Treatment Of Chemotherapy-induced Neuropathy Research Articles

Insights into the Pathogenesis and Treatment of Chemotherapy-Induced Neuropathy: A Focus on Oxidative Stress and Neuroinflammation.

Cancer is a high-morbidity disease prevalent worldwide. Chemotherapy is the primarily used regimen for cancer treatment; however, it also brings severe side effects. Chemotherapy-induced Peripheral Neuropathy (CIPN) and Chemotherapy-induced Cognitive Impairment (CICI) are two main complications occurring in chemotherapy. They are both associated with nervous system injury and are therefore collectively referred to as Chemotherapy-induced Neuropathy (CIN). CIPN induces neuralgia and numbness in limbs, while CICI causes amnesia and cognitive dysfunction. Currently, there are no effective therapeutics to prevent or cure CIN, so research into new drugs to alleviate CIN becomes urgent. Oxidative stress and neuroinflammation are the common pathogenic mechanisms of CIPN and CICI. Excessive Reactive Oxygen Species (ROS) and pro-inflammatory cytokines cause peripheral nervous system damage and hence CIPN. Peripheral ROS and cytokines also change the permeability of the blood-brain barrier, thereby increasing oxidative stress and neuroinflammation in the central nervous system, ultimately leading to CICI. Several antidepressants have been used to treat CIN and exhibited good clinical effects. Their potential pharmacological mechanism has been reported to ameliorate oxidative stress and neuroinflammation, guiding a new feasible way for effective therapeutic development against CIN. This mini-review has summarized the latest advances in the research on CIN with respect to clinical status, pathogenesis, and treatment. It has also discussed the potential of repurposing antidepressants for CIN treatment and prospected the strategy of developing therapeutics by targeting oxidative stress and neuroinflammation against CIN.

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.

Modulation of Glutamate Transporter EAAT1 and Inward-Rectifier Potassium Channel Kir4.1 Expression in Cultured Spinal Cord Astrocytes by Platinum-Based Chemotherapeutics.

Platinum-based chemotherapeutics still play an essential role in cancer treatment. Despite their high effectiveness, severe side effects such as chemotherapy-induced neuropathy (CIPN) occur frequently. The pathophysiology of CIPN by platinum-based chemotherapeutics is not fully understood yet, but primarily the disturbance of dorsal root ganglion cells is discussed. However, there is increasing evidence of central nervous system involvement with activation of spinal cord astrocytes after treatment with chemotherapeutics. We investigated the influence of cis- or oxaliplatin on the functionality of cultured rat spinal cord astrocytes by using immunocytochemistry and patch-clamp electrophysiology. Cis- or oxaliplatin activated spinal astrocytes and led to downregulation of the excitatory amino acid transporter 1 (EAAT1) expression. Furthermore, the expression and function of potassium channel Kir4.1 were modulated. Pre-exposure to a specific Kir4.1 blocker in control astrocytes led to a reduced immune reactivity (IR) of EAAT1 and a nearly complete block of the current density. When spinal astrocytes were pre-exposed to antibiotic minocycline, all effects of cis- or oxaliplatin were abolished. Taken together, the modulation of Kir4.1 and EAAT1 proteins in astrocytes could be linked to the direct impact of cis- or oxaliplatin, identifying spinal astrocytes as a potential target in the prevention and treatment of chemotherapy-induced neuropathy.

Vortioxetine reduces pain hypersensitivity and associated depression-like behavior in mice with oxaliplatin-induced neuropathy

Chronic pain and depression commonly occur together so dual-acting agents might be particularly useful. The population of patients with chemotherapy-induced neuropathy is increasing in parallel with the increase of population of cancer survivors and there is a compelling need for satisfactory treatment of symptoms of neuropathy and concomitant depression. We examined the effects of vortioxetine, a novel antidepressant with unique mechanism of action, on pain hypersensitivity and depression-like behavior in oxaliplatin-induced neuropathy model in mice (OIPN). Vortioxetine (1–10 mg/kg, p.o.) significantly and dose-dependently reduced mechanical allodynia in von Frey test and cold allodynia in acetone test in OIPN mice, in both repeated prophylactic and acute therapeutic treatment regimens. It also reduced depression-like behavior in the forced swimming test in OIPN mice, in both treatment paradigms. Its antiallodynic and antidepressive-like effects were comparable to those exerted by duloxetine (1–15 mg/kg, p.o.). The antiallodynic and antidepressive-like effects of repeatedly administered vortioxetine might be related to the increased content of 5-hydroxytryptamine (5-HT) and noradrenaline (NA), detected in the brainstem of treated OIPN mice. These results indicate that vortioxetine could be potentially useful in prevention and treatment of chemotherapy-induced neuropathy, for the relief of pain and concomitant depressive symptoms. It should be further tested to this regard in clinical settings.

Sirt2-associated transcriptome modifications in cisplatin-induced neuronal injury

BackgroundChemotherapy-induced peripheral neuropathy is not only one of the most common causes of dose reduction or discontinuation of cancer treatment, but it can also permanently decrease the quality of life of cancer patients and survivors. Notably, Sirt2 protects many organs from various injuries, including diabetic peripheral neuropathy. As demonstrated previously by our laboratory and others, the overexpression of Sirt2 can improve cisplatin-induced neuropathy, although the mechanism is still unclear.ResultsIn this study, the underlying mechanism by which Sirt2 protects neurons from cisplatin-induced injury was explored using the RNAseq technique in cultured rodent neurons. Sirt2 status was modified by genetic knockout (Sirt2/KO) and was then reconstituted in Sirt2/KO cells (Sirt2/Res). We observed 323 upregulated genes and 277 downregulated genes in Sirt2-expressing cells (Sirt2/Res) compared to Sirt2-deficient cells (Sirt2/KO). Pathway analysis suggested that Sirt2 may affect several pathways, such as MAPK, TNF, and cytokine–cytokine interaction. Furthermore, cisplatin-induced changes to the transcriptome are strongly associated with Sirt2 status. Cisplatin induced distinctive transcriptome changes for 227 genes in Sirt2-expressing cells and for 783 genes in Sirt2-deficient cells, while changes in only 138 of these genes were independent of Sirt2 status. Interestingly, changes in the p53 pathway, ECM–receptor interactions, and cytokine–cytokine receptor interactions were induced by cisplatin only in Sirt2-deficient cells.ConclusionsThis study demonstrated that Sirt2 regulates the transcriptome in cultured rodent neuronal cells. Furthermore, Sirt2-associated transcriptome regulation may be an important mechanism underlying the role of Sirt2 in organ protection, such as in cisplatin-induced neuronal injury. Sirt2 may be a potential target for the prevention and treatment of chemotherapy-induced neuropathy.

Activation of sphingosine 1-phosphate receptor 2 attenuates chemotherapy-induced neuropathy.

Platinum-based therapeutics are used to manage many forms of cancer, but frequently result in peripheral neuropathy. Currently, the only option available to attenuate chemotherapy-induced neuropathy is to limit or discontinue this treatment. Sphingosine 1-phosphate (S1P) is a lipid-based signaling molecule involved in neuroinflammatory processes by interacting with its five cognate receptors: S1P1-5 In this study, using a combination of drug pharmacodynamic analysis in human study participants, disease modeling in rodents, and cell-based assays, we examined whether S1P signaling may represent a potential target in the treatment of chemotherapy-induced neuropathy. To this end, we first investigated the effects of platinum-based drugs on plasma S1P levels in human cancer patients. Our analysis revealed that oxaliplatin treatment specifically increases one S1P species, d16:1 S1P, in these patients. Although d16:1 S1P is an S1P2 agonist, it has lower potency than the most abundant S1P species (d18:1 S1P). Therefore, as d16:1 S1P concentration increases, it is likely to disproportionately activate proinflammatory S1P1 signaling, shifting the balance away from S1P2 We further show that a selective S1P2 agonist, CYM-5478, reduces allodynia in a rat model of cisplatin-induced neuropathy and attenuates the associated inflammatory processes in the dorsal root ganglia, likely by activating stress-response proteins, including ATF3 and HO-1. Cumulatively, the findings of our study suggest that the development of a specific S1P2 agonist may represent a promising therapeutic approach for the management of chemotherapy-induced neuropathy.

Preliminary Effectiveness of Auricular Point Acupressure on Chemotherapy-Induced Neuropathy: Part 2 Laboratory-Assessed and Objective Outcomes

PurposeTo manage chemotherapy-induced neuropathy (CIN), this paper explores reliable and valid objectives measures to evaluate the treatment effects of auricular point acupressure (APA). Design/MethodThis study was a repeated-measures one-group design. Participants received four weeks of APA to manage their CIN. The laboratory-assessed and objective outcomes included quantitative sensory testing, grip and pinch strength, and inflammatory biomarkers. Wilcoxon matched pairs signed-rank tests were conducted to determine change scores of outcomes at pre- vs. post- and pre- vs. 1-month follow-up. Spearman’s rho correlation coefficient was used to examine the linear association of score changes of all objective study outcomes. ResultsComparing pre-and-post APA, (1) the mean score of the monofilament for all lower extremity sites tested decreased after APA, indicating sensory improvement; (2) the suprathreshold pinprick stimuli mean scores on the upper extremities increased, except the scores from the index finger and thumb; (3) the pain tolerance of thumb and trapezius areas increased; (4) decreasing IL1β (p = .05), IFNγ (p = .02), IL-2 (p = .03), IL-6 (p = .05), IL-10 (p = .05), and IP10/CXCL10 (p = .04) were observed pre-post APA. Conditional pain modulation was significantly (p< .05) associated with pain intensity (r = 0.55), tingling (r = 0.59); and IL1β concentration (r = 0.53) pre-post APA. The sustained effects of 4-week APA were observed at the 1-month follow-up. ConclusionsOur study findings demonstrated the promising effectiveness of APA in the management of CIN, and these treatment effects can be assessed using reliable and valid objective measures. Clinical ImplicationsIf the efficacy of APA to manage CIN is confirmed in a larger sample, APA has the potential to be a scalable treatment for CIN because it is a reproducible, standardized, and easy-to-perform intervention.

Abstract P6-11-05: Incidence and Treatment of Chemotherapy-Induced Neuropathy in Metastatic Breast Cancer: A Claims Database Analysis

Abstract Background: Peripheral neuropathy is a well-known consequence of many cancer chemotherapy agents, particularly the taxanes, platinum compounds, epothilones, and vinca alkaloids. Chemotherapy-induced neuropathy (CIPN) may develop over the course of several cycles of chemotherapy and is characterized by numbness, pain, tingling, weakness, and increased sensitivity that often begins in the fingers and toes spreads proximally. Our objective was to describe the incidence of CIPN in patients with metastatic breast cancer (MBC), the characteristics of patients with CIPN, and the impact of developing CIPN on treatment. Methods: A claims-based analysis was conducted using commercial, Medicare Advantage and Medicaid data from a national commercial health insurer covering approximately 14 million lives annually. Patients included in the study were female, at least 18 years old, and diagnosed with MBC (at least 2 claims each for breast cancer and metastatic disease, ICD-9-CM codes 174.xx and 196.xx-198.xx, 199.0x) from 01 January 2005 to 31 December 2008. Patients were required to have at least one claim for chemotherapy or one fill date for an oral chemotherapy agent and continuous enrollment with medical and pharmacy benefits for a minimum of 6 months prior to (baseline period), and six months after (follow-up period), the first observed chemotherapy claim date. Patients with evidence of CIPN (at least 2 claims with a peripheral neuropathy (PN) diagnosis on separate days) or receipt of chemotherapy in the baseline period were excluded from the analysis. Descriptive statistics compared baseline characteristics and treatment of patients with and without CIPN. Results: 1875 patients met full inclusion criteria, with a mean (SD) follow-up period of 592 (340) days. Incident CIPN developed in 213 (11.4%) patients. Patients with and without CIPN did not differ significantly in age, insurance coverage type, prior history of surgery or radiation therapy. Patients with CIPN had a longer mean follow-up duration (713 vs. 576 days, P&amp;lt;0.001) which could include chemotherapy rest periods. Gabapentin use was present in 8.9% of patients with and 3.7% patients without CIPN (P&amp;lt;0.001). No significant difference in use of antidepressants or anticonvulsants was noted. Further, more patients with CIPN had neurologist visits (9.9% vs. 5.8%, p=0.023), physical therapy (21.6% vs. 15.4%, p=0.021), and acupuncture (2.4% vs. 0.7%, p=0.012). Among patients treated with chemotherapy agents commonly associated with CIPN, the proportion with PN diagnoses was not significantly different compared to the proportion with CIPN diagnoses among those treated with chemotherapy agents not usually associated with CIPN (11.7% vs 10.1%). Discussion: Recognition of CIPN may be under-reported in routine clinical practice. In this claims-based analysis, peripheral neuropathy was diagnosed in approximately 11 % of patients with MBC and was associated with more frequent use of neurologist visits, acupuncture, physical therapy, and gabapentin. There was no significant difference in reporting rates between higher and lower risk compounds, which in part may be due to a lack of systematic surveillance. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-05.

A randomized controlled trial evaluating a topical treatment for chemotherapy-induced neuropathy: NCCTG trial N06CA

9531 Background: Chemotherapy induced peripheral neuropathy (CIPN) is a prevalent dose limiting toxicity for several important cancer treatment agents. CIPN can impair function and cause distress. There are no proven pharmacologic treatments for established CIPN currently. This double blind randomized placebo controlled trial evaluated a compounded topical gel for this problem. The novelty of this treatment is that it might incorporate several agents with different mechanisms of action to provide relief locally without negative systemic effects. Methods: Patients with CIPN (rated ≥4 out of 10) for at least one month, related to previous and/or concurrent exposure to neurotoxic agents, were randomized to baclofen 10 mg, amitriptyline HCL 40 mg and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) vs placebo (PLO) to determine its effect on numbness, tingling, pain, and motor function. Exclusion criteria included other causes and/or current treatment for peripheral neuropathy. The primary endpoint was the baseline adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. Results: Between February and May 2008, 208 patients were enrolled onto this trial. Four week data are shown in the table below, higher numbers being better. The percentage of patients that had improvements of at least 10, on a 100 point scale, in the motor subscale was statistically significantly higher in the BAK-PLO arm, p=.04. There were no unwanted toxicities associated with the BAK-PLO that were significantly different from placebo and no evidence of CNS or systemic toxicity. Conclusions: Topical treatment with BAK-PLO appears to moderately improve symptoms of CIPN. This topical gel was well tolerated without systemic side effects. [Table: see text] No significant financial relationships to disclose.