Paclitaxel-induced Neuropathy Research Articles

Role of alpha-lipoic acid in counteracting paclitaxel- and doxorubicin-induced toxicities: a randomized controlled trial in breast cancer patients

Background and objectivePaclitaxel and doxorubicin are associated with neurotoxicity and cardiotoxicity respectively. This study aimed at investigating the role of alpha-lipoic acid (ALA) in counteracting paclitaxel-induced neuropathy and doxorubicin-associated cardiotoxicity in women with breast cancer.Patients and methodsThis randomized double-blind placebo-controlled prospective study included 64 patients with breast cancer who were randomized into control group (n = 32) which received 4 cycles of doxorubicin plus cyclophosphamide (every 21 days) followed by weekly doses of paclitaxel for 12 weeks plus placebo tablets once daily and ALA group (n = 32) which received the same chemotherapeutic regimen plus ALA 600 once daily for 6 months. Patients were assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.0) for grading of neuropathy and by 12-item neurotoxicity questionnaire (Ntx-12). The assessment included also echocardiography and evaluation of serum levels of brain natriuretic peptide (BNP), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), and neurotensin (NT). Data were analyzed by paired and unpaired t-test, Mann–Whitney U test, and chi-square test.ResultsAs compared to placebo, ALA provoked significant improvement in NCI-CTCAE neuropathy grading and Ntx-12 score after the end of 9th and 12th weeks of paclitaxel intake (p = 0.039, p = 0.039, p = 0.03, p = 0.004, respectively). At the end of the chemotherapy cycles, ALA resulted in significant decline in serum levels of BNP, TNF-α, MDA, and neurotensin (p < 0.05) as compared to baseline data and placebo.ConclusionAlpha-lipoic acid may represent a promising adjuvant therapy to attenuate paclitaxel-associated neuropathy and doxorubicin-induced cardiotoxicity in women with breast cancer.Trial registrationClinicalTrials.gov: NCT03908528.

Paclitaxel in vitro reversibly sensitizes the excitability of IB4(-) and IB4(+) sensory neurons from male and female rats.

Background and PurposePaclitaxel produces a chemotherapy‐induced peripheral neuropathy that persists in 50–60% of cancer patients upon treatment. Evidence from animal models suggests an axonopathy of peripheral A‐ and C‐type fibres that affects their excitability. However, direct effects of paclitaxel on sensory neuron excitability and sexual dimorphism remain poorly understood.Experimental ApproachWe used a long‐lasting (10 days in vitro) primary culture of rat dorsal root ganglion (DRG) neurons to investigate the time course effect of paclitaxel on the electrical activity of IB4(−) and IB4(+) sensory neurons of female and male adult Wistar rats.Key ResultsPaclitaxel strongly and reversibly stimulated spontaneous activity and augmented action potential tonic firing in IB4(−) and IB4(+) neurons in both sexes, peaking at 48 h post‐treatment and virtually disappearing at 96 h. Paclitaxel decreased the current rheobase for action potential firing by reducing and accelerating the after‐hyperpolarization phase. Molecularly, paclitaxel modulated Na+ and K+ ion currents. Particularly, the drug significantly augmented the function of Nav1.8, TRPV1 and TRPM8 channels. Furthermore, paclitaxel increased Nav1.8 and TRPV1 expression at 48 h post‐treatment. Notably, we observed that female DRG neurons appear more sensitive to paclitaxel sensitization than their male counterparts.Conclusions and ImplicationsOur data indicate that paclitaxel similarly potentiated IB4(−) and IB4(+) electrogenicity and uncover a potential sex dimorphism in paclitaxel‐induced chemotherapy‐induced peripheral neuropathy. Our in vitro, pre‐clinical, chemotherapy‐induced peripheral neuropathy paradigm provides a tool for studying the dynamics and underlying molecular mechanisms contributing to nociceptor sensitization in peripheral neuropathies and for testing desensitizing compounds.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Neuroendocrine Stress Axis-Dependence of Duloxetine Analgesia (Anti-Hyperalgesia) in Chemotherapy-Induced Peripheral Neuropathy

Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is the best-established treatment for painful chemotherapy-induced peripheral neuropathy (CIPN). While it is only effective in little more than half of patients, our ability to predict patient response remains incompletely understood. Given that stress exacerbates CIPN, and that the therapeutic effect of duloxetine is thought to be mediated, at least in part, via its effects on adrenergic mechanisms, we evaluated the contribution of neuroendocrine stress axes, sympathoadrenal and hypothalamic-pituitary-adrenal, to the effect of duloxetine in preclinical models of oxaliplatin- and paclitaxel-induced CIPN. Systemic administration of duloxetine, which alone had no effect on nociceptive threshold, both prevented and reversed mechanical hyperalgesia associated with oxaliplatin- and paclitaxel-CIPN. It more robustly attenuated oxaliplatin CIPN in male rats, while it was more effective for paclitaxel CIPN in females. Gonadectomy attenuated these sex differences in the effect of duloxetine. To assess the role of neuroendocrine stress axes in the effect of duloxetine on CIPN, rats of both sexes were submitted to adrenalectomy combined with fixed level replacement of corticosterone and epinephrine. While CIPN, in these rats, was of similar magnitude to that observed in adrenal-intact animals, rats of neither sex responded to duloxetine. Furthermore, duloxetine blunted an increase in corticosterone induced by oxaliplatin, and prevented the exacerbation of CIPN by sound stress. Our results demonstrate a role of neuroendocrine stress axes in duloxetine analgesia (anti-hyperalgesia) for the treatment of CIPN.SIGNIFICANCE STATEMENT Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating dose-dependent and therapy-limiting side effect of many of the cytostatic drugs used to treat cancer (Argyriou et al., 2010; Marmiroli et al., 2017). Duloxetine is the only treatment for CIPN currently recommended by the American Society of Clinical Oncology (Hershman et al., 2014). In the present study, focused on elucidating mechanisms mediating the response of oxaliplatin- and paclitaxel-induced painful peripheral neuropathy to duloxetine, we demonstrate a major contribution to its effect of neuroendocrine stress axis function. These findings, which parallel the clinical observation that stress may impact response of CIPN to duloxetine (Taylor et al., 2007), open new approaches to the treatment of CIPN and other stress-associated pain syndromes.

Nuclear PPAR-γ Activation Modulates Inflammation and Oxidative Stress in Attenuating Chemotherapy-Induced Neuropathic Pain in Vivo

Background: Paclitaxel-induced painful neuropathy is a major dose-limiting side effect and can persist for up to two years after completing treatment that greatly affects both the course of chemotherapy and quality of life in cancer patients. Peroxisome proliferator-activated receptor (PPAR)-γ belongs to a family of nuclear receptors known for their transcriptional and regulatory roles in metabolism, inflammation, and oxidative stress. However, the role of PPAR-γ activation on paclitaxel-induced neuropathic pain is not yet known.&#x0D; Objective: To investigate whether pioglitazone, a PPAR-γ agonist reduce paclitaxel-induced neuropathic pain and to elucidate underlying mechanisms.&#x0D; Methodology: Peripheral neuropathy was induced by administration of paclitaxel (2 mg/kg per injection) intraperitoneally on four alternate days (days 0, 2, 4, 6). Thermal hyperalgesia and mechanical allodynia were assessed and the markers of inflammation and nitroso-oxidative stress were estimated.&#x0D; Results: Pioglitazone did not induce hypoalgesia and had no effect on locomotor activity. Repeated oral administration of pioglitazone (10 and 20 mg/kg,) for 2 weeks started 14 days after paclitaxel injection markedly attenuated paw withdrawal responses to thermal (hyperalgesia) and mechanical (allodynia) stimuli. Further, pioglitazone administration significantly reduced elevated level of pro-inflammatory cytokine, TNF-α, in both the dorsal root ganglia and the spinal cord accompanied by marked decrease in oxidative stress parameters as well as increase in activity of antioxidant defense enzyme, superoxide dismutase, in the spinal cord after paclitaxel injection.&#x0D; Conclusion: The results of the present study demonstrate that pioglitazone, a PPAR-γ agonist exerted antinociceptive effect in paclitaxel-induced neuropathic pain through inhibiting neuroimmune inflammation in both the periphery and spinal cord and by reducing nitroso-oxidative stress in spinal cord. Our findings strongly suggest pharmacological activation of PPAR-g as a promising therapeutic target in paclitaxel-induced peripheral neuropathy and provide rationale for the clinical evaluation.

Drug-interaction between paclitaxel and goshajinkigan extract and its constituents

Paclitaxel, a standard chemotherapeutic agent for several types of cancer, including ovarian, breast, and non-small-cell lung cancer, causes peripheral neuropathy as an adverse effect in 60–70% of the patients. The utility of combination therapy with paclitaxel and goshajinkigan, a traditional Japanese Kampo medicine, in managing paclitaxel-induced neuropathy during chemotherapy has been explored. Paclitaxel is predominantly metabolized in the liver by cytochrome P450 (CYP) 2C8 to produce 6α-hydroxypaclitaxel and by CYP3A4 to produce 3′-p-hydroxypaclitaxel. In this study, we evaluated the inhibitory or inducing effects of goshajinkigan extract (GJG) and its representative and bioavailable constituents, geniposidic acid, plantagoguanidinic acid, paeoniflorin, catalpol, loganin, and neoline, on the metabolism of paclitaxel via CYP2C8 and CYP3A4 using pooled human liver microsomes and cultured human cryopreserved hepatocytes to provide the drug information about the pharmacokinetic interaction of this combination therapy. GJG significantly inhibited the production of 3’-p-hydroxypaclitaxel and 6α-hydroxypaclitaxel in vitro in a concentration-dependent manner. The half maximal inhibitory concentration (IC50) values of GJG were 4.5 and 7.8 mg/ml, respectively, for 3′-p-hydroxypaclitaxel and 6α-hydroxypaclitaxel productions. Neoline inhibited the production of 3′-p-hydroxypaclitaxel at 50 μM, but not at lower concentrations. Apart from neoline, other GJG constituents (at concentrations up to 50 or 10 μM of all test substances) did not exhibit inhibitory or inducing effects. Since GJG showed the inhibitory effect on the metabolism of paclitaxel at much higher concentrations than those used clinically, it can be concluded that GJG product does not exhibit any pharmacokinetic interaction with paclitaxel in clinical practice.Graphic abstract

Pain Relieving and Neuroprotective Effects of Non-opioid Compound, DDD-028, in the Rat Model of Paclitaxel-Induced Neuropathy

Chemotherapy-induced neuropathy (CIN) is a major dose-limiting side effect of anticancer therapy that can compel therapy discontinuation. Inadequate analgesic efficacy of current pharmacological approaches requires the identification of innovative therapeutics and, hence, the purpose of this study is to conduct a preclinical evaluation of the efficacy of DDD-028, a versatile pentacyclic pyridoindole derivative, against paclitaxel-induced neuropathic pain. In two separate experiments, DDD-028 was administered per os acutely (1–25 mg kg−1) or repeatedly (10 mg kg−1) in paclitaxel-treated rats. The response to mechanical noxious stimulus (paw pressure) as well as to non-noxious mechanical (von Frey) and thermal (cold plate) stimuli was investigated. Acute administration of DDD-028 induced a dose-dependent anti-neuropathic pain effect in all tests performed. Further, repeated daily treatment for 18 consecutive days (starting the first day of paclitaxel administration) significantly reduced the development of pain over time without the development of tolerance to the anti-hyperalgesic effect. Ex vivo analysis showed that DDD-028 was able to reduce oxidative damage of dorsal root ganglia as evidenced by the increase in the level of carbonylated proteins and the decrease in catalase activity. In the lumbar spinal cord, periaqueductal gray matter, thalamus, and somatosensory cortex 1, DDD-28 significantly prevented the activation of microglia and astrocytes. The pharmacodynamic study revealed that the pain-relieving effects of DDD-028 were fully blocked by both the non-selective nicotinic receptor (nAChR) antagonist mecamylamine and by the selective α7 nAChR antagonist methyllycaconitine. In conclusion, DDD-028 was active in reducing paclitaxel-induced neuropathic pain after single or repeated administrations without tolerance development and displaying a double symptomatic and neuroprotective profile. DDD-028 could represent a valuable candidate for the treatment of CIN.

Morphological manifestations of experimental paclitaxel-induced sciatic neuropathy under correction of 2-ethyl-6-methyl-3-hydroxypyridine succinate

Paclitaxel is an effective chemotherapeutic agent for many cancers, but it has a number of limiting side effects that not only significantly reduce the quality of life of patients, but also limit their further treatment. Peripheral neuropathy is one of these, but there are currently no proven effective druHS for the prevention or treatment of paclitaxel-induced neuropathic pain (PINP) in particular, or chemotherapy-induced peripheral neuropathy (CIPN) in general. 2-ethyl-6-methyl-3-hydroxypyridine succinate (HS) is a derivative of succinic acid with neuroprotective, antihypoxic, membrane-protective, nootropic, sedative effects.&#x0D; The aim of the study was to study the effect of the neuroprotective agent HS on the pathomorphogenesis of the sciatic nerves under conditions of paclitaxel-induced peripheral neuropathy in the experiment.&#x0D; Materials and methods. The experiment was carried out on 80 white rats, which were injected intraperitoneally with paclitaxel (Actavis, Romania), previously dissolved in isotonic saline at a dose of 2 mg / kg of body weight four times every other day until a total dose of 8 mg / kg was reached. Then forty of these animals were injected intraperitoneally with 2-ethyl-6-methyl-3-hydroxypyridine succinate at a dose of 10 mg / kg (the remaining 40 rats received intraperitoneal water for injection). Morphological studies were carried out on the first, seventh, fifteenth, twenty-eighth, sixtieth, ninetieth and one hundred and twentieth days after the last injection of the drug. We investigated the pharmacological potential of HS in the prevention and treatment of CIPN at the level of sciatic nerve (SN) morphology.&#x0D; Results. The maximum value of the average profile area of myelinated nerve fibers with the use of HS is significantly lower than with uncorrected flow, and is (78.12±2.24) μm2 compared to (94.04±1.03) μm2 (p &lt;0.001). The introduction of HS provides a stable content of the value of the ratio of the areas of the axial cylinder and the fiber within 0.39±0.01 (first day) - 0.44±0.01 (ninetieth day), and a rapid recovery of the indicator value to normal values during the final 30 days of the experiment. the maximum value of the index of the profile area of the myelin sheath with the introduction of HS is 1.4 times less than with an uncorrected flow, and is, respectively, (49.01±1.59) μm2 and (69.77±1.87) μm2 (p &lt;0.001). HS provides a more intensive restoration of the indicator of the area of the myelin sheath during the 90th - 120th day of the experiment.&#x0D; Conclusions. Our results allow us to conclude that the introduction of HS creates a protective effect against paclitaxel-induced peripheral neuropathy (PIPN) by acting on both the axial cylinder and the myelin sheath of the heart failure. Due to the known pathophysiological mechanisms of the development of neuropathy, this method can be a promising therapeutic agent for the prevention and treatment of PIPN

Antinociceptive Profile of ARN19702, (2-Ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone, a Novel Orally Active N-Acylethanolamine Acid Amidase Inhibitor, in Animal Models.

N-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase that stops the physiologic actions of palmitoylethanolamide, an endogenous lipid messenger that activates the transcription factor, peroxisome proliferator-activated receptor-α We have previously reported that the compound ARN19702 [(2-ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone] is an orally active, reversible NAAA inhibitor (IC50 on human NAAA = 230 nM) that produces remarkable protective effects against multiple sclerosis in mice. In the present study, we assessed the profile of ARN19702 in mouse and rat models of acute and neuropathic pain. Oral administration in male mice attenuated in a dose-dependent manner the spontaneous nocifensive response elicited by intraplantar formalin injection and the hypersensitivity caused by intraplantar carrageenan injection, paw incision, or sciatic nerve ligation. In male rats, ARN19702 reduced nociception associated with paclitaxel-induced neuropathy without development of subacute antinociceptive tolerance. Finally, ARN19702 (30 mg/kg, oral) did not produce place preference or alter exploratory motor behavior in male mice. The findings support the conclusion that NAAA is a suitable molecular target for the discovery of efficacious analgesic drugs devoid of rewarding potential. SIGNIFICANCE STATEMENT: This study evaluated the pharmacological profile of the orally bioavailable N-acylethanolamine acid amidase (NAAA) inhibitor (2-ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone (ARN19702) in mouse and rat models of neurogenic and inflammatory pain. The compound's potential rewarding and sedative effects were also examined. It is concluded that ARN19702 exhibits a broad analgesic profile that can be generalized across rodent species. The findings point to NAAA as a control node in the processing of neuropathic and inflammatory pain and to ARN19702 as a lead to uncover novel pain therapeutics devoid of addictive potential .

Effects of Chronic Oral Probiotic Treatment in Paclitaxel-Induced Neuropathic Pain.

Chemotherapy-induced peripheral neuropathy (CIPN) represents one of the most prevalent and potentially disabling side effects due to the use of anticancer drugs, one of the primary neuropathies detected is peripheral neuropathy induced by administration of taxanes, including paclitaxel. It has been demonstrated that gut microbiota is crucial for the therapeutic effect of chemotherapeutic drugs for inhibiting tumor growth and contributed to the pathogenesis of the CIPN. The use of nutraceuticals has receiving growing attention from the research community due to their phytochemical, biological, and pharmacological properties. It has been demonstrated that probiotic formulations may both reduce inflammation and modulate the expression of pain receptors. Our studies tested the efficacy of a probiotic formulation, SLAB51, in preventing paclitaxel-induced neuropathy. Interestingly, our probiotic formulation was able to keep the gut integrity, preserving its functionality, in CIPN-mice, moreover, it prevented the mechanical and cold hypersensitivity induced in paclitaxel-mice. Additionally, ex-vivo analysis showed that in CIPN-mice the pro-biotic treatment increased the expression of opioid and cannabinoid receptors in spinal cord, it prevented in the reduction in nerve fiber damage in the paws and modulated the serum proinflammatory cytokines concentration. On basis of these data, the use of this specific probiotic formulation may represent a valid adjuvant agent to paclitaxel, useful and not toxic for long-lasting therapies.

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.

Preventive and therapeutic effects of JM-20 on paclitaxel-evoked painful peripheral neuropathy in rats

Context: JM-20 is a hybrid synthetic molecule, which is based on a multimodal drug design paradigm for cerebrovascular disease. In addition to its neuroprotective effects, JM-20 also decreased sciatic nerve chronic constriction injury (CCI)-induced mechanical hypersensitivity in rats. JM-20 has a strong mitoprotective ability, and its effects could be in correspondence with the mitotoxicity hypothesis for paclitaxel-induced painful peripheral neuropathy. Aims: To evaluate the efficacy of the JM-20 to reduce neuropathic pain manifestations induced by the administration of paclitaxel in rats. Methods: In this study was implemented a rat model of painful peripheral neuropathy, produced by the chemotherapeutic agent paclitaxel, to determine whether JM-20 (10 mg/kg, p.o) could prevent the development of neuropathic pain during the exposure to paclitaxel. As well as to determine whether JM-20 (20 mg/kg, p.o) could reverse the established neuropathic pain. Mechanical behavioral assessment using von Frey filaments applied to the hind paws was applied before, during, and after treatments for 35 days. Results: Giving JM-20 during the exposure to paclitaxel significantly reduced the severity of mechanical allodynia and mechanical hyperalgesia. Moreover, JM-20 significantly reduced both established neuropathic pain manifestations. There was no evidence of tolerance to the effect during three days of dosing, and a long-term effect was observed after JM-20 discontinuation. Conclusions: JM-20 may be clinically relevant for both the prevention and treatment of paclitaxel-induced painful peripheral neuropathy.

Protective Effects of Oxytocin and Progesterone on Paclitaxel-Induced Neuropathy in Rats

Objective: Paclitaxel (Ptx), used to treat cancer, still causes neuropathic pain and peripheral neuropathy today. This study was conducted to evaluate the effects of progesterone (Pg) and oxytocin (Oxy) on peripheral neuropathy rat model induced by Ptx. Materials and Methods: A total of 38 male Sprague–Dawley rats were randomly divided into five groups, e.g., control (n = 6), Ptx (n = 8), Ptx + Oxy (n = 8), Ptx + Pg (n = 8), and Ptx + Oxy + Pg (n = 8). The rats were monitored daily for body weight change throughout the experiment. To evaluate peripheral neuropathy, electroneuromyography measurements (latency, amplitude, and motor nerve conduction velocity (MNCV)) were recorded from the sciatic nerve innervating the gastrocnemius muscle. Sciatic nerve tissue samples were collected for histopathological evaluation. Results: Ptx led to significant reductions in body weight from day 6 (P &lt; 0.05). There was no difference between groups in the distal latency and amplitudes (P &gt; 0.05). Proximal latency was prolonged in Ptx group rats than in other groups (P &lt; 0.05). Importantly, it was found that MNCV was higher in the Ptx + Pg group than Ptx, Ptx + Oxy, and Ptx + Oxy + Pg groups (P &lt; 0.05). Furthermore, Pg-administered rats had the lowest nerve degeneration compared to rats administered Oxy and Oxy + Pg (P &lt; 0.05). Conclusions: The present findings suggest that Pg has a protective effect on peripheral neuropathy induced by Ptx in rat.

Gabapentin and Duloxetine Prevent Oxaliplatin- and Paclitaxel-Induced Peripheral Neuropathy by Inhibiting Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Phosphorylation in Spinal Cords of Mice.

Chemotherapy-induced peripheral neuropathy is a common factor in limiting therapy which can result in therapy cessation or dose reduction. Gabapentin, a calcium channel inhibitor, and duloxetine, a serotonin noradrenaline reuptake inhibitor, are used to treat a variety of pain conditions such as chronic low back pain, postherpetic neuralgia, and diabetic neuropathy. It has been reported that administration of gabapentin suppressed oxaliplatin- and paclitaxel-induced mechanical hyperalgesia in rats. Moreover, duloxetine has been shown to suppress oxaliplatin-induced cold allodynia in rats. However, the mechanisms by which these drugs prevent oxaliplatin- and paclitaxel-induced neuropathy remain unknown. Behavioral assays were performed using cold plate and the von Frey test. The expression levels of proteins were examined using western blot analysis. In this study, we investigated the mechanisms by which gabapentin and duloxetine prevent oxaliplatin- and paclitaxel-induced neuropathy in mice. We found that gabapentin and duloxetine prevented the development of oxaliplatin- and paclitaxel-induced cold and mechanical allodynia. In addition, our results revealed that gabapentin and duloxetine suppressed extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation in the spinal cord of mice. Moreover, PD0325901 prevented the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 activation in the spinal cord of mice. In summary, our findings suggest that gabapentin, duloxetine, and PD0325901 prevent the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 phosphorylation in mice. Therefore, inhibiting ERK1/2 phosphorylation could be an effective preventive strategy against oxaliplatin- and paclitaxel-induced neuropathy.

Effects of paclitaxel on the viscoelastic properties of mouse sensory nerves

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

NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel

BackgroundThe major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified.MethodsPaw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, and microarray analysis were performed to explore the molecular mechanism.ResultsWe found that paclitaxel treatment increased the nuclear expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TTS of target genes in dorsal horn after paclitaxel treatment.We further found that NFATc2 occupancy may directly upregulate the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel.ConclusionThese results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain.

Dysregulation of EAAT2 and VGLUT2 Spinal Glutamate Transports via Histone Deacetylase 2 (HDAC2) Contributes to Paclitaxel-induced Painful Neuropathy.

Effective treatments for chemotherapy-induced peripheral neuropathy (CIPN) remain unavailable. Given the significance of spinal cord glutamate transporters in neuronal plasticity and central sensitization, this study investigated the role of excitatory amino acid transporter 2 (EAAT2) and vesicular-glutamate transporter 2 (VGLUT2) in the development of paclitaxel-induced painful neuropathy. Paclitaxel (2 mg/kg, i.p., cumulative dose 8 mg/kg) induced long-lasting mechanical allodynia (>28 days) with increased glutamate concentration and decreased EAAT2 expression with no changes in GABA/glycine or VGAT (vesicular GABA transporter) in rat spinal dorsal horn. VGLUT2 expression was upregulated and coexpressed with enhanced synaptophysin, characterizing nociceptive afferent sprouting and new synapse formation of glutamatergic neurons in the spinal cord dorsal horn. HDAC2 and transcription factor YY1 were also upregulated, and their interaction and colocalization were confirmed following paclitaxel treatment using co-immunoprecipitation. Inhibition or knockdown of HDAC2 expression by valproic acid, BRD6688, or HDAC2 siRNA not only attenuated paclitaxel-induced mechanical allodynia but also suppressed HDAC2 upregulation, glutamate accumulation, and the corresponding changes in EAAT2/VGLUT/synaptophysin expression and HDAC2/YY1 interaction. These findings indicate that loss of the balance between glutamate release and reuptake due to dysregulation EAAT2/VGLUT2/synaptophysin cascade in the spinal dorsal horn plays an important role in the development of paclitaxel-induced neuropathic pain. HDAC2/YY1 interaction as a complex appears essential in regulating this pathway, which can potentially be a therapeutic target to relieve CIPN by reversing central sensitization of spinal nociceptive neurons.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Paclitaxel-induced peripheral neuropathy in early-stage breast cancer patients.

e12503 Background: Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and can persist for up to two years after completing treatment, greatly affecting both the course of chemotherapy and quality of patients. Few studies have characterized the side effect profiles of two commonly used paclitaxel-based adjuvant regimens, dose-dense biweekly paclitaxel with growth factor support (ddP, 175 mg/m2 biweekly for four cycles) and weekly paclitaxel (wP, 80 mg/m2 weekly for 12 cycles). Conflicting results exist regarding the incidence of paclitaxel-induced neuropathy related to either administration scheme. Methods: This is a data-only retrospective cohort study that consisted of adult patients with early-stage breast cancer who received either ddP or wP at Kaiser Permanente Diablo Service Area (Walnut Creek and Antioch Medical Centers) between January 1, 2010 and January 1, 2019. The primary endpoint was the proportion of patients with dose-limiting chemotherapy-induced peripheral neuropathy (DL CIPN). Results: 244 patients were included in the final analysis with 159 and 85 patients receiving wP and ddP, respectively. Baseline demographics were well matched between the two groups. There was no significant difference in the proportion of patients who experienced DL CIPN with wP (17.6%) compared to ddP (19.1%) (p = 0.647). Grade 3 or 4 adverse events occurred in 8.9% of patients who received wP and 10.6% of patients who received ddP. No significant difference was observed (p = 0.650). Conclusions: The results of this study support the current National Comprehensive Cancer Network (NCCN) guidelines, which recommend dose-dense doxorubicin and cyclophosphamide (ddAC) followed by either sequential wP or sequential ddP with growth factor support as preoperative and/or adjuvant therapy for the treatment of early-stage breast cancer. The selection of an appropriate paclitaxel schedule is provider preference and largely based on the consideration of patient tolerability. These findings suggest that the concern for paclitaxel-induced peripheral neuropathy, including DL CIPN, may potentially play a smaller role in helping guide clinicians who are choosing between the two paclitaxel-based adjuvant regimens.

Concomitant limb cryocompression and scalp cooling to reduce paclitaxel-induced neuropathy and alopecia.

e24157 Background: Scalp cooling is an FDA approved method to mitigate chemotherapy-induced alopecia (CIA) caused by paclitaxel. Chemotherapy-induced peripheral neuropathy (CIPN) is a dose limiting toxicity of paclitaxel. Several recent randomized studies have suggested limb hypothermia as a mechanism to ameliorate paclitaxel-induced neuropathy. The safety, tolerability and feasibility of concomitant limb hypothermia and scalp cooling to prevent these two common adverse effects of paclitaxel has not been previously studied. Methods: A proof-of-concept study was conducted in breast cancer patients receiving weekly paclitaxel chemotherapy. Each subject underwent concomitant scalp and four-limb cryocompression with each chemotherapy infusion (3 hours) for a maximum of 12 cycles. Limb cryocompression was administered at cyclic pressure (5-15 mmHg) and temperatures starting at 11°C (established as lowest tolerable temperature in a separate healthy volunteer study) and adjusted according to patient tolerability. Skin surface temperature and tolerance scores were recorded. CIPN was assessed via EORTC Quality of Life Questionnaire-CIPN before (QOLpre), after completion (QOLpost) and 3-months post chemotherapy (QOL3m). Results: Fifteen patients enrolled in the study, of which 14 completed all 12 cycles of concomitant scalp cooling and limb cryocompression during chemotherapy without any side effects barring transient erythema over the limbs. None had intolerance to scalp cooling. Eight patients safely tolerated 12 cycles of cryocompression at 11°C. Of the remaining, 6 completed all 12 cycles at device temperatures ranging from 14-25°C. One patient withdrew at the 6th cycle, finding 25°C intolerable. Median QOLpre was 19 (range 17-19), QOLpost 20 (18-29) (p = 0.04, Wilcoxon signed-rank) and QOL3m was 19 (18-21) (vs QOLpre; p = 1). QOL showed no significant differences from pre-chemotherapy to 3 months post-chemotherapy suggesting preservation of nerve function. Conclusions: Delivery of concomitant scalp cooling and limb cryocompression is feasible, safe and generally well-tolerated. Future limb hypothermia trials should not preclude patients from undergoing scalp-cooling concomitantly to reduce CIA. Clinical trial information: NCT03248193 .