blocking complement C3aR1 signaling could suppress the expansion of both CCR2+ and CX3CR1+ macrophages in DRG after paclitaxel treatment. 28

Besides macrophages, T lymphocytes also contribute to CIPN. 61 Paclitaxel induces a significant increase in the percentage of CD3+ T cells in mouse DRG.62,63 Flow cytometric analysis revealed that the majority of T cells in the DRG were CD8+ T cells. 63 CD8+ T cells may play different roles in the development and resolution of CIPN. An early study reported that adoptive transfer of proinflammatory CD8+ T cells exacerbated neuropathic pain, whereas adoptive transfer of anti-inflammatory Treg cells or intrathecal injection of CD8-neutralizing antibody reduced pain hypersensitivity. 64 A more recent study reported that paclitaxel-induced mechanical allodynia was prolonged in T cell-deficient (Rag1(−/−)) mice. 63 Adoptive transfer of either CD3+ or CD8+ T cells to Rag1(−/−) mice normalized resolution of CIPN. Paclitaxel also increased DRG IL-10 receptor expression, an effect which required CD8+ T cells. 63 Both T cell receptor and co-stimulator signals are required for T cell activation. Intrathecal injection of the inducible co-stimulatory molecule agonist antibody to activate DRG T cells has been shown to facilitate the resolution of paclitaxel-induced mechanical hypersensitivity by increasing IL-10 expression in the DRG of female mice. 62

Signal transduction in the DRG

Intracellular pathways, transcription factors, and mitochondrial damage in cells of the DRG appear to play significant roles in the pathophysiology of CIPN. 65 Activated intracellular pathways, such as protein kinase A, protein kinase B, protein kinase C, protein phospholipase C, phosphoinositide 3-kinase (PI3K), and proteinase-activated receptor 2, could induce hyperalgesia in paclitaxel-treated mice.66,67 The calcium ion is the main secondary messenger that mediates depolarization and synaptic activity of a neuron. An increase in cytosolic calcium can lead to membrane excitability, release of neurotransmitter, and excitotoxicity.68,69 Intrathecal administration of drugs that decrease the extracellular and intracellular availability of calcium could ameliorate taxane-induced mechano-allodynia and mechano-hyperalgesia in rodents. 70 However, Boehmerle et al. 71 found that paclitaxel-induced calcium oscillations were independent of extracellular and mitochondrial calcium but dependent on the interaction of a paclitaxel binding protein, neuronal calcium sensor 1 (NCS-1), with inositol 1,4,5-trisphosphate receptors (IP3R). The interaction of NCS-1 with IP3R and aberrant calcium signaling can be inhibited by lithium, a mood stabilizer that could prevent paclitaxel-induced peripheral neuropathy in rodents.72,73 Role of IP3R has also been indicated in paclitaxel-induced axonal degeneration. Paclitaxel treatment significantly reduced ATP-evoked IP3R-mediated calcium release in DRG neurons. Paclitaxel causes degeneration by reducing the synthesis of Bclw, a Bcl2 family member that binds to axonal IP3R and prevents axon degeneration. 74

Transcriptome analysis has demonstrated that crosstalk between neuroactive ligand-receptor and cytokine–cytokine receptor plays a critical role in the dysregulation of neuronal function in the DRG. 65 Paclitaxel increases the expression of pERK, pp38, C–C chemokine ligand 2, TLR4, MyD88, and IL-6 in primary rat DRG cultures. 75 Other pathways involving Wnt/β-catenin signaling, TLR4, and receptor-interacting protein kinase 3/mixed-lineage kinase domain-like protein have been found to influence the mediation of neuropathic pain in paclitaxel-treated rats.43,59,76–78 Transcription factors such as nuclear factor erythroid 2-related factor 2 have shown a significant antioxidant role in the DRG, but are actively suppressed by paclitaxel. 79 Transcriptome profiling has revealed long noncoding RNAs and mRNAs that impact immune and inflammatory responses to induce neuronal apoptosis, contributing to CIPN. 80 A similar pathway linked to a mitochondrial etiology of CIPN is the sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) pathway. The use of resveratrol has been demonstrated to prevent paclitaxel-induced mitochondrial damage and apoptosis by the PI3K and PGC-1α signaling pathways. 47

CIPN induced by other agents

Animal models of CIPN induced by several other chemotherapy agents have been used to study the mechanisms and potential therapeutic strategies. In this section, we review evidence from studies focusing on platinum-based agents, vinca alkaloids, proteasome inhibitors, immunomodulators, and alkylating agents.

Platinum -based agents

Platinum-based chemotherapeutic agents, such as oxaliplatin and cisplatin, have generally been used to treat solid-based tumors, including lung, breast, ovarian, colorectal, and testicular cancer. 81 The anticancer activity of platinum-based agents is believed due to their interaction with DNA. 82 Platinum agents form DNA–platinum interstrand crosslink compounds that interfere with tumor cell proliferation via DNA inhibition. 19 These chemotherapeutic agents have been associated with high rates of CIPN, affecting 70–92% of patients treated with these medications. 83 Cumulative doses of cisplatin as low as 350–600 mg/m2 could produce CIPN, with higher doses resulting in worse symptoms. 84 For oxaliplatin, CIPN has been found with doses starting at 540 mg/m2. 85

Platinum-based agents have been associated with CIPN mechanisms similar to those of taxanes. 86 Sensory neuronal cells and mitochondria in the DRG are the main target for neurotoxicity induced by these agents.87,88 Novel in vitro assays have been developed to mirror in vivo pathways in DRG explants to better elucidate toxic processes. 89 Postulated mechanisms of injury involve channel-based, proinflammatory, and apoptotic pathways.

Oxaliplatin has been reported to induce CIPN by downregulating Kv4.3 potassium channels and A-type potassium currents, disrupting nerve depolarization, and elevating nerve excitability. 90 Similarly, it was found to increase sodium current and compound action potentials through voltage-gated sodium channels within DRG. 91 Oxaliplatin-induced cold hyperalgesia has been identified as a downstream effect of calcium influx via L-type calcium channels through the transient receptor potential melastatin 8 pathway. 92 Cisplatin was also shown to upregulate N-type voltage-gated calcium channels in rat DRG, leading to thermal and mechanical hyperalgesia even in the absence of structural cell damage.93–95

The effects of ion channel disruption parallel the influence of inflammatory mediators and biochemical pathways in the presentation of CIPN. Activation of proinflammatory markers and macrophages by TLR4 cascade signaling creates a positive feedback loop, further increasing inflammatory mediators and ROS in the DRG.96,97 Similar to taxanes, oxaliplatin activates SGCs and increases gap-junction-mediated coupling of SGCs in the DRG. 49 Platinum-induced proinflammatory molecules, such as IL-1β, IL-6, and TNF-α, accelerate inflammatory DRG neuron destruction, thereby promoting CIPN. 98 Recent studies have shown that CD8+ T cells alleviate CIPN induced by cisplatin via an increase in the expression of IL-10 receptors in the DRG. 99 Adoptive transfer of CD8+ T cells facilitates resolution of cisplatin-induced mechanical allodynia and spontaneous pain. Interestingly, the effect of CD8+ T cells requires in vivo exposure (‘education’) of these cells to cisplatin. 99

Cellular uptake of platinum derivatives in the DRG has been considered vital in understanding CIPN development. 86 Accumulation of these platinum DNA adducts inhibits DNA repair pathways, inducing apoptosis and damaging DRG to induce CIPN.100,101 Apoptosis of neuronal and glial cells in the DRG via oxidative stress-activated caspases and mitogen-activated kinases have also contributed to platinum-induced CIPN. 102 These apoptotic pathways are postulated to be induced by MAPKs, which activate p38 and ERK1/2 pathways to further promote neuronal DRG death and resultant neuropathy. 103 In vitro studies have also suggested that oxaliplatin-induced oxidative stress can destroy neuronal DRG bodies. 104 Organic cation transporter 2 (OCT2), which facilitates oxaliplatin accumulation in these neurons, has been implicated in increasing oxidative stress and inhibiting neurite regrowth.89,105 Inhibiting this mechanism through agents such as l-tetrahydropalmatine and duloxetine has been demonstrated to reduce oxaliplatin uptake in DRG and attenuate peripheral neurotoxic effects.106,107

Vinca alkaloids

Among vinca alkaloids, vincristine is the most likely to induce dose-dependent CIPN compared to its counterparts: vinblastine, vinflunine, and vinorelbine.108,109 The incidence and prevalence of CIPN after treatment with vinca alkaloids have been reported at 17.5% and 91%, respectively, with symptoms often continuing beyond 12 months post-cessation. 110 This group works by manipulating microtubule assembly and mitotic spindle formation, disrupting and inhibiting cell structure and cytoskeleton axonal transport. 111 This mechanism of action has a direct influence on CIPN, with obstructed neural axoplasmic transport inducing nerve failure and fiber apoptosis via organelle axonal accumulation, length-dependent nerve conduction inhibition, and disrupted neuronal growth and swelling.112,113 The tubular mechanism also disrupts mitochondrial membrane structure and excitability, vacuolating channels and pores to disrupt mitochondrial concentration gradients and electron transport chains, especially with calcium ion gradients.70,114 Studies have shown that the acute exposure of isolated sensory neurons to vinca alkaloids results in CIPN by generating a TrpA1-dependent depolarizing sodium current to increase the excitability of the sensory neurons. The hypersensitization to painful stimuli in response to the acute exposure to vinca alkaloids is reduced in TrpA1-mutant flies and mice. 115 Other biochemical enzymatic pathways, such as SARM1, have mediated vinca-induced axonal destruction. 116 Mice deficient in SARM1 are protected from vincristine-induced neuropathy (VIN). 116 In addition, similarly to other chemotherapeutic agents, vinca alkaloids can increase inflammatory markers (TNF-α, IL-1β) and cells (macrophages) that promote CIPN symptoms. 117

Proteasome inhibitors

Proteasome inhibitors are commonly used for the treatment of multiple myeloma and certain types of lymphoma. Common proteasome inhibitors include bortezomib, ixazomib, and carfilzomib. 118 With bortezomib, 31–37% of patients in phase II trials have been diagnosed with CIPN 119 ; the incidences of CIPN in ixazomib and carfilzomib are significantly less.120,121 As with other chemotherapies, dosage and duration greatly affect CIPN symptoms. 122 This group of agents induces the accumulation of abnormally folded proteins by inhibiting the β proteolytic tubulin subunits of proteasome, resulting in cellular apoptosis. 123 Similar to taxanes and vinca alkaloids, bortezomib has been shown to influence tubulin function, microtubule stability, and structural dynamics of neurons, resulting in axonopathy and axonal degeneration in the DRG.124,125 Chronic treatment with bortezomib induced a marked upregulation of ATF3 in most DRG neuron nuclei as well as damage of sensory neurons and satellite cells. 126 This is further explained by long neuritic processes susceptible to insults and axonal transport disruption in the DRG of rat models of bortezomib-induced neuropathy. 127 Additionally, ion channels, especially calcium, are deranged by bortezomib, leading to caspase activation, membrane potential disruption, and eventual neuronal apoptosis. 128 Further studies have also shown direct peripheral nerve fiber insults and swelling via mitochondrial damage and energy disruption induced by bortezomib treatments. 129 Inflammatory activation of cell signaling cascades via NF-κB, TNF-α, sphingosine-1 phosphate, and dihydrosphingosine-1-phosphate in dorsal horn neurons have demonstrated similar CIPN mechanisms and presentations as other chemotherapeutic agents.130–132

Immunomodulators

The immunomodulatory agent most commonly associated with CIPN is thalidomide, with 25–75% of patients diagnosed in relation to dose and severity. 133 In many cases, a minimal 200 mg/m2 daily dose with a cumulative dose of 20 g can result in CIPN symptoms. 134 Its mechanism of action is poorly expounded, however, with few studies elucidating its pathophysiology. 135 Current hypotheses have centered on the inhibition of TNF-α and NF-κB to accelerate DRG hypoxia via neurotrophin blockade. 136 Its antiangiogenic effect via fibroblast growth factor and vascular endothelial growth factor blockade also influence tumor and CIPN presentations via further neuronal cell death. 136

Alkylating agents

Alkylating agents, such as cyclophosphamide, nitrosoureas, procarbazine, and thiotepa, rarely cause CIPN. 8 The alkylating agent most likely to produce CIPN is ifosfamide, at about 8% of cases; however, its mechanism and effect on the DRG are poorly studied to date.7,137,138

Management of CIPN

At present, there are no medications recommended by the American Society of Clinical Oncology for the prevention of CIPN. Out of numerous alternatives purported both for preventative and therapeutic use, duloxetine is the only agent that has established efficacy for the treatment of painful CIPN, and even then with limited benefit. 139 While many preclinical studies have proposed pharmacological approaches targeting the various affected pathways within the DRG, clinical evidence remains lacking. An alternative treatment strategy that may simultaneously target more mechanisms, DRG neuromodulation, has also been explored in both preclinical and clinical settings.

Pharmacological therapies

Preclinical studies

The majority of preclinical research on DRG-focused management of CIPN involves pharmacologic interventions. Many cellular mechanisms have been targeted in preclinical models, including drug transport, neuronal degeneration and apoptosis, oxidative stress, and channel dysfunction.

One preventative strategy has been to limit the accumulation and direct neurotoxicity of chemotherapeutic drugs within DRG neurons. For instance, tyrosine kinase inhibitors such as nilotinib and dasatinib may be able to block anion and cation transporters, such as OCTs, to inhibit drug accumulation without affecting antitumor efficacy. 4 Ethoxyquin may prevent paclitaxel- and cisplatin-induced axonal degeneration via heat shock protein 90 (HSP 90) modulation without compromising antitumor effects. 140 In addition, agents such as fingolimod and nicotine that have downstream inhibition of NF-κB may be able to prevent and treat CIPN associated with different chemotherapeutic classes by preventing neuronal apoptosis. 4 However, these effects remain to be demonstrated clinically.

Other agents have been proposed to target oxidative stress. Carvedilol, which has been studied a cardio-protective drug in cancer patients, has also been shown to reduce mitochondrial superoxide dismutase expression in rat DRG, consequently attenuating oxaliplatin-induced sensorimotor deficits. 141 The neurohormone melatonin prevented the loss of antioxidant enzymes and expression of proinflammatory cytokines in human colon cancer cell lines treated with oxaliplatin and prevented neuronal apoptosis through the LC3A/3B pathway in rat DRG, preventing cold and mechanical allodynia and hyperalgesia.142,143 The reversal of these symptoms with melatonin was also demonstrated in paclitaxel-treated rats. 144

Finally, given their ubiquitous role in chemotherapeutic toxicity, several drugs have targeted ion channels. Carbamazepine and arylsulfonamides, which are sodium channel antagonists, have been demonstrated to reverse hyperalgesia in preclinical models.91,145 Multiple calcium channel blockers, such as verapamil, nifedipine, diltiazem, and mexiletine, have also been reported to inhibit L-type calcium channels and nuclear factor of activated T-cell translocation in DRG and oxaliplatin-induced cold hyperalgesia in animal models.89,92 Unfortunately, none of these drugs are supported by clinical evidence at this time.

Clinical studies

A small number of DRG-targeting pharmacological agents have been tested in the clinical setting with variable results on CIPN. For instance, calmangafodipir, which mimics manganese superoxide dismutase, is known to reduce ROS and hyperalgesia in rat models. 146 One double-blinded randomized controlled phase II trial showed that calmangafodipir significantly reduced sensory disturbances in patients with colon cancer treated with oxaliplatin. 147 However, in two subsequent international trials studying this population (POLAR A and M), calmangafodipir actually exacerbated CIPN incidence, likely due to redox interactions between the metal cations.148,149

More promising evidence has emerged with glutathione and its precursor N-acetylcysteine, which can increase antioxidant activity and downregulate proinflammatory (e.g. IL-1b and TNF-α) and apoptotic (e.g. p53) pathways in animal models of platinum-induced CIPN.150,151 Some randomized controlled trials have reported subjective neuroprotective effects of these agents when administered along with platinum drugs.152–154 However, no objective benefits were shown in nerve studies, and some trials reported conflicting results. 155

Lithium, which is known to interfere with IP3R and aberrant calcium signaling in rat DRG, was associated with a decreased incidence of CIPN in cancer patients in a retrospective study. 156 However, a double-blinded randomized clinical trial showed that, compared to placebo, 300-mg lithium once daily for 5 days was not effective in preventing CIPN in breast cancer patients. 157 A larger phase II trial using lithium to prevent paclitaxel-related neurological side effects is underway. 158

Interventional therapies

Preclinical studies

DRG interventions targeting CIPN include DRG stimulation (DRG-S) and ablation, which may be able to modulate multiple neurotoxic mechanisms co-occurring within DRG. In contrast to pharmacological evidence, our literature search yielded no preclinical studies evaluating the use of DRG-S or radiofrequency ablation for CIPN. Two related publications evaluated the effectiveness of focused ultrasound ablation for VIN in rodent models.

In their 2018 publication, Youn et al. 159 applied internal high-intensity focused ultrasound (HIFU) therapy to exposed DRG of VIN rats. Rodents in the treatment group received ultrasound therapy to the left L5 DRG at 3 W for 3 min at 11 MHz, pulsed at 38 Hz with a period 90 ns and a width of 13 ms. Utilizing von Frey Fibers (VFF) to evaluate innocuous mechanical thresholds, Randall–Selitto testing for noxious mechanical thresholds, and hot plate testing (HPT) for thermal mechanical thresholds, the authors noted significant reductions in mechanical allodynia as well as mechanical and thermal hyperalgesia with HIFU therapy. Histological evidence of transient cellular edema was found within the HIFU-treated group, though this was diminished 48 h after treatment. The first of its kind, this study revealed the potential for neuromodulation targeting the DRG in chemotherapy-induced neuropathy.

In a similar 2020 publication from the same group of authors, internal or external low-intensity focused ultrasound (LIFU) (2.5 or 8 W, respectively) was evaluated as a treatment for VIN in rats. 160 VFF were again used to evaluate mechanical nociceptive thresholds, and HPT to evaluate thermal nociceptive thresholds. Mechanical and thermal thresholds were significantly improved in both internal and external treatment groups. Internal LIFU did not result in histological evidence of edema but did result in significant increases in mechanical and thermal nociceptive thresholds. Interestingly, VFF nociceptive thresholds also increased in the untreated right hind paw following internal LIFU, and though the significant ipsilateral threshold changes had been observed to be similar between internal and external LIFU treatment groups, only the internal LIFU treatment group was found to have significant contralateral sensory threshold improvement. External LIFU resulted in a less rise in mean temperature. This study, in redemonstrating the potential for DRG-targeted neuromodulation in VIN, also suggests that benefit may be realized with contralateral improvement and without the histological changes accompanying HIFU.

Clinical studies

Clinical evidence on the efficacy of neuromodulation in treating CIPN also remains lacking. 16 At present, published research on the use of DRG-S and ablation for CIPN consists mostly of case reports. Our literature search yielded a total of 10 reports representing eight unique cases (Table 1)161–170 and one retrospective study describing 9 additional cases. 18

Table 1. Summary of case reports on the use of DRG interventions for CIPN.

Author	Patient age (years)	Patient gender	Chemotherapy	Modality	Pain reduction	Follow-up (months)	Other outcomes	
Chapman 161	52	Female	Cyclophosphamide, thalidomide	DRG-S	VAS 8/10 to 1/10	5	Improvements in standing tolerance, EQ-5D, SF-36	
Finney 163	47	Male	Oxaliplatin	DRG-S	50%	1	NR	
Grabnar 164	50	Female	NR	DRG-S	100%	36	NR	
Rao 165	53	Male	NR	DRG-S	75% with trial	NR	S1 nerve root compression requiring device replacement	
Sindhi 166	23	Male	Rituximab	DRG-S	60%	5	Dorsal migration of leads requiring revision	
Yelle 167	49	Female	Rituximab	DRG-S	>60%	NR	Increased pain-free walking distance, improved mood, improved sleep	
Ahmadi 168	61	Female	NR	DRG-S	75% with trial	NR	Improved phantom limb pain	
Yadav 169	63	Male	Docetaxel	DRG RFA	‘Good’	8	Pain worsened after 8 months	
CIPN, chemotherapy-induced peripheral neuropathy; DRG-S, dorsal root ganglion stimulation; EQ-5D, EuroQol-5D; NR, not reported; RFA, radiofrequency ablation; SF-36, Short Form 36; VAS, Visual Analog Scale.

The isolated cases included patients of both genders, with ages ranging from 23 to 63 years old. Where specified, DRG-S leads were placed anywhere from L3 to S3, with half of the cases reporting multiple levels. Pain reduction with DRG-S ranged from 50% to 100%, with a maximum follow-up of 36 months. Pain reduction with the single case of DRG radiofrequency ablation was described as good but transient, worsening after 8 months. Additional outcomes with DRG-S included improvements in standing tolerance, pain-free-walking distance, mood, sleep, and phantom limb pain. Complications included dorsal lead migration and S1 nerve root compression in separate cases, both of which required subsequent revision.

More recently, we published the only retrospective review available on this topic describing nine patients who underwent DRG-S for CIPN. 18 This study demonstrated significant reductions in pain scores after DRG-S trial and implantation for up to a year of follow-up. Reported improvements also included reduced sensory symptoms, improved mobility, and decreased pain medication burden within the first year. No complications were reported.

Discussion

The results of this literature review highlight several important themes among existing studies on the role of the DRG in the development and management of CIPN. Nearly all agents known to cause CIPN have been shown to induce neuronal damage and cell death within the DRG, resulting in sensory disturbances and neuropathic pain in various in vivo models. Some classes of chemotherapeutics, such as platinum agents, have been reported to increase apoptosis of neuronal and glial cells within the DRG directly through DNA damage, axonal destruction, and oxidative stress. Others, such as taxanes and immunomodulators, appear to induce neuronal hypoxia and necroptosis via downstream effects of macrophage infiltration and inflammatory pathways. Moreover, similar to other peripheral neuropathies, the increases in inflammatory mediators and decreases in anti-inflammatory mediators and antioxidants in the DRG appear to contribute to the pathophysiology of CIPN. Importantly, the disruption and reversal of many of these processes has shown the potential to reduce CIPN symptoms and increase analgesia in animal models.

Taxanes, platinum-based agents, vinca alkaloids, and proteasome inhibitors have also been implicated in dysregulation of sodium, potassium, and calcium channels within the DRG, resulting in hyperexcitability in pain signaling in both rats and humans. Through complementary effects on ion channels, receptors, and neurotransmission, the increased depolarization and spontaneous activity in injured DRG neurons are imperative to the progression and persistence of CIPN. Again, the disruption of these toxic effects has been reported to reduce neuropathic symptoms in vivo. This suggests that targeting these pathways may be key to developing effective therapies for CIPN.

While neuroprotective agents have been trialed in preclinical studies, the multimodality of chemotherapeutic toxicity and the sheer amount of involved pathways make it difficult to treat CIPN with targeted drug therapy. Pharmacological interventions that block specific processes only have partial protective effects and have demonstrated conflicting results in clinical trials. 4 Though such agents may eventually play a role in the prevention and even management of subclasses of CIPN, there currently remain no FDA-approved therapies and only one general anti-neuropathic drug recommended for this condition. Given the availability of minimally invasive interventions such as neurostimulation and neuroablation, this offers promise in the possibility of managing CIPN symptoms through the modulation of multiple pathways at the level of the DRG.

When exploring the management of CIPN through neuromodulation of DRG, existing studies have addressed three potential modalities: ultrasound therapy, DRG-S, and radiofrequency ablation. The two animal experiments studying the use of HIFU and LIFU on the DRG of vincristine-induced rodents found significant increases in mechanical and thermal nociceptive thresholds, one even noting sensory improvement on the nontreated side. In humans, case reports and the single retrospective study on DRG-S demonstrated improvements in pain scores as well as other functional measures related to CIPN. Overall, though limited in scope, these results suggest that interventional treatments targeting the DRG carry promise in the management of CIPN.

While these findings are promising, the true therapeutic potential of DRG modulation in the management of CIPN remains underexplored. A notable limitation to this literature review is the relatively small number of studies published on this topic, especially in the clinical space. The low level of evidence on therapeutic modalities, such as DRG-S, ablation, and ultrasound therapy, makes it difficult to draw conclusions on their efficacy at this time. Furthermore, the majority of the reviewed publications are animal studies that may have limited applicability to human subjects. While human DRG show overall similar immunoreactivities for pain-related molecules to those of laboratory animals, they do differ in aspects such as neuronal size, electrophysiology, and expression of channel proteins and receptors. 9 These differences and the lack of subjective feedback (e.g. pain scoring) further amplify the need for better clinical research studying human responses.

In the future, investigators should explore potential therapies through larger studies designed specifically to evaluate their effects on the physiologic mechanisms and symptoms associated with CIPN. When applicable, randomized, controlled, prospective study designs should be utilized. Clinically under-explored modalities such as ultrasound stimulation deserve further consideration in human populations, and more widely used treatments such as DRG-S deserve more rigorous evaluation in patients with CIPN. Alternative modalities, such as rhizotomy and radiofrequency ablation of the DRG, are also being trialed in similar populations, including patients with cancer pain. 170 Given the mechanistic evidence supporting DRG-targeted therapies in the treatment of peripheral neuropathy, such interventions should be further considered in cancer survivors suffering from refractory CIPN symptoms.

Conclusion and perspectives

CIPN remains a pressing challenge in cancer chemotherapy. The National Cancer Institute’s Symptom Management and Health-Related Quality of Life Steering Committee has prioritized CIPN for translational research. 171 Numerous animal studies have targeted neuronal and nonneuronal (SGCs, macrophages, and T cells) pathological mechanisms in DRG to reverse or prevent CIPN. However, there is a paucity of clinical trials studying therapies that pursue these mechanisms. Because the DRG are a major target of neurotoxicity caused by multiple chemotherapy agents, DRG neuromodulation warrants further exploration for the management of persistent CIPN that has not responded to conventional therapies.

None.

Declarations

ORCID iD: Eliana Ege https://orcid.org/0000-0003-4928-4051

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Author contributions: Eliana Ege: Conceptualization; Data curation; Investigation; Methodology; Project administration; Supervision; Visualization; Writing – original draft; Writing – review & editing.

Daniel Briggi: Data curation; Investigation; Methodology; Writing – original draft.

Peter Vu: Data curation; Investigation; Writing – original draft.

Jianguo Cheng: Conceptualization; Funding acquisition; Investigation; Resources; Writing – review & editing.

Feng Lin: Conceptualization; Funding acquisition; Investigation; Resources; Writing – review & editing.

Jijun Xu: Conceptualization; Data curation; Funding acquisition; Methodology; Project administration; Resources; Supervision; Writing – original draft; Writing – review & editing.

Competing interests: The authors declare that there are no competing interests.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institutes of Health grants, NS127258 (to JC), EY032458 (to FL), and CA228039 (to JX). JX is also supported by the Steve and Melody Golding Foundation and the VeloSano program at Cleveland Clinic.

Availability of data and materials: Figures and tables are available for use with written permission from the corresponding author by reasonable request.
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References

1 Gutiérrez-Gutiérrez G Sereno M Miralles A , et al . Chemotherapy-induced peripheral neuropathy: clinical features, diagnosis, prevention and treatment strategies. Clin Transl Oncol 2010; 12 : 81–91.20156778
2 Cooper C. Chemotherapy-induced peripheral neuropathy. In: Wietlisbach C (ed.) Cooper’s fundamental of hand therapy. 3 ed. Mosby, 2020, pp. 495–500.
3 Shah A Hoffman EM Mauermann ML , et al . Incidence and disease burden of chemotherapy-induced peripheral neuropathy in a population-based cohort. J Neurol Neurosurg Psychiatry 2018; 89 : 636–641.29439162
4 Hu S Huang KM Adams EJ , et al . Recent developments of novel pharmacologic therapeutics for prevention of chemotherapy-induced peripheral neuropathy. Clin Cancer Res 2019; 25 : 6295–6301.31123053
5 Seretny M Currie GL Sena ES , et al . Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Pain 2014; 155 : 2461–2470.25261162
6 Park SB Goldstein D Krishnan AV , et al . Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin 2013; 63 : 419–437.24590861
7 Eldridge S Guo L Hamre J. A comparative review of chemotherapy-induced peripheral neuropathy in in vivo and in vitro models. Toxicol Pathol 2020; 48 : 190–201.31331249
8 Grisold W Cavaletti G Windebank AJ. Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neuro Oncol 2012; 14 (Suppl. 4 ): iv45–iv54.
9 Haberberger RV Barry C Dominguez N , et al . Human dorsal root ganglia. Front Cell Neurosci 2019; 13 : 271.31293388
10 Jimenez-Andrade JM Herrera MB Ghilardi JR , et al . Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: implications for chemical-induced peripheral sensory neuropathies. Mol Pain 2008; 4 : 10.18353190
11 Duarte RV Nevitt S McNicol E , et al . Systematic review and meta-analysis of placebo/sham controlled randomised trials of spinal cord stimulation for neuropathic pain. Pain 2020; 161 : 24–35.31453983
12 Strand NH Burkey AR. Neuromodulation in the treatment of painful diabetic neuropathy: a review of evidence for spinal cord stimulation. J Diabetes Sci Technol 2022; 16 : 332–340.34842478
13 Xu J Liu A Cheng J. New advancements in spinal cord stimulation for chronic pain management. Curr Opin Anaesthesiol 2017; 30 : 710–717.28938297
14 Xu L Sun Z Casserly E , et al . Advances in interventional therapies for painful diabetic neuropathy: a systematic review. Anesth Analg 2022; 134 : 1215–1228.35051958
15 Xu J Sun Z Wu J , et al . Peripheral nerve stimulation in pain management: a systematic review. Pain Physician 2021; 24 : E131–E152.
16 D’Souza RS Her YF Jin MY , et al . Neuromodulation therapy for chemotherapy-induced peripheral neuropathy: a systematic review. Biomedicines 2022; 10 : 1909.36009456
17 Sheldon BL Bao J Khazen O , et al . Spinal cord stimulation as treatment for cancer and chemotherapy-induced pain. Front Pain Res (Lausanne) 2021; 2 : 699993.35295456
18 Ege E Briggi D Mach S , et al . Dorsal root ganglion stimulation for chemotherapy-induced peripheral neuropathy. Pain Pract 2023; 23 : 793–799.37260046
19 Starobova H Vetter I. Pathophysiology of chemotherapy-induced peripheral neuropathy. Front Mol Neurosci 2017; 10 : 174.28620280
20 Yared JA Tkaczuk KH. Update on taxane development: new analogs and new formulations. Drug Des Devel Ther 2012; 6 : 371–384.
21 Xu Y Jiang Z Chen X. Mechanisms underlying paclitaxel-induced neuropathic pain: channels, inflammation and immune regulations. Eur J Pharmacol 2022; 933 : 175288.36122757
22 Peters CM Jimenez-Andrade JM Kuskowski MA , et al . An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat. Brain Res 2007; 1168 : 46–59.17698044
23 Elfarnawany A Dehghani F. Palmitoylethanolamide mitigates paclitaxel toxicity in primary dorsal root ganglion neurons. Biomolecules 2022; 12 : 1873.36551301
24 Scuteri A Nicolini G Miloso M , et al . Paclitaxel toxicity in post-mitotic dorsal root ganglion (DRG) cells. Anticancer Res 2006; 26 : 1065–1070.16619507
25 Staff NP Fehrenbacher JC Caillaud M , et al . Pathogenesis of paclitaxel-induced peripheral neuropathy: a current review of in vitro and in vivo findings using rodent and human model systems. Exp Neurol 2020; 324 : 113121.31758983
26 Hara T Chiba T Abe K , et al . Effect of paclitaxel on transient receptor potential vanilloid 1 in rat dorsal root ganglion. Pain 2013; 154 : 882–889.23602343
27 Li Y Adamek P Zhang H , et al . The cancer chemotherapeutic paclitaxel increases human and rodent sensory neuron responses to TRPV1 by activation of TLR4. J Neurosci 2015; 35 : 13487–13500.26424893
28 Xu J Huang P Bie B , et al . Complement receptor C3aR1 contributes to paclitaxel-induced peripheral neuropathic pain in mice and rats. J Immunol 2023; 211 : 1736–1746.37861348
29 Hsieh MC Lai CY Cho WL , et al . Phosphate NIMA-related kinase 2-dependent epigenetic pathways in dorsal root ganglion neurons mediates paclitaxel-induced neuropathic pain. Anesth Analg 2023; 137 : 1289–1301.36753440
30 Wu Z Wang S Wu I , et al . Activation of TLR-4 to produce tumour necrosis factor-α in neuropathic pain caused by paclitaxel. Eur J Pain 2015; 19 : 889–898.25388329
31 Li Y North RY Rhines LD , et al . DRG voltage-gated sodium channel 1.7 is upregulated in paclitaxel-induced neuropathy in rats and in humans with neuropathic pain. J Neurosci 2018; 38 : 1124–1136.29255002
32 Akin EJ Alsaloum M Higerd GP , et al . Paclitaxel increases axonal localization and vesicular trafficking of Nav1.7. Brain 2021; 144 : 1727–1737.33734317
33 Chang W Berta T Kim YH , et al . Expression and role of voltage-gated sodium channels in human dorsal root ganglion neurons with special focus on Nav1.7, species differences, and regulation by paclitaxel. Neurosci Bull 2018; 34 : 4–12.28424991
34 Moreno AM Aleman F Catroli GF , et al . Long-lasting analgesia via targeted in situ repression of Na(V)1.7 in mice. Sci Transl Med 2021; 13 : eaay9056.
35 Mao Q Wu S Gu X , et al . DNMT3a-triggered downregulation of K2p 1.1 gene in primary sensory neurons contributes to paclitaxel-induced neuropathic pain. Int J Cancer 2019; 145 : 2122–2134.30684388
36 Kawakami K Chiba T Katagiri N , et al . Paclitaxel increases high voltage-dependent calcium channel current in dorsal root ganglion neurons of the rat. J Pharmacol Sci 2012; 120 : 187–195.23090716
37 Li Y Tatsui CE Rhines LD , et al . Dorsal root ganglion neurons become hyperexcitable and increase expression of voltage-gated T-type calcium channels (Cav3.2) in paclitaxel-induced peripheral neuropathy. Pain 2017; 158 : 417–429.27902567
38 Flatters SJL Bennett GJ . Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain 2006; 122 : 245–257.16530964
39 Xiao WH Bennett GJ. Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin. Pain 2012; 153 : 704–709.22244441
40 Areti A Yerra VG Naidu V , et al . Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. Redox Biol 2014; 2 : 289–295.24494204
41 Zhu J Chen W Mi R , et al . Ethoxyquin prevents chemotherapy-induced neurotoxicity via Hsp90 modulation. Ann Neurol 2013; 74 : 893–904.23955554
42 Vermeer CJC Hiensch AE Cleenewerk L , et al . Neuro-immune interactions in paclitaxel-induced peripheral neuropathy. Acta Oncol 2021; 60 : 1369–1382.34313190
43 Li Y Zhang H Zhang H , et al . Toll-like receptor 4 signaling contributes to paclitaxel-induced peripheral neuropathy. J Pain 2014; 15 : 712–725.24755282
44 Xu J Zhang L Xie M , et al . Role of complement in a rat model of paclitaxel-induced peripheral neuropathy. J Immunol 2018; 200 : 4094–4101.29695418
45 Wu P Chen Y. Evodiamine ameliorates paclitaxel-induced neuropathic pain by inhibiting inflammation and maintaining mitochondrial anti-oxidant functions. Hum Cell 2019; 32 : 251–259.30701373
46 Nie B Liu C Bai X , et al . AKAP150 involved in paclitaxel-induced neuropathic pain via inhibiting CN/NFAT2 pathway and downregulating IL-4. Brain Behav Immun 2018; 68 : 158–168.29056557
47 Li X Yang S Wang L , et al . Resveratrol inhibits paclitaxel-induced neuropathic pain by the activation of PI3K/Akt and SIRT1/PGC1α pathway. J Pain Res 2019; 12 : 879–890.30881098
48 Avraham O Deng PY Jones S , et al . Satellite glial cells promote regenerative growth in sensory neurons. Nat Commun 2020; 11 : 4891.32994417
49 Warwick RA Hanani M. The contribution of satellite glial cells to chemotherapy-induced neuropathic pain. Eur J Pain 2013; 17 : 571–580.23065831
50 Ji RR Chamessian A Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Science 2016; 354 : 572–577.27811267
51 Hanani M Spray DC. Emerging importance of satellite glia in nervous system function and dysfunction. Nat Rev Neurosci 2020; 21 : 485–498.32699292
52 Pozzi E Ballarini E Rodriguez-Menendez V , et al . Paclitaxel, but not cisplatin, affects satellite glial cells in dorsal root ganglia of rats with chemotherapy-induced peripheral neurotoxicity. Toxics 2023; 11 : 93.36850969
53 Jimenez-Andrade JM Peters CM Mejia NA , et al . Sensory neurons and their supporting cells located in the trigeminal, thoracic and lumbar ganglia differentially express markers of injury following intravenous administration of paclitaxel in the rat. Neurosci Lett 2006; 405 : 62–67.16854522
54 Tonello R Silveira Prudente A Hoon Lee S , et al . Single-cell analysis of dorsal root ganglia reveals metalloproteinase signaling in satellite glial cells and pain. Brain Behav Immun 2023; 113 : 401–414.37557960
55 Zhang H Li Y de Carvalho-Barbosa M , et al . Dorsal root ganglion infiltration by macrophages contributes to paclitaxel chemotherapy-induced peripheral neuropathy. J Pain 2016; 17 : 775–786.26979998
56 Huang Z-Z Li D Liu C-C , et al . CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy. Brain Behav Immun 2014; 40 : 155–165.24681252
57 Nishida K Kuchiiwa S Oiso S , et al . Up-regulation of matrix metalloproteinase-3 in the dorsal root ganglion of rats with paclitaxel-induced neuropathy. Cancer Sci 2008; 99 : 1618–1625.18754875
58 Luo X Huh Y Bang S , et al . Macrophage toll-like receptor 9 contributes to chemotherapy-induced neuropathic pain in male mice. J Neurosci 2019; 39 : 6848–6864.31270160
59 Ma D Wang X Liu X , et al . Macrophage infiltration initiates RIP3/MLKL-dependent necroptosis in paclitaxel-induced neuropathic pain. Mediators Inflamm 2022; 2022 : 1567210.36164389
60 Sekiguchi F Domoto R Nakashima K , et al . Paclitaxel-induced HMGB1 release from macrophages and its implication for peripheral neuropathy in mice: evidence for a neuroimmune crosstalk. Neuropharmacology 2018; 141 : 201–213.30179591
61 Laumet G Ma J Robison AJ , et al . T cells as an emerging target for chronic pain therapy. Front Mol Neurosci 2019; 12 : 216.31572125
62 Sankaranarayanan I Tavares-Ferreira D Mwirigi JM , et al . Inducible co-stimulatory molecule (ICOS) alleviates paclitaxel-induced neuropathic pain via an IL-10-mediated mechanism in female mice. J Neuroinflammation 2023; 20 : 32.36774519
63 Krukowski K Eijkelkamp N Laumet G , et al . CD8+ T cells and endogenous IL-10 are required for resolution of chemotherapy-induced neuropathic pain. J Neurosci 2016; 36 : 11074–11083.27798187
64 Liu XJ Zhang Y Liu T , et al . Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter. Cell Res 2014; 24 : 1374–1377.25112711
65 Sun W Yang S Wu S , et al . Transcriptome analysis reveals dysregulation of inflammatory and neuronal function in dorsal root ganglion of paclitaxel-induced peripheral neuropathy rats. Mol Pain 2023; 19 : 17448069221106167.
66 Chen Y Yang C Wang ZJ. Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain. Neuroscience 2011; 193 : 440–451.21763756
67 Adamek P Heles M Bhattacharyya A , et al . Dual PI3Kδ/γ inhibitor duvelisib prevents development of neuropathic pain in model of paclitaxel-induced peripheral neuropathy. J Neurosci 2022; 42 : 1864–1881.35042769
68 Bagur R Hajnóczky G. Intracellular Ca(2+) sensing: its role in calcium homeostasis and signaling. Mol Cell 2017; 66 : 780–788.28622523
69 Berridge MJ Lipp P Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 2000; 1 : 11–21.11413485
70 Siau C Bennett GJ. Dysregulation of cellular calcium homeostasis in chemotherapy-evoked painful peripheral neuropathy. Anesth Analg 2006; 102 : 1485–1490.16632831
71 Boehmerle W Splittgerber U Lazarus MB , et al . Paclitaxel induces calcium oscillations via an inositol 1,4,5-trisphosphate receptor and neuronal calcium sensor 1-dependent mechanism. Proc Natl Acad Sci U S A 2006; 103 : 18356–18361.17114292
72 Mo M Erdelyi I Szigeti-Buck K , et al . Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment. FASEB J 2012; 26 : 4696–4709.22889832
73 Pourmohammadi N Alimoradi H Mehr SE , et al . Lithium attenuates peripheral neuropathy induced by paclitaxel in rats. Basic Clin Pharmacol Toxicol 2012; 110 : 231–237.21917116
74 Pease-Raissi SE Pazyra-Murphy MF Li Y , et al . Paclitaxel reduces axonal Bclw to initiate IP(3)R1-dependent axon degeneration. Neuron 2017; 96 : 373–386.e6.
75 Li Y Marri T North RY , et al . Chemotherapy-induced peripheral neuropathy in a dish: dorsal root ganglion cells treated in vitro with paclitaxel show biochemical and physiological responses parallel to that seen in vivo. Pain 2021; 162 : 84–96.32694383
76 Kaldis P Pagano M. Wnt signaling in mitosis. Dev Cell 2009; 17 : 749–750.20059944
77 Li Y Zhang H Kosturakis AK , et al . MAPK signaling downstream to TLR4 contributes to paclitaxel-induced peripheral neuropathy. Brain Behav Immun 2015; 49 : 255–266.26065826
78 Guo LM Wang Z Li SP , et al . RIP3/MLKL-mediated neuronal necroptosis induced by methamphetamine at 39°C. Neural Regen Res 2020; 15 : 865–874.31719251
79 Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 2013; 53 : 401–426.23294312
80 Li Y Yin C Liu B , et al . Transcriptome profiling of long noncoding RNAs and mRNAs in spinal cord of a rat model of paclitaxel-induced peripheral neuropathy identifies potential mechanisms mediating neuroinflammation and pain. J Neuroinflammation 2021; 18 : 48.33602238
81 Zhang C Xu C Gao X , et al . Platinum-based drugs for cancer therapy and anti-tumor strategies. Theranostics 2022; 12 : 2115–2132.35265202
82 Ahmad S. Platinum–DNA interactions and subsequent cellular processes controlling sensitivity to anticancer platinum complexes. Chem Biodivers 2010; 7 : 543–566.20232326
83 Krøigård T Schrøder HD Qvortrup C , et al . Characterization and diagnostic evaluation of chronic polyneuropathies induced by oxaliplatin and docetaxel comparing skin biopsy to quantitative sensory testing and nerve conduction studies. Eur J Neurol 2014; 21 : 623–629.24460946
84 Krarup-Hansen A Helweg-Larsen S Schmalbruch H , et al . Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies. Brain 2007; 130 : 1076–1088.17301082
85 Argyriou AA Cavaletti G Antonacopoulou A , et al . Voltage-gated sodium channel polymorphisms play a pivotal role in the development of oxaliplatin-induced peripheral neurotoxicity: results from a prospective multicenter study. Cancer 2013; 119 : 3570–3577.23821303
86 Liu JJ Kim Y Yan F , et al . Contributions of rat Ctr1 to the uptake and toxicity of copper and platinum anticancer drugs in dorsal root ganglion neurons. Biochem Pharmacol 2013; 85 : 207–215.23123662
87 Burgess J Ferdousi M Gosal D , et al . Chemotherapy-induced peripheral neuropathy: epidemiology, pathomechanisms and treatment. Oncol Ther 2021; 9 : 385–450.34655433
88 Zheng H Xiao WH Bennett GJ. Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy. Exp Neurol 2011; 232 : 154–161.21907196
89 Du J Sudlow LC Luzhansky ID , et al . DRG explant model: elucidating mechanisms of oxaliplatin-induced peripheral neuropathy and identifying potential therapeutic targets. bioRxiv 2023. DOI: 10.1101/2023.10.05.560580.
90 Viatchenko-Karpinski V Ling J Gu JG. Down-regulation of Kv4.3 channels and a-type K+ currents in V2 trigeminal ganglion neurons of rats following oxaliplatin treatment. Mol Pain 2018; 14 : 1744806917750995.
91 Adelsberger H Quasthoff S Grosskreutz J , et al . The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons. Eur J Pharmacol 2000; 406 : 25–32.11011028
92 Kawashiri T Egashira N Kurobe K , et al . L type Ca²+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats. Mol Pain 2012; 8 : 7.22292988
93 Leo M Schmitt LI Jastrow H , et al . Cisplatin alters the function and expression of N-type voltage-gated calcium channels in the absence of morphological damage of sensory neurons. Mol Pain 2017; 13 : 1744806917746565.
94 Schmitt L-I Leo M Kleinschnitz C , et al . Oxaliplatin modulates the characteristics of voltage-gated calcium channels and action potentials in small dorsal root ganglion neurons of rats. Mol Neurobiol 2018; 55 : 8842–8855.29603093
95 Leo M Schmitt L-I Erkel M , et al . Cisplatin-induced neuropathic pain is mediated by upregulation of N-type voltage-gated calcium channels in dorsal root ganglion neurons. Exp Neurol 2017; 288 : 62–74.27823926
96 Illias AM Yu K-J Hwang S-H , et al . Dorsal root ganglion toll-like receptor 4 signaling contributes to oxaliplatin-induced peripheral neuropathy. Pain 2022; 163 : 923–935.34490849
97 Gu H Wang C Li J , et al . High mobility group box-1-toll-like receptor 4-phosphatidylinositol 3-kinase/protein kinase B-mediated generation of matrix metalloproteinase-9 in the dorsal root ganglion promotes chemotherapy-induced peripheral neuropathy. Int J Cancer 2020; 146 : 2810–2821.31465111
98 Leo M Schmitt L-I Kutritz A , et al . Cisplatin-induced activation and functional modulation of satellite glial cells lead to cytokine-mediated modulation of sensory neuron excitability. Exp Neurol 2021; 341 : 113695.33727094
99 Laumet G Edralin JD Dantzer R , et al . Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice. Pain 2019; 160 : 1459–1468.30720585
100 Banach M Juranek JK Zygulska AL. Chemotherapy-induced neuropathies – a growing problem for patients and health care providers. Brain Behav 2017; 7 : e00558.
101 Ta LE Espeset L Podratz J , et al . Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum–DNA binding. Neurotoxicology 2006; 27 : 992–1002.16797073
102 Carozzi VA Canta A Chiorazzi A. Chemotherapy-induced peripheral neuropathy: what do we know about mechanisms? Neurosci Lett 2015; 596 : 90–107.25459280
103 Scuteri A Galimberti A Maggioni D , et al . Role of MAPKs in platinum-induced neuronal apoptosis. Neurotoxicology 2009; 30 : 312–319.19428505
104 Di Cesare Mannelli L Zanardelli M Failli P , et al. Oxaliplatin-induced oxidative stress in nervous system-derived cellular models: could it correlate with in vivo neuropathy? Free Radic Biol Med 2013; 61 : 143–150.
105 Fujita S Hirota T Sakiyama R , et al . Identification of drug transporters contributing to oxaliplatin-induced peripheral neuropathy. J Neurochem 2019; 148 : 373–385.30295925
106 Yi Y Li L Song F , et al . L-tetrahydropalmatine reduces oxaliplatin accumulation in the dorsal root ganglion and mitochondria through selectively inhibiting the transporter-mediated uptake thereby attenuates peripheral neurotoxicity. Toxicology 2021; 459 : 152853.34252480
107 Nepal MR Taheri H Li Y , et al . Targeting OCT2 with duloxetine to prevent oxaliplatin-induced peripheral neurotoxicity. Cancer Res Commun 2022; 2 : 1334–1343.36506732
108 Verstappen CC Koeppen S Heimans JJ , et al . Dose-related vincristine-induced peripheral neuropathy with unexpected off-therapy worsening. Neurology 2005; 64 : 1076–1077.15781834
109 Madsen ML Due H Ejskjær N , et al . Aspects of vincristine-induced neuropathy in hematologic malignancies: a systematic review. Cancer Chemother Pharmacol 2019; 84 : 471–485.31214762
110 Kandula T Farrar MA Cohn RJ , et al . Chemotherapy-induced peripheral neuropathy in long-term survivors of childhood cancer: clinical, neurophysiological, functional, and patient-reported outcomes. JAMA Neurol 2018; 75 : 980–988.29799906
111 Stanton RA Gernert KM Nettles JH , et al . Drugs that target dynamic microtubules: a new molecular perspective. Med Res Rev 2011; 31 : 443–481.21381049
112 Pollard KJ Bolon B Moore MJ. Comparative analysis of chemotherapy-induced peripheral neuropathy in bioengineered sensory nerve tissue distinguishes mechanistic differences in early-stage vincristine-, cisplatin-, and paclitaxel-induced nerve damage. Toxicol Sci 2021; 180 : 76–88.33410881
113 Au NP Fang Y Xi N , et al . Probing for chemotherapy-induced peripheral neuropathy in live dorsal root ganglion neurons with atomic force microscopy. Nanomedicine 2014; 10 : 1323–1333.24632247
114 Joseph EK Levine JD. Mitochondrial electron transport in models of neuropathic and inflammatory pain. Pain 2006; 121 : 105–114.16472913
115 Boiko N Medrano G Montano E , et al . TrpA1 activation in peripheral sensory neurons underlies the ionic basis of pain hypersensitivity in response to vinca alkaloids. PLoS One 2017; 12 : e0186888.
116 Geisler S Doan RA Strickland A , et al . Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice. Brain 2016; 139 : 3092–3108.27797810
117 Liu W Ye J Yan H. Investigation of key genes and pathways in inhibition of oxycodone on vincristine-induced microglia activation by using bioinformatics analysis. Dis Markers 2019; 2019 : 3521746.30881521
118 Kane RC Bross PF Farrell AT , et al . Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 2003; 8 : 508–513.14657528
119 Richardson PG Barlogie B Berenson J , et al . A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348 : 2609–2617.12826635
120 Martin TG. Peripheral neuropathy experience in patients with relapsed and/or refractory multiple myeloma treated with carfilzomib. Oncology (Williston Park) 2013; 27 (Suppl. 3 ): 4–10.25184230
121 Kumar SK Berdeja JG Niesvizky R , et al . Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including ixazomib maintenance. Leukemia 2019; 33 : 1736–1746.30696949
122 Hu B Zhou Q Wu T , et al . Efficacy and safety of subcutaneous versus intravenous bortezomib in multiple myeloma: a meta-analysis. Int J Clin Pharmacol Ther 2017; 55 : 329–338.28079515
123 Nunes AT Annunziata CM . Proteasome inhibitors: structure and function. Semin Oncol 2017; 44 : 377–380.29935898
124 Pero ME Meregalli C Qu X , et al . Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy. Proc Natl Acad Sci U S A 2021; 118 : e2012685118.
125 Cavaletti G Gilardini A Canta A , et al . Bortezomib-induced peripheral neurotoxicity: a neurophysiological and pathological study in the rat. Exp Neurol 2007; 204 : 317–325.17214983
126 Carozzi VA Renn CL Bardini M , et al . Bortezomib-induced painful peripheral neuropathy: an electrophysiological, behavioral, morphological and mechanistic study in the mouse. PLoS One 2013; 8 : e72995.
127 Staff NP Podratz JL Grassner L , et al . Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons. Neurotoxicology 2013; 39 : 124–131.24035926
128 Landowski TH Megli CJ Nullmeyer KD , et al . Mitochondrial-mediated disregulation of Ca2+ is a critical determinant of Velcade (PS-341/bortezomib) cytotoxicity in myeloma cell lines. Cancer Res 2005; 65 : 3828–3836.15867381
129 Zheng H Xiao WH Bennett GJ. Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy. Exp Neurol 2012; 238 : 225–234.22947198
130 Alé A Bruna J Calls A , et al . Inhibition of the neuronal NFκB pathway attenuates bortezomib-induced neuropathy in a mouse model. Neurotoxicology 2016; 55 : 58–64.27211850
131 Zhao W Wang W Li X , et al . Peripheral neuropathy following bortezomib therapy in multiple myeloma patients: association with cumulative dose, heparanase, and TNF-α. Ann Hematol 2019; 98 : 2793–2803.31650289
132 Broyl A Corthals SL Jongen JL , et al . Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol 2010; 11 : 1057–1065.20864405
133 Morawska M Grzasko N Kostyra M , et al . Therapy-related peripheral neuropathy in multiple myeloma patients. Hematol Oncol 2015; 33 : 113–119.
134 Wechalekar AD Chen CI Sutton D , et al . Intermediate dose thalidomide (200 mg daily) has comparable efficacy and less toxicity than higher doses in relapsed multiple myeloma. Leuk Lymphoma 2003; 44 : 1147–1149.12916866
135 Zaja̦czkowska R Kocot-Kȩpska M Leppert W , et al . Mechanisms of chemotherapy-induced peripheral neuropathy. Int J Mol Sci 2019; 20 : 1451.30909387
136 Fernyhough P Smith DR Schapansky J , et al . Activation of nuclear factor-kappaB via endogenous tumor necrosis factor alpha regulates survival of axotomized adult sensory neurons. J Neurosci 2005; 25 : 1682–1690.15716404
137 Shepherd FA Latreille J Crump M , et al . Phase I study of paclitaxel (Taxol) and ifosfamide in previously untreated patients with advanced non-small-cell lung cancer. A study of the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol 1996; 7 : 311–313.8740797
138 Patel SR Vadhan-Raj S Papadopolous N , et al . High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies – dose–response and schedule dependence. J Clin Oncol 1997; 15 : 2378–2384.9196153
139 Loprinzi CL Lacchetti C Bleeker J , et al . Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: ASCO guideline update. J Clin Oncol 2020; 38 : 3325–3348.32663120
140 Zhu J Carozzi VA Reed N , et al . Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity. Sci Rep 2016; 6 : 28861.27350330
141 Areti A Komirishetty P Kumar A. Carvedilol prevents functional deficits in peripheral nerve mitochondria of rats with oxaliplatin-evoked painful peripheral neuropathy. Toxicol Appl Pharmacol 2017; 322 : 97–103.28286117
142 Areti A Komirishetty P Akuthota M , et al . Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy. J Pineal Res 2017; 62 : e12393.
143 Waseem M Sahu U Salman M , et al . Melatonin pre-treatment mitigates SHSY-5Y cells against oxaliplatin induced mitochondrial stress and apoptotic cell death. PLoS One 2017; 12 : e0180953.
144 Hsieh MC Lai CY Lin LT , et al . Melatonin relieves paclitaxel-induced neuropathic pain by regulating pNEK2-dependent epigenetic pathways in DRG neurons. ACS Chem Neurosci 2023; 14 : 4227–4239.37978917
145 Bankar G Goodchild SJ Howard S , et al . Selective Na(V)1.7 antagonists with long residence time show improved efficacy against inflammatory and neuropathic pain. Cell Rep 2018; 24 : 3133–3145.30231997
146 Canta A Chiorazzi A Pozzi E , et al . Calmangafodipir reduces sensory alterations and prevents intraepidermal nerve fibers loss in a mouse model of oxaliplatin induced peripheral neurotoxicity. Antioxidants (Basel) 2020; 9 : 594.32645985
147 Glimelius B Manojlovic N Pfeiffer P , et al . Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx(®)): a placebo-controlled randomised phase II study (PLIANT). Acta Oncol 2018; 57 : 393–402.29140155
148 Karlsson JOG Jynge P Ignarro LJ. Exacerbated neuropathy in POLAR A and M trials due to redox interaction of PledOx-associated Mn(2+) and oxaliplatin-associated Pt(2). Antioxidants (Basel) 2023; 12 : 608.36978857
149 Pfeiffer P Lustberg M Näsström J , et al . Calmangafodipir for prevention of oxaliplatin-induced peripheral neuropathy: two placebo-controlled, randomized phase 3 studies (POLAR-A/POLAR-M). JNCI Cancer Spectr 2022; 6 : pkac075.
150 Agnes JP Santos VWD das Neves RN , et al . Antioxidants improve oxaliplatin-induced peripheral neuropathy in tumor-bearing mice model: role of spinal cord oxidative stress and inflammation. J Pain 2021; 22 : 996–1013.33774154
151 Park SA Choi KS Bang JH , et al . Cisplatin-induced apoptotic cell death in mouse hybrid neurons is blocked by antioxidants through suppression of cisplatin-mediated accumulation of p53 but not of Fas/Fas ligand. J Neurochem 2000; 75 : 946–953.10936175
152 Bondad N Boostani R Barri A , et al . Protective effect of N-acetylcysteine on oxaliplatin-induced neurotoxicity in patients with colorectal and gastric cancers: a randomized, double blind, placebo-controlled, clinical trial. J Oncol Pharm Pract 2020; 26 : 1575–1582.32063109
153 Cascinu S Catalano V Cordella L , et al . Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2002; 20 : 3478–3483.12177109
154 Khalefa HG Shawki MA Aboelhassan R , et al . Evaluation of the effect of N-acetylcysteine on the prevention and amelioration of paclitaxel-induced peripheral neuropathy in breast cancer patients: a randomized controlled study. Breast Cancer Res Treat 2020; 183 : 117–125.32601973
155 Leal AD Qin R Atherton PJ , et al . North Central Cancer Treatment Group/Alliance trial N08CA – the use of glutathione for prevention of paclitaxel/carboplatin-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled study. Cancer 2014; 120 : 1890–1897.24619793
156 Wadia RJ Stolar M Grens C , et al . The prevention of chemotherapy induced peripheral neuropathy by concurrent treatment with drugs used for bipolar disease: a retrospective chart analysis in human cancer patients. Oncotarget 2018; 9 : 7322–7331.29484113
157 Najafi S Heidarali Z Rajabi M , et al . Lithium and preventing chemotherapy-induced peripheral neuropathy in breast cancer patients: a placebo-controlled randomized clinical trial. Trials 2021; 22 : 835.34819131
158 Huehnchen P Bangemann N Lischewski S , et al . Rationale and design of the prevention of paclitaxel-related neurological side effects with lithium trial – protocol of a multicenter, randomized, double-blind, placebo-controlled proof-of-concept phase-2 clinical trial. Front Med (Lausanne) 2022; 9 : 967964.36035422
159 Youn Y Hellman A Walling I , et al . High-intensity ultrasound treatment for vincristine-induced neuropathic pain. Neurosurgery 2018; 83 : 1068–1075.29438546
160 Hellman A Maietta T Byraju K , et al . Low intensity focused ultrasound modulation of vincristine induced neuropathy. Neuroscience 2020; 430 : 82–93.32032575
161 Chapman KB Groenen PS van Helmond N. Dorsal root ganglion stimulation to treat chemotherapy-induced peripheral neuropathy: a case report. Neuromodulation 2019; 20 : e198.
162 Groenen PS van Helmond N Chapman KB. Chemotherapy-induced peripheral neuropathy treated with dorsal root ganglion stimulation. Pain Med 2019; 20 : 857–859.30412243
163 Finney J Helm E. (462) Dorsal root ganglion stimulation for chemotherapy-induced peripheral neuropathy: a case report. J Pain 2017; 18 : S89.
164 Grabnar M Kim C. Dorsal root ganglion stimulation for chemotherapy-induced neuropathy. Am J Phys Med Rehabil 2021; 100 : e52–e54.
165 Rao J Chiravuri S. A complication of dorsal root ganglion stimulation. Pain Med 2019; 20 : 635.
166 Sindhi V Hillegass M. Penile lymphoma in a 23-year-old male complicated with neuropathic genital pain treated with sacral neuromodulation. Neuromodulation 2021; 23 : e127.
167 Yelle MD Carter J. Dorsal root ganglion stimulation in the treatment of medically refractory drug-induced painful peripheral neuropathy. Neuromodulation Technol Neural Interface 2017; 20 : e213–e214.
168 Ahmadi PA Ali BM Fotovat-Ahmadi P , et al . Dorsal root ganglion (DRG) stimulator trial eradicates phantom limb syndrome and chemotherapy-induced peripheral neuropathy: a case report. PM&R 2022; 14 : S144–S145 (conference abstract).
169 Yadav N Philip FA Gogia V , et al . Radio frequency ablation in drug resistant chemotherapy-induced peripheral neuropathy: a case report and review of literature. Indian J Palliat Care 2010; 16 : 48–51.20859472
170 Reyad RM Ghobrial HZ Shaker EH , et al . Modified technique for thermal radiofrequency ablation of thoracic dorsal root ganglia under combined fluoroscopy and CT guidance: a randomized clinical trial. BMC Anesthesiol 2019; 19 : 234.31852438
171 Dorsey SG Kleckner IR Barton D , et al . The National Cancer Institute clinical trials planning meeting for prevention and treatment of chemotherapy-induced peripheral neuropathy. J Natl Cancer Inst 2019; 111 : 531–537.30715378
