Model Of Chemotherapy-induced Peripheral Neuropathy Research Articles

Downregulation of metallothionein-2 contributes to oxaliplatin-induced neuropathic pain

BackgroundWe previously reported a correlation between small doses of oxaliplatin penetrating onto the spinal cord and acute pain after chemotherapy. Here, we propose that MT2 within the spinal dorsal horns participates in the development of oxaliplatin-induced neuropathic pain and may be a pharmacological target for the prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN).MethodsThe rat model of CIPN was established by 5 consecutive injections of oxaliplatin (0.4 mg/100 g/day). Genetic restoration of neuron-specific metallothionein-2 was implemented 21 days before oxaliplatin treatment, and also, genetic inhibition by metallothionein-2 siRNA was performed. Mechanical allodynia and locomotor activity were assayed. Cell-specific expression of metallothionein-2, the mRNA levels of pro-inflammatory cytokines, nuclear translocation of NF-κB, the protein levels of expression of IκB-α, and interaction between IκB-α and P65 were evaluated in the spinal dorsal horns. Also, in vitro interaction of sequentially deleted IκB-α promoter with metallothionein-2 was used to assess the signal transduction mechanism.ResultsWe found that oxaliplatin induced downregulation of metallothionein-2 in rat spinal cord neurons. By contrast, genetic restoration of metallothionein-2 in the spinal dorsal horn neuron blocked and reversed neuropathic pain in oxaliplatin-treated rats of both sexes, whereas genetic inhibition of metallothionein-2 triggered neuropathic pain in normal rats. Overall locomotor activity was not impaired after the genetic alterations of metallothionein-2. At the molecular level, metallothionein-2 modulated oxaliplatin-induced neuroinflammation, activation of NF-κB, and inactive transcriptional expression of IκB-α promoter, and these processes could be blocked by genetic restoration of metallothionein-2 in the spinal dorsal horn neurons.ConclusionsMetallothionein-2 is a potential target for the prevention and treatment of CIPN. A reduction of NF-κB activation and inflammatory responses by enhancing the transcription of IκB-α promoter is proposed in the mechanism.

Cilostazol is an effective causal therapy for preventing paclitaxel-induced peripheral neuropathy by suppression of Schwann cell dedifferentiation

Chemotherapy-induced peripheral neuropathy (CIPN) can lead to discontinuation of chemotherapy and is consequently a serious impediment to effective cancer treatment. Due to our limited understanding of mechanisms underlying the pathogenesis of CIPN, no causal therapy has been approved for relief of this condition. We previously demonstrated that taxanes (paclitaxel and docetaxel) induce Schwann cell dedifferentiation, characterized by increased expression of p75 and galectin-3, ultimately leading to demyelination. These changes appear to be responsible for CIPN pathogenesis. This study was designed to identify a novel candidate therapeutic for CIPN with the ability to suppress paclitaxel-induced Schwann cell dedifferentiation. Given that elevation of cyclic adenosine monophosphate (cAMP) signaling participates in Schwann cell differentiation, we performed immunocytochemical screening of phosphodiesterase (PDE) inhibitors. We found that the PDE3 inhibitor cilostazol strongly promoted differentiation of primary cultures of rat Schwann cells via a mechanism involving cAMP/exchange protein directly activated by cAMP (Epac) signaling. Co-treatment with cilostazol prevented paclitaxel-induced dedifferentiation of Schwann cell cultures and demyelination in a mixed culture of Schwann cells and dorsal root ganglia neurons. Notably, continuous oral administration of cilostazol suppressed Schwann cell dedifferentiation within the sciatic nerve and the development of mechanical hypersensitivity in a mouse model of paclitaxel-related CIPN. Importantly, cilostazol potentiated, rather than inhibited, the anti-cancer effect of paclitaxel on the human breast cancer cell line MDA-MB-231. These findings highlight the potential utility of cilostazol as a causal therapeutic that avoids the development of paclitaxel-related CIPN without compromising anti-cancer properties.

Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy.

Peripheral neuropathies are characterized by nerves damage and axonal loss, and they could be classified in hereditary or acquired forms. Acquired peripheral neuropathies are associated with several causes, including toxic agent exposure, among which the antineoplastic compounds are responsible for the so called Chemotherapy-Induced Peripheral Neuropathy (CIPN). Several clinical features are related to the use of anticancer drugs which exert their action by affecting different mechanisms and structures of the peripheral nervous system: the axons (axonopathy) or the dorsal root ganglia (DRG) neurons cell body (neuronopathy/ganglionopathy). In addition, antineoplastic treatments may affect the blood brain barrier integrity, leading to cognitive impairment that may be severe and long-lasting. CIPN may affect patient quality of life leading to modification or discontinuation of the anticancer therapy. Although the mechanisms of the damage are not completely understood, several hypotheses have been proposed, among which neuroinflammation is now emerging to be relevant in CIPN pathophysiology. In this review, we consider different aspects of neuro-immune interactions in several CIPN preclinical studies which suggest a critical connection between chemotherapeutic agents and neurotoxicity. The features of the neuroinflammatory processes may be different depending on the type of drug (platinum derivatives, taxanes, vinca alkaloids and proteasome inhibitors). In particular, recent studies have demonstrated an involvement of the immune response (both innate and adaptive) and the stimulation and secretion of mediators (cytokines and chemokines) that may be responsible for the painful symptoms, whereas glial cells such as satellite and Schwann cells might contribute to the maintenance of the neuroinflammatory process in DRG and axons respectively. Moreover, neuroinflammatory components have also been shown in the spinal cord with microglia and astrocytes playing an important role in CIPN development. Taking together, better understanding of these aspects would permit the development of possible strategies in order to improve the management of CIPN.

SARM1 is required in human derived sensory neurons for injury-induced and neurotoxic axon degeneration

Axonal degeneration contributes to the pathogenesis of many neurodegenerative disorders, motivating efforts to dissect the mechanism of pathological axon loss in order to develop therapies for axonal preservation. SARM1 is a particularly attractive therapeutic target, as it is an inducible NAD+ cleaving enzyme that is required for axon loss in multiple mouse models of traumatic and degenerative neurological disease. However, it is essential to establish whether SARM1 triggers axon degeneration in human neurons before proceeding with the development of SARM1-directed therapeutics. Here we combine genome engineering with the production of human stem cell-derived neurons to test the role of human SARM1 in traumatic and neurotoxic axon degeneration. We have generated two independent SARM1 knockout human iPSC lines that do not express SARM1 protein upon differentiation into neurons. We have developed a modified sensory neuron differentiation protocol that generates human sensory neurons with high yield and purity. We find that SARM1 is required for axon degeneration in response to both physical trauma and in a cellular model of chemotherapy-induced peripheral neuropathy. Finally, we identify cADPR as a biomarker of SARM1 enzyme activity in both healthy and injured human sensory neurons. These findings are consistent with prior molecular and cellular studies in mouse neurons, and highlight the therapeutic potential of SARM1 inhibition for the prevention and treatment of human neurological disease.

Protection against oxaliplatin-induced mechanical and thermal hypersensitivity in Sarm1−/− mice

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of cancer treatment, often associated with degeneration of sensory axons or their terminal regions. Presence of the slow Wallerian degeneration protein (WLDS), or genetic deletion of sterile alpha and TIR motif containing protein 1 (SARM1), which strongly protect axons from degeneration after injury or axonal transport block, alleviate pain in several CIPN models. However, oxaliplatin can cause an acute pain response, suggesting a different mechanism of pain generation. Here, we tested whether the presence of WLDS or absence of SARM1 protects against acute oxaliplatin-induced pain in mice after a single oxaliplatin injection. In BL/6 and WldS mice, oxaliplatin induced significant mechanical and cold hypersensitivities which were absent in Sarm1−/− mice. Despite the presence of hypersensitivity there was no significant loss of intraepidermal nerve fibers (IENFs) in the footpads of any mice after oxaliplatin treatment, suggesting that early stages of pain hypersensitivity could be independent of axon degeneration. To identify other changes that could underlie the pain response, RNA sequencing was carried out in DRGs from treated and control mice of each genotype. Sarm1−/− mice had fewer gene expression changes than either BL/6 or WldS mice. This is consistent with the pain measurements in demonstrating that Sarm1−/− DRGs remain relatively unchanged after oxaliplatin treatment, unlike those in BL/6 and WldS mice. Changes in levels of four transcripts – Alas2, Hba-a1, Hba-a2, and Tfrc – correlated with oxaliplatin-induced pain, or absence thereof, across the three genotypes. Our findings suggest that targeting SARM1 could be a viable therapeutic approach to prevent oxaliplatin-induced acute neuropathic pain.

Herbal Decoction Divya-Peedantak-Kwath Alleviates Allodynia and Hyperalgesia in Mice Model of Chemotherapy-Induced Peripheral Neuropathy via Modulation in Cytokine Response.

The widely used cancer treatment, chemotherapy, causes severe long-term neuropathic pain in 30–40% cases, the condition clinically known as chemotherapy-induced peripheral neuropathy (CIPN). Approved conventional analgesics are sometimes ineffective, while others like opioids have undesirable side effects like addiction, seizures, and respiratory malfunctioning. Tricyclic antidepressants and anticonvulsants, although exhibit anti-allodynic effects in neuropathy, also have unpleasant side effects. Thus, alternative medicines are being explored for CIPN treatment. Despite scattered reports on different extracts from different plants having potential anti-allodynic effects against CIPN, no established medicine or formulation of herbal origin exists. In this study, efficacy of an herbal decoction, formulated based on ancient medicinal principles and protocols for treating neuropathic pain, Divya-Peedantak-Kwath (DPK), has been evaluated in a paclitaxel (PTX)-induced peripheral neuropathic mouse model. We observed that DPK has prominent anti-allodynic and anti-hyperalgesic effects and acts as a nociceptive modulator for CIPN. With exhibited antioxidative effects, DPK restored the redox potential of the sciatic nerves to the normal. On histopathological evaluation, DPK prevented the PTX-induced lesions in the sciatic nerve, in a dose-dependent manner. It also prevented inflammation by modulating the levels of pro-inflammatory cytokines involved in CIPN pathogenesis. Our observations evinced that DPK can alleviate CIPN by attenuating oxidative stress and concomitant neuroinflammation through immune modulation.

Prokineticin Receptor Inhibition With PC1 Protects Mouse Primary Sensory Neurons From Neurotoxic Effects of Chemotherapeutic Drugs in vitro.

Neurotoxicity is a common side effect of chemotherapeutics that often leads to the development of chemotherapy-induced peripheral neuropathy (CIPN). The peptide Prokineticin 2 (PK2) has a key role in experimental models of CIPN and can be considered an insult-inducible endangering mediator. Since primary afferent sensory neurons are highly sensitive to anticancer drugs, giving rise to dysesthesias, the aim of our study was to evaluate the alterations induced by vincristine (VCR) and bortezomib (BTZ) exposure in sensory neuron cultures and the possible preventive effect of blocking PK2 signaling. Both VCR and BTZ induced a concentration-dependent reduction of total neurite length that was prevented by the PK receptor antagonist PC1. Antagonizing the PK system also reduced the upregulation of PK2, PK-R1, TLR4, IL-6, and IL-10 expression induced by chemotherapeutic drugs. In conclusion, inhibition of PK signaling with PC1 prevented the neurotoxic effects of chemotherapeutics, suggesting a promising strategy for neuroprotective therapies against the sensory neuron damage induced by exposure to these drugs.

Therapeutic and Preventive Effects of TRK-700 in Rat Models of Chemotherapy-induced Peripheral Neuropathy (CIPN).

Therapeutic and Preventive Effects of TRK-700 in Rat Models of Chemotherapy-induced Peripheral Neuropathy (CIPN).

A Chemotherapy-Induced Peripheral Neuropathy Model in Drosophila melanogaster.

Peripheral neuropathies are one of the largest categories of neurodegenerative diseases. To investigate their mechanisms, many in vitro and in vivo models can be employed. Here we present a protocol for the induction of chemotherapy-induced peripheral neuropathy (CIPN) in the Drosophila melanogaster (fruit fly) model system. Using a clinically relevant degeneration initiator, paclitaxel (taxol), it is possible to model many aspects of axon and dendrite degeneration while in a genetically tractable, in vivo system. In this protocol, we feed larval stage Drosophila neurotoxic chemotherapy drugs during the duration of larval development, followed by dissection and imaging of genetically labeled sensory axons and dendrites. Both axons and dendrites degenerate with taxol exposure. Our protocol should facilitate the adoption and expansion of this model to include other neurotoxic compounds.

P.121 Comparison the analgesic effect of bromhexine and ambroxol in the oxaliplatin model of chemotherapy-induced peripheral neuropathy

P.121 Comparison the analgesic effect of bromhexine and ambroxol in the oxaliplatin model of chemotherapy-induced peripheral neuropathy

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.

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of chemotherapeutics. The mechanisms of CIPN remain substantially unidentified, although inflammation-induced peripheral sensitization has been indicated as an important factor. Here, we aimed to illustrate the role of the matrix metalloproteinase (MMP)-9-related signaling pathway in the process of CIPN. Oxaliplatin (L-OHP) was administered to mice to establish the CIPN model. Gelatin zymography was used to measure MMP-9/2 activities. Western blotting and immunohistochemistry were used to measure the expression of high-mobility group box-1 (HMGB-1), calcitonin gene-related peptide and ionized calcium-binding adapter molecule 1. Mechanical withdrawal was measured by von Frey hairs testing. Raw 264.7 cells and SH-SY5Y cells were cultured to investigate cell signaling in vitro. Here, we report that L-OHP-induced mechanical pain in mice with significant MMP-9/2 activation in dorsal root ganglion (DRG) neurons. MMP-9 inhibition or knockout alleviated the occurrence of CIPN directly. MMP-9/2 were released from macrophages and neurons in the DRG via the HMGB-1-toll-like receptor 4 (TLR4)-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) axis, because MMP-9/2 activities could be reduced by macrophage scavengers or PI3Kγ knockout in CIPN mice. The in vitro data revealed that induced MMP-9 activity by recombinant HMGB-1 could be abolished by TLR4, PI3K or Akt inhibitors. Finally, it was shown that N-acetyl-cysteine (NAC) could reduce MMP-9/2 activities and attenuate CIPN effectively and safely. The HMGB-1-TLR4-PI3K/Akt-MMP-9 axis is involved in the crosstalk between macrophages and neurons in the pathological process of CIPN in mice. Direct inhibition of MMP-9 by NAC may be a potential therapeutic regimen for CIPN treatment.

Nerve conduction assessments detect early changes in sensory and motor nerve function in a preclinical mouse model of chemotherapy-induced peripheral neuropathy (CIPN)

Nerve conduction assessments detect early changes in sensory and motor nerve function in a preclinical mouse model of chemotherapy-induced peripheral neuropathy (CIPN)

Voluntary exercise reduces both chemotherapy-induced neuropathic nociception and deficits in hippocampal cellular proliferation in a mouse model of paclitaxel-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side-effect of all major chemotherapeutic agents. Here, we explored efficacy of voluntary exercise as a nonpharmacological strategy for suppressing two distinct adverse side effects of chemotherapy treatment. We evaluated whether voluntary running would suppress both neuropathic pain and deficits in hippocampal cell proliferation in a mouse model of CIPN induced by the taxane chemotherapeutic agent paclitaxel. Mice were given free access to running wheels or were housed without running wheels during one of three different intervention phases: 1) during the onset (i.e. development phase) of paclitaxel-induced neuropathy, 2) prior to dosing with paclitaxel or its vehicle, or 3) following the establishment (i.e. maintenance phase) of paclitaxel-induced neuropathy. Paclitaxel treatment did not alter running wheel behavior relative to vehicle-treated animals in any study. Animals that engaged in voluntary running during the development phase of paclitaxel-induced neuropathy failed to display mechanical or cold hypersensitivities relative to sedentary control animals that did not have access to running wheels. A prior history of voluntary running delayed the onset of, but did not fully prevent, development of paclitaxel-induced neuropathic pain behavior. Voluntary running reduced already established mechanical and cold allodynia induced by paclitaxel. Importantly, voluntary running did not alter mechanical or cold responsivity in vehicle-treated animals, suggesting that the observed antinociceptive effect of exercise was dependent upon the presence of the pathological pain state. In the same animals evaluated for nociceptive responding, paclitaxel also reduced cellular proliferation but not cellular survival in the dentate gyrus of the hippocampus, as measured by immunohistochemistry for Ki67 and BrdU expression, respectively. Voluntary running abrogated paclitaxel-induced reductions in cellular proliferation to levels observed in vehicle-treated mice and also increased BrdU expression levels irrespective of chemotherapy treatment. Our studies support the hypothesis that voluntary exercise may be beneficial in suppressing both neuropathic pain and markers of hippocampal cellular function that are impacted by toxic challenge with chemotherapeutic agents.

A Comparative Review of Chemotherapy-Induced Peripheral Neuropathy in In Vivo and In Vitro Models.

Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse effect caused by several classes of widely used anticancer therapeutics. Chemotherapy-induced peripheral neuropathy frequently leads to dose reduction or discontinuation of chemotherapy regimens, and CIPN symptoms can persist long after completion of chemotherapy and severely diminish the quality of life of patients. Differences in the clinical presentation of CIPN by widely diverse classifications of anticancer agents have spawned multiple mechanistic hypotheses that seek to explain the pathogenesis of CIPN. Despite its clinical relevance, common occurrence, and extensive investigation, the pathophysiology of CIPN remains unclear. Furthermore, there is no unequivocal gold standard for the prevention and treatment of CIPN. Herein, we review in vivo and in vitro models of CIPN with a focus on histopathological changes and morphological features aimed at understanding the pathophysiology of CIPN and identify gaps requiring deeper exploration. An elucidation of the underlying mechanisms of CIPN is imperative to identify potential targets and approaches for prevention and treatment.

P38/TF/HIF-α Signaling Pathway Participates in the Progression of CIPN in Mice

Chemotherapy induced peripheral neuropathy (CIPN) is a serious adverse effect of chemotherapeutics with limited pathogenetic mechanism been known. Whether microcirculatory disturbance is involved in CIPN has not been reported. Considering that tissue factor (TF) is an endogenous coagulation factor, we hypothesize CIPN may be induced by the high expression of TF in macrophages and sciatic nerve, which induces the molecular signal related to ischemia and hypoxia. Oxaliplatin (L-OHP) was used to establish CIPN model. Von Frey Hairs was used to measure nociception. The murine macrophage cell line Raw 264.7 was used for cell experiments. Gelatin zymography and western blotting were used to measure the activity or expression of protein. TF expression and MMP-9/2 activity in sciatic nerve and blood are significantly increased by L-OHP. L-OHP increased the release of HSP70 from macrophage and enhanced the expression of p-p38 and HIF-1α in vivo and in vitro. Hirudin significantly suppressed the overexpression of p38, HIF-1α and activation of MMP-9/2 induced by L-OHP and attenuated CIPN in mice. This study suggests that a novel HSP70-TLR-4-p38-TF-HIF-1a axis may play a pivotal role in the pathological process of CIPN. It is also shown that the use of anticoagulant Hirudin can inhibit the above mechanisms and improve CIPN.

Therapeutic benefits of maintaining mitochondrial integrity and calcium homeostasis by forced expression of Hsp27 in chemotherapy-induced peripheral neuropathy

BackgroundVincristine, a widely used antineoplastic agent, is known to be neurotoxic and to lead to chemotherapy-induced peripheral neuropathy (CIPN), which is characterized by nerve damage. Growing evidence suggests that disruption of intracellular calcium homeostasis in peripheral neurons contributes largely to the pathological conditions of CIPN. Our previous study showed that forced expression of a peripheral nerve injury-induced small heat shock protein (Hsp), Hsp27, accelerates axon regeneration and functional recovery. In the current study, we examined whether neuronal expression of human Hsp27 (hHsp27) can prevent the inhibitory effects of vincristine in two mouse models of peripheral nerve injury, namely, sciatic nerve crush and CIPN. MethodsThe protective effects of hHsp27 against vincristine were examined in mouse models of both sciatic nerve crush and CIPN using multiple approaches, including animal behavioral tests, histology, electrophysiology, transmission electron microscopy and calcium imaging. ResultsVincristine delayed functional recovery in littermate mice; however, hHsp27 Tg mice were unaffected after vincristine treatment and sciatic nerve crush. In CIPN mice, hHsp27 protected against vincristine-induced mechanical and cold allodynia by preventing axonal degeneration, demyelination, mitochondrial dysfunction, and apoptosis. Strikingly, vincristine-induced calcium influx was markedly attenuated in sensory neurons of hHsp27 Tg mice. ConclusionsOur findings suggest that preserving myelin and mitochondrial integrity as well as maintaining intracellular calcium homeostasis is beneficial for preventing CIPN, and these findings shed new light on the development of anti-CIPN drugs.

Animal models of chemotherapy-induced peripheral neuropathy: A machine-assisted systematic review and meta-analysis.

We report a systematic review and meta-analysis of research using animal models of chemotherapy-induced peripheral neuropathy (CIPN). We systematically searched 5 online databases in September 2012 and updated the search in November 2015 using machine learning and text mining to reduce the screening for inclusion workload and improve accuracy. For each comparison, we calculated a standardised mean difference (SMD) effect size, and then combined effects in a random-effects meta-analysis. We assessed the impact of study design factors and reporting of measures to reduce risks of bias. We present power analyses for the most frequently reported behavioural tests; 337 publications were included. Most studies (84%) used male animals only. The most frequently reported outcome measure was evoked limb withdrawal in response to mechanical monofilaments. There was modest reporting of measures to reduce risks of bias. The number of animals required to obtain 80% power with a significance level of 0.05 varied substantially across behavioural tests. In this comprehensive summary of the use of animal models of CIPN, we have identified areas in which the value of preclinical CIPN studies might be increased. Using both sexes of animals in the modelling of CIPN, ensuring that outcome measures align with those most relevant in the clinic, and the animal’s pain contextualised ethology will likely improve external validity. Measures to reduce risk of bias should be employed to increase the internal validity of studies. Different outcome measures have different statistical power, and this can refine our approaches in the modelling of CIPN.

Knockdown siRNA Targeting the Mitochondrial Sodium-Calcium Exchanger-1 Inhibits the Protective Effects of Two Cannabinoids Against Acute Paclitaxel Toxicity.

Treatment with cannabidiol (CBD) or KLS-13019 (novel CBD analog), has previously been shown to prevent paclitaxel-induced mechanical allodynia in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). The mechanism of action for CBD- and KLS-13019-mediated protection now has been explored with dissociated dorsal root ganglion (DRG) cultures using small interfering RNA (siRNA) to the mitochondrial Na+ Ca2+ exchanger-1 (mNCX-1). Treatment with this siRNA produced a 50-55% decrease in the immunoreactive (IR) area for mNCX-1 in neuronal cell bodies and a 72-80% decrease in neuritic IR area as determined with high-content image analysis. After treatment with 100nM KLS-13019 and siRNA, DRG cultures exhibited a 75 ± 5% decrease in protection from paclitaxel-induced toxicity; whereas siRNA studies with 10μM CBD produced a 74 ± 3% decrease in protection. Treatment with mNCX-1 siRNA alone did not produce toxicity. The protective action of cannabidiol and KLS-13019 against paclitaxel-induced toxicity during a 5-h test period was significantly attenuated after a 4-day knockdown of mNCX-1 that was not attributable to toxicity. These data indicate that decreases in neuritic mNCX-1 corresponded closely with decreased protection after siRNA treatment. Pharmacological blockade of mNCX-1 with CGP-37157 produced complete inhibition of cannabinoid-mediated protection from paclitaxel in DRG cultures, supporting the observed siRNA effects on mechanism.

Searching for analgesic drug candidates alleviating oxaliplatin-induced cold hypersensitivity in mice.

Oxaliplatin is a third-generation, platinum-based derivative used to treat advanced colorectal cancer. Within the patient population on oxaliplatin therapy, a lower incidence of hematological adverse effects and gastrointestinal toxicity is noted, but severe neuropathic pain episodes characterized by increased cold and tactile hypersensitivity are present in ~95% of patients. This drug is also used to induce a rodent model of chemotherapy-induced peripheral neuropathy (CIPN)-related neuropathic pain which is widely used in the search for novel therapies for CIPN prevention and treatment. This paper provides a step-by-step, detailed description of the prevention and intervention protocols used in our laboratory for the assessment of oxaliplatin-induced cold allodynia in mice. To establish cold sensitivity in mice, the cold plate test was used. Latencies to pain reaction in response to cold stimulus (2.5°C) for vehicle-treated non-neuropathic mice, vehicle-treated mice injected with oxaliplatin (neuropathic control), and oxaliplatin-treated mice treated additionally with duloxetine are compared. Duloxetine is a serotonin/noradrenaline reuptake inhibitor which was found to produce significant pain relief in patients with CIPN symptoms. In our present study, duloxetine administered intraperitoneally at the dose of 30mg/kg served as a model antiallodynic drug which attenuated or partially prevented cold allodynia caused by oxaliplatin.

Medicinal plants and their isolated phytochemicals for the management of chemotherapy-induced neuropathy: therapeutic targets and clinical perspective.

Chemotherapy, as one of the main approaches of cancer treatment, is accompanied with several adverse effects, including chemotherapy-induced peripheral neuropathy (CIPN). Since current methods to control the condition are not completely effective, new treatment options should be introduced. Medicinal plants can be suitable candidates to be assessed regarding their effects in CIPN. Current paper reviews the available preclinical and clinical studies on the efficacy of herbal medicines in CIPN. Electronic databases including PubMed, Scopus, and Cochrane library were searched with the keywords "neuropathy" in the title/abstract and "plant", "extract", or "herb" in the whole text. Data were collected from inception until April 2018. Plants such as chamomile (Matricaria chamomilla L.), sage (Salvia officinalis L.), cinnamon (Cinnamomum cassia (L.) D. Don), and sweet flag (Acorus calamus L.) as well as phytochemicals like matrine, curcumin, and thioctic acid have demonstrated beneficial effects in animal models of CIPN via prevention of axonal degeneration, decrease in total calcium level, improvement of endogenous antioxidant defense mechanisms such as superoxide dismutase and reduced glutathione, and regulation of neural cell apoptosis, nuclear factor-ĸB, cyclooxygenase-2, and nitric oxide signaling. Also, five clinical trials have evaluated the effect of herbal products in patients with CIPN. There are currently limited clinical evidence on medicinal plants for CIPN which shows the necessity of future mechanistic studies, as well as well-designed clinical trial for further confirmation of the safety and efficacy of herbal medicines in CIPN. Graphical abstract Schematic mechanisms of medicinal plants to prevent chemotherapy-induced neuropathy: NO: nitric oxide, TNF: tumor necrosis factor, PG: prostaglandin, NF-ĸB: nuclear factor kappa B, LPO: lipid peroxidation, ROS: reactive oxygen species, COX: cyclooxygenase, IL: interleukin, ERK: extracellular signal-related kinase, X: inhibition, ↓: induction.