Cisplatin-induced Peripheral Neuropathy Research Articles

Effect of Silybum Marianum on Reduction of Chemotherapy-Induced Peripheral Neurotoxicity with Cisplatin.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the major complications of chemotherapy regimens commonly used in the treatment of solid and hematologic cancers. Given the high incidence of CIPN in antitumor therapies in patients and limited studies on antioxidants, this study was aimed to investigate the effect of Silybum marianum (SM) on cisplatin-induced peripheral neuropathy. This double-blind randomized clinical trial study was performed on 60 cancer patients treated with cisplatin chemotherapy at Seyyed-o-Shohada Hospital of Isfahan during 2019-2020. The patients were divided into two parallel groups as intervention (treated by SM) and placebo, and DN4 (Douleur neuropathique 4 questions) and CIPNAT (chemotherapy-induced peripheral neuropathy assessment tool) were completed for patients in the before and after intervention groups and compared between the two groups. The mean of DN4 score in the before and after study in the intervention group was in 1.76 ± 1.24 and 2.07 ± 2.03, respectively (P = 0.38), and in the control group was 1.41 ± 1.28 ± 3.11 ± 2.86, respectively (P = 0.012). The mean CIPNAT score in the intervention groups was 5.93 ± 3.65 and 4.20 ± 3.23 (P = 0.01), and in the control group was 4.20 ± 4.22 and 4.16 ± 4.03 (P = 0.39). Based on our data, SM is an effective agent in reducing peripheral neuropathy. The use of SM was associated with decreased scores of peripheral neuropathy and was helpful in patients undergoing chemotherapy with cisplatin.

G Protein-Coupled Receptors and Ion Channels Involvement in Cisplatin-Induced Peripheral Neuropathy: A Review of Preclinical Studies

Cisplatin is a platinum-based chemotherapy drug widely used to treat various solid tumours. Although it is effective in anti-cancer therapy, many patients develop peripheral neuropathy during and after cisplatin treatment. Peripheral neuropathy results from lesions or diseases in the peripheral somatosensory nervous system and is a significant cause of debilitation and suffering in patients. In recent years, preclinical studies have been conducted to elucidate the mechanisms involved in chemotherapy-induced peripheral neuropathic pain, as well as to promote new therapeutic targets since current treatments are ineffective and are associated with adverse effects. G-protein coupled receptors and ion channels play a significant role in pain processing and may represent promising targets for improving the management of cisplatin-induced neuropathic pain. This review describes the role of G protein-coupled receptors and ion channels in cisplatin-induced pain, analysing preclinical experimental studies that investigated the role of each receptor subtype in the modulation of cisplatin-induced pain.

Spinal Neuronal miR-124 Inhibits Microglial Activation and Contributes to Preventive Effect of Electroacupuncture on Chemotherapy-Induced Peripheral Neuropathy in Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a persistent and irreversible side effect of antineoplastic agents. Patients with CIPN usually show chronic pain and sensory deficits with glove-and-stocking distribution. However, whether spinal neuronal microRNA (miR)-124 is involved in cisplatin-induced peripheral neuropathy remains to be studied. In this study, miR-124 was significantly reduced in the spinal dorsal horn in CIPN mice. Overexpression of neuronal miR-124 induced by injecting adeno-associated virus with neuron-specific promoter into the spinal cord of mice prevented the development of mechanical allodynia, sensory deficits, and the loss of intraepidermal nerve fibers induced by cisplatin. Meanwhile, cisplatin-induced M1 microglia activation and the release of proinflammatory cytokines were significantly inhibited by overexpression of neuronal miR-124. Furthermore, electroacupuncture (EA) treatment upregulated miR-124 expression in the spinal dorsal horn of CIPN mice. Interestingly, downregulation of spinal neuronal miR-124 significantly inhibited the regulatory effect of EA on CIPN and microglia activity as well as spinal neuroinflammation induced by cisplatin. These results demonstrate that spinal neuronal miR-124 is involved in the prevention and treatment of EA on cisplatin-induced peripheral neuropathy in mice. Our findings suggest that spinal neuronal miR-124 might be a potential target for EA effect, and we provide, to our knowledge, a new experimental basis for EA prevention of CIPN.

Chronic Cannabigerol as an Effective Therapeutic for Cisplatin-Induced Neuropathic Pain.

Cannabigerol (CBG), derived from the cannabis plant, acts as an acute analgesic in a model of cisplatin-induced peripheral neuropathy (CIPN) in mice. There are no curative, long-lasting treatments for CIPN available to humans. We investigated the ability of chronic CBG to alleviate mechanical hypersensitivity due to CIPN in mice by measuring responses to 7 and 14 days of daily CBG. We found that CBG treatment (i.p.) for 7 and 14 consecutive days significantly reduced mechanical hypersensitivity in male and female mice with CIPN and reduced pain sensitivity up to 60-70% of baseline levels (p < 0.001 for all), 24 h after the last injection. Additionally, we found that daily treatment with CBG did not evoke tolerance and did not incur significant weight change or adverse events. The efficacy of CBG was independent of the estrous cycle phase. Therefore, chronic CBG administration can provide at least 24 h of antinociceptive effect in mice. These findings support the study of CBG as a long-lasting neuropathic pain therapy, which acts without tolerance in both males and females.

Kinin B2 Receptor Mediates Cisplatin-Induced Painful Peripheral Neuropathy by Intracellular Kinase Pathways and TRPA1 Channel Sensitisation.

Chemotherapy-induced peripheral neuropathy is a severe clinical problem frequently associated with cisplatin use. Although its pathophysiology is poorly understood, it is known that kinin receptors and the transient receptor potential ankyrin 1 (TRPA1) channel play a significant role in the peripheral neuropathy induced by cisplatin in rodents. However, the role of signalling pathways downstream from B2 kinin receptors activation and sensitisation of the TRPA1 channel remains unknown in this model. The cisplatin-induced neuropathy model caused mechanical and cold allodynia in male Swiss mice. Antagonists for kinin B2 and B1 receptors and the TRPA1 channel attenuated the painful parameters. Local sub-nociceptive doses of kinin B2 receptor (bradykinin) and TRPA1 channel (allyl isothiocyanate; AITC) agonists enhanced the painful parameters in cisplatin-treated mice, which their respective antagonists attenuated. Furthermore, we demonstrated the interaction between the kinin B2 receptor and the TRPA1 channel in cisplatin-induced peripheral neuropathy since phospholipase C (PLC) and protein kinase C epsilon (PKCε) inhibitors attenuated the increase in mechanical and cold allodynia evoked by bradykinin and AITC in cisplatin-treated mice. Therefore, regulating the activation of signalling pathways downstream from the kinin B2 receptors activation and TRPA1 channel sensitisation can mitigate the painful peripheral neuropathy decurrent of the oncology treatment with cisplatin.

The impact of population pharmacogenomics and risk allele frequencies on cisplatin-induced peripheral sensory neuropathy (PSN).

12092 Background: Taxane-treated breast cancer patients with genetically African ancestry have worse PSN than other groups. However, no study has examined the association between ancestry and PSN after cisplatin-based chemotherapy. Increased risk could be partially explained by differing risk allele frequencies across populations for alleles increasing the general vulnerability to PSN or altering drug metabolism. Methods: The Platinum Study enrolled cisplatin-treated testicular cancer survivors (TCS) who completed clinical exams and surveys. A PSN score was derived from the mean of 8 sensory items (using EORTC-CIPN20), assigning severity on a 0-2 scale. Multidimensional scaling scores for each TCS were calculated, plotted and anchored by data from the 1000 Genomes Reference population to determine genetic ancestry. Multinomial logistic regression assessed the association between genetic ancestry and PSN. To determine risk alleles for PSN and allele frequencies across populations, risk allele panels were created, including ancestry-informative markers (AIMs) determined by the AncestrySNPMiner tool. Allele frequencies were calculated in each group; SNPs with frequency differences &gt; 0.3 in the African (AFRAFR) population vs. others were included. For filtering the AIMs, GTEx data was used to identify expression quantitative trait loci (eQTL) or splicing quantitative trait loci (sQTL) in nerve/brain tissue. Multinomial logistic regression assessed associations between SNP genotype and PSN phenotype for SNPs with differing allele frequencies across populations. Results: Despite small numbers of non-Europeans, TCS with African ancestry had increased incidence and severity of PSN vs. TCS with European ancestry. In a subset analysis of EUR (n = 681) and AFRAFR (n = 13) patients who received 400-450 mg/m2 of cisplatin, the relative risk ratio (RRR) in the AFRAFR vs. EUR TCS of severe neuropathy vs. none was 7.96 (P = 0.074) and the RRR for any neuropathy vs. none was 7.79 (P = 0.049). There were 394 independent AIMs with significant ( &gt; 0.3) allele frequency differences between the AFRAFR and other populations that were eQTLs and/or sQTLs in nerve/brain tissue. Using multinominal logistic regression between genotype and phenotype for all TCS (n = 1513) with covariates for age at survey and 10 genetic principal components: 16 SNPs had P-values &lt; 0.05 for severe PSN vs. none and/or any PSN vs. none. Although not statistically significant with multiple testing corrections, these suggestively significant SNPs could be potentially validated in additional populations. Conclusions: These results are preliminary evidence for the potential importance of differing risk allele frequencies across populations in explaining some disparities in cisplatin-related PSN. If confirmed, genotyping for risk variants could impact treatment decisions and enable monitoring to mitigate PSN.

A Case of Mononeuopathy Multiplex in the Setting of Durvalumab Therapy (P13-8.002)

<h3>Objective:</h3> NA <h3>Background:</h3> As immune checkpoint inhibitors (ICIs) become a mainstay of treatment for several malignancies, neurological complications associated with their use have been increasingly recognized. We present a case of mononeuropathy multiplex (MM) in the setting of durvalumab (PD-L1 inhibitor) use. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 68-year-old man with stage III non-small cell lung cancer (NSCLC) was seen for the evaluation of asymmetric, painful bilateral upper extremity weakness of 2 months’ duration. He had pre-existing painless glove-and-stocking sensory loss, attributed to cisplatin-induced peripheral neuropathy. Following 4 cycles of cisplatin-based chemotherapy, the patient was started on durvalumab 4 months prior to presentation. Key exam findings included weakness affecting right digit I flexion, wrist and finger extension as well as left interphalangeal joint flexion affecting digits II–V, glove-and-stocking sensory loss, and diffuse areflexia. Upper extremity EMG findings were notable for active denervation changes restricted to multiple bilateral radial- and median-innervated muscles. Following initial assessment, the right wrist drop continued to progress, and a decision was taken to discontinue durvalumab given the concern for peripheral neurotoxicity. The left arm weakness resolved over 3–4 weeks, while the right wrist drop had improved only partially at last assessment 5 months later. The patient had declined a trial of steroids or IVIG. <h3>Conclusions:</h3> The clinical and EMG findings were consistent with MM and bore a temporal relation to durvalumab use. No alternate etiology was identified. ICI-mediated toxicity can result in sensory, motor and autonomic peripheral nerve involvement with a myriad of clinical presentations. In the existing literature, MM has been described with both ipilimumab and nivolumab, but to our knowledge, this is the first reported case of MM with durvalumab use. Early identification of often severe neurological adverse events is crucial due to implications for treatment and decisions regarding continued immune checkpoint therapy. <b>Disclosure:</b> Miss Scurfield has nothing to disclose. Miss Kelly has nothing to disclose. Dr. Desai has nothing to disclose. Dr. Dhanjal has nothing to disclose.

Kinin B1 and B2 Receptors Contribute to Cisplatin-Induced Painful Peripheral Neuropathy in Male Mice

Cisplatin is the preferential chemotherapeutic drug for highly prevalent solid tumours. However, its clinical efficacy is frequently limited due to neurotoxic effects such as peripheral neuropathy. Chemotherapy-induced peripheral neuropathy is a dose-dependent adverse condition that negatively impacts quality of life, and it may determine dosage limitations or even cancer treatment cessation. Thus, it is urgently necessary to identify pathophysiological mechanisms underlying these painful symptoms. As kinins and their B1 and B2 receptors contribute to the development of chronic painful conditions, including those induced by chemotherapy, the contribution of these receptors to cisplatin-induced peripheral neuropathy was evaluated via pharmacological antagonism and genetic manipulation in male Swiss mice. Cisplatin causes painful symptoms and impaired working and spatial memory. Kinin B1 (DALBK) and B2 (Icatibant) receptor antagonists attenuated some painful parameters. Local administration of kinin B1 and B2 receptor agonists (in sub-nociceptive doses) intensified the cisplatin-induced mechanical nociception attenuated by DALBK and Icatibant, respectively. In addition, antisense oligonucleotides to kinin B1 and B2 receptors reduced cisplatin-induced mechanical allodynia. Thus, kinin B1 and B2 receptors appear to be potential targets for the treatment of cisplatin-induced painful symptoms and may improve patients' adherence to treatment and their quality of life.

Resolution of cisplatin-induced fatigue does not require endogenous interleukin-10 in male mice

Based on previous results showing a pivotal role of endogenous interleukin-10 (IL-10) in the recovery from cisplatin-induced peripheral neuropathy, the present experiments were carried out to determine whether this cytokine plays any role in the recovery from cisplatin-induced fatigue in male mice. Fatigue was measured by decreased voluntary wheel running in mice trained to run in a wheel in response to cisplatin. Mice were treated with a monoclonal neutralizing antibody (IL-10na) administered intranasally during the recovery period to neutralize endogenous IL-10. In the first experiment, mice were treated with cisplatin (2.83 mg/kg/day) for five days and IL-10na (12 μg/day for three days) five days later. In the second experiment, they were treated with cisplatin (2.3 mg/kg/day for 5 days twice at a five-day interval) and IL10na (12 μg/day for three days) immediately after the last injection of cisplatin. In both experiments, cisplatin decreased body weight and reduced voluntary wheel running. However, IL-10na did not impair recovery from these effects. These results show that the recovery from the cisplatin-induced decrease in wheel running does not require endogenous IL-10 in contrast to the recovery from cisplatin-induced peripheral neuropathy

Investigation of effects of quercetin and low-level laser therapy in cisplatin-induced in vitro peripheral neuropathy model.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the dose-dependent side effects of cisplatin. The loss of sensory neurons is observed in CIPN. There are many methods to minimalize CIPN symptoms such as pharmacological agents and photobiostimulation but the mechanisms of these methods are unclear. Our study is aimed at determining the effects of quercetin and low-level laser therapy (LLLT) in undifferentiated and nerve growth factor-differentiated PC12 cells in cisplatin-induced peripheral neuropathy. PC12 cells with cisplatin were co-treated with quercetin and LLLT (diode pumped all-solid-state laser, 670 nm, output 500 mW, and the laser beam surface area was 1.96 cm2). The effects of quercetin and LLLT on GAP-43 and Synapsin I expressions were analyzed by real-time PCR, cell viability was assessed by MTT assay, Annexin and dead assay measured the induction of apoptosis, the alterations in mitopotential were assessed by mitopotential assay, and lactate dehydrogenase activity in cells was analyzed. All experiment data were analyzed by the Tukey test and applied as a post hoc test, and statistical evaluation was made. Our results indicated that cisplatin increased apoptosis (24,210 ± 2189, 46,504 ± 8246) cells, mitochondrial dysfunction (44,312 ± 0.751, 68,788 ± 1271), and LDH activity (62,821 ± 8245, 87,838 ± 8116). Furthermore, it decreased cell viability (42,447 ± 1780, 36,140 ± 3682) and inhibited GAP-43 and Synapsin I genes in undifferentiated and differentiated PC12 cells. However, apoptosis, the alterations in mitopotential, and lactate dehydrogenase activity decreased by applications of quercetin and LLLT. It has been recommended that quercetin and low-level laser therapy roles on cisplatin-induced peripheral neuropathy should be investigated in vivo, and the relationship between quercetin and low-level laser therapy should be molecular.

Time dependent cisplatin dosing differences on hypoalgesia focusing on oxidative stress

Although cisplatin is a key drug in cancer chemotherapy, it often causes sensory peripheral neuropathy, presenting as allodynia in the early stage and hypoalgesia in the serious stage. Chronotherapy has previously been shown to ameliorate cisplatin-induced peripheral neuropathy that was severe enough to cause hypoalgesia in rats. It also has adverse effects such as renal dysfunction and ototoxicity, which are induced by oxidative stress. Here, we show that oxidative stress causes severe cisplatin-induced peripheral neuropathy, and that differences in oxidative stress occur depending on the dosing time of cisplatin.Cisplatin was administered to rats at 5:00 or 17:00 every seven days for four weeks. The antioxidant agent, 1,3-Dimethylthiourea (DMTU), was administered before and after the administration of cisplatin. The hot plate test was used to assess hypoalgesia. Oxidative stress in the sciatic nerve was assessed from thiobarbituric acid reactive substances (TBARs) and superoxide dismutase (SOD) activity. Nerve apoptosis was analysed with qRT-PCR.We observed an increase in TBARs and a decrease in SOD activity with the development of cisplatin-induced hypoalgesia, which was ameliorated by DMTU treatment. Furthermore, differences in the dosing time of cisplatin caused differences in oxidative stress which were correlated with cisplatin-induced hypoalgesia.Severe oxidative stress caused cisplatin-induced hypoalgesia, and chronotherapy with cisplatin ameliorated hypoalgesia by reducing oxidative stress. In the future, chronotherapy with cisplatin may contribute to the treatment of cancer in humans.

Targeting Oxidative Stress, Autophagy, and Apoptosis by Quercetin to Ameliorate Cisplatin-induced Peripheral Neuropathy in Rats.

Quercetin is a flavonoid, with antioxidant and autophagy-modulating activities. Cisplatin is one of the platinum-based anticancer drugs. Early development of peripheral neuropathy as an adverse effect of cisplatin interferes with the continuation of therapy. Oxidative stress and autophagy impairment may play a role. This study aimed to explore the possible protective effects of quercetin against cisplatin-induced peripheral neuropathy. Twenty-four male Wistar rats were divided into three groups: Group 1 (control group) and Group 2 (cisplatin group) where peripheral neuropathy was induced using single ip injection of cisplatin. Group 3 (cisplatin + quercetin group) received single ip injection of cisplatin and was then treated with quercetin for 14 days. At the end of the experiment, nociception was evaluated by tail immersion test, and then, blood was collected for analysis of nerve growth factor. Sciatic nerve was used to assess histopathological changes and light chain 3-II by immunohistochemical staining. Reduced glutathione, malondialdehyde, mTOR, and caspase-3 were estimated in sciatic nerve tissue homogenate. This research work revealed that quercetin significantly improved cisplatin-induced nociceptive impairment, attenuated cisplatin-induced oxidative stress, autophagy, and apoptosis to protect against neuronal death. From the current study, quercetin can act as a promising protective agent against cisplatin-induced peripheral neuropathy.

Nicotinamide Riboside Alleviates Cisplatin-Induced Peripheral Neuropathy via SIRT2 Activation

<h3>Purpose/Objective(s)</h3> Chemotherapy-induced peripheral neuropathy represents a major impairment to the quality of life of cancer patients and is one of the most common dose-limiting adverse effects of cancer treatment. Despite its prevalence, no effective treatment or prevention strategy exists. We have previously provided genetic evidence that the NAD+-dependent deacetylase, SIRT2, protects against cisplatin-induced peripheral neuronal cell death and neuropathy by enhancing nucleotide excision repair. In this study, we aimed to examine whether pharmacologic activation of SIRT2 would provide effective prevention and treatment of cisplatin-induced peripheral neuropathy (CIPN) without compromising tumor cell cytotoxic response to cisplatin. <h3>Materials/Methods</h3> Using von Frey tests, we studied the use of nicotinamide riboside (NR) to prevent and treat CIPN in WT and <i>Sirt2</i>-KO mouse models. We also performed cell survival assays to investigate the effect of NAD+ supplementation on cisplatin toxicity in neuronal and cancer cells. <h3>Results</h3> We show that NR, an NAD+ precursor and pharmacologic activator of SIRT2, effectively prevents and alleviates CIPN in mice. We present in vitro and in vivo genetic evidence to illustrate the specific dependence on SIRT2 of NR-mediated CIPN mitigation. Importantly, we demonstrate that NAD+ mediates SIRT2-dependent neuroprotection without inhibiting cisplatin cytotoxic activity against cancer cells. NAD+ may, in fact, further sensitize certain cancer cell types to cisplatin. <h3>Conclusion</h3> Together, our results identify SIRT2-targeted activity of nicotinamide riboside as a potential therapy to alleviate the debilitating and potentially permanent toxicity, CIPN.

TENS Improves Cisplatin-Induced Neuropathy in Lung Cancer Patients.

Background: Cisplatin-induced peripheral neuropathy is a common complication of cisplatin therapy, which develops in most patients with lung cancer. There are no effective preventive measures and once it occurs there is no effective therapy, except symptomatic. In this study, we aimed to assess the effect of transcutaneous electrical nerve stimulation (TENS) therapy on the pain intensity and the quality of life of patients with cisplatin-induced neuropathy. Material and Methods: A prospective cohort study was performed from 2013 to 2018, at the Clinical Center of Serbia. After the initial evaluation of 106 newly diagnosed patients with lung cancer, 68 patients did not have peripheral neuropathy. These 68 patients continued in the study and started the cisplatin chemotherapy. Forty of these patients developed cisplatin-induced neuropathy, which was manifested by neuropathic symptoms and proven by ENG examination. All patients with cisplatin-induced neuropathy were treated with TENS therapy. Their neuropathic pain and quality of life were evaluated using the following questionnaires at diagnosis, after cisplatin therapy and after four weeks of TENS use: DN4, VAS scale, EORTC QLQ-C30 and FACT-L. Results: Two thirds (68%) of the patients with cisplatin-induced neuropathy were male and the majority were smokers (70%). Adenocarcinoma was the most common (38%), followed by squamous (33%) and small-cell carcinoma (28%). The application of TENS therapy had a positive effect on reducing the neuropathic pain and increasing the quality of life for patients with painful cisplatin-induced neuropathy. The VAS and DN4 scores significantly decreased after TENS therapy, in comparison to its values after cisplatin therapy (p < 0.001). After TENS therapy, patients had significantly higher values in most of the domains of EORTC QLQ-C30 and FACT- L, in comparison with the values after cisplatin therapy (p < 0.001). Conclusion: The application of TENS therapy has a positive effect on reducing neuropathic pain and increasing the quality of life for patients with lung cancer and cisplatin-induced neuropathy.

Dexamethasone and Citicoline Mitigate Cisplatin-Induced Peripheral Neuropathy: A Novel Experimental Study in Mice.

Given the rising prevalence of cisplatin-induced peripheral neuropathy (CisIPN), investigations to alleviate its adverse effects are required. Oxidative stress and free radical development are essential pathways of CisIPN. Specifically, dexamethasone and citicoline are characterized by anti-inflammatory and antioxidant activities that might reduce CisIPN incidence and severity. The current study assessed the possible impacts of novel interventions, dexamethasone, and, citicoline on CisIPN. Seventy-two male mice were randomly allocated into nine groups (n: 8/each group). Different doses of dexamethasone (7.5, 15, 30 mg/kg, i.p.), citicoline (10, 20, 40 mg/kg, i.p.), and the combination (dexamethasone 7.5 mg/kg + citicoline 10 mg/kg, i.p.) were injected in the first three days and one day before receiving cisplatin (2 mg/kg, i.p.). The tail-flick method was used for assessing nociception. Besides, malondialdehyde (MDA), interleukin-1 beta (IL-1β), tumor necrosis factor-α (TNF-α), total antioxidant capacity (TAC), and mice weight differences (ΔW) were measured. Different doses of dexamethasone and citicoline enhanced latency time (p<0.05). Moreover, dexamethasone 15 mg/kg diminished the level of MDA and increased TAC (p<0.05) and in 30 mg/kg, MDA was reduced (p<0.05). Besides, 20 and 40 mg/kg of citicoline reduced MDA and elevated TAC (p<0.05), and 10 mg/kg merely reduced MDA (p<0.05). Dexamethasone in all doses declined IL-1β and TNF-α levels, and citicoline only at 40 mg/kg lessened their levels (p<0.05). Interestingly, ΔW declined more in the dexamethasone and citicoline groups than the cisplatin group (p<0.05). Dexamethasone and citicoline attenuate CisIPN through anti-inflammatory activity, improving the antioxidant capacity, and inhibiting lipid peroxidation.

Alleviation of cisplatin-induced neuropathic pain, neuronal apoptosis, and systemic inflammation in mice by rapamycin.

Platinum-based chemotherapeutic treatment of cancer patients is associated with debilitating adverse effects. Several adverse effects have been well investigated, and can be managed satisfactorily, but chemotherapy-induced peripheral neuropathy (CIPN) remains poorly treated. Our primary aim in this study was to investigate the neuroprotective effect of the immunomodulatory drug rapamycin in the mitigation of cisplatin-induced neurotoxicity. Pain assays were performed in vivo to determine whether rapamycin would prevent or significantly decrease cisplatin-induced neurotoxicity in adult male Balb/c mice. Neuropathic pain induced by both chronic and acute exposure to cisplatin was measured by hot plate assay, cold plate assay, tail-flick test, and plantar test. Rapamycin co-treatment resulted in significant reduction in cisplatin-induced nociceptive-like symptoms. To understand the underlying mechanisms behind rapamycin-mediated neuroprotection, we investigated its effect on certain inflammatory mediators implicated in the propagation of chemotherapy-induced neurotoxicity. Interestingly, cisplatin was found to significantly increase peripheral IL-17A expression and CD8- T cells, which were remarkably reversed by the pre-treatment of mice with rapamycin. In addition, rapamycin reduced the cisplatin-induced neuronal apoptosis marked by decreased neuronal caspase-3 activity. The rapamycin neuroprotective effect was also associated with reversal of the changes in protein expression of p21Cip1, p53, and PUMA. Collectively, rapamycin alleviated some features of cisplatin-induced neurotoxicity in mice and can be further investigated for the treatment of cisplatin-induced peripheral neuropathy.

Discovery of pyrazole-1-carboxamide derivatives as novel Gi-biased μ-opioid receptor agonists.

μ-Opioid receptor (MOR) Gi-biased agonists with no recruitment of β-arrestin were introduced as a new analgesic strategy to overcome the conventional undesirable side effects of opioid receptor-targeted drugs, such as tolerance, addiction, respiratory depression, and constipation. For the development of novel Gi-biased MOR agonists, the design, synthesis, and structure-activity relationship(SAR) analysis of the aminopyrazole core skeleton were conducted according to the current SAR data of PZM21 (2a) and its derivatives. New derivatives were biologically evaluated for their agonistic effects on cyclic adenosine monophosphate(cAMP) levels for the Gi pathway and β-arrestin recruitment in MOR/κ-opioid receptor/δ opioid receptor. An optimized selective Gi-biased agonist, Compound 17a, was discovered with potent cAMP inhibitory activities, with a 50% efficacy concentration valueof 87.1 nM and no activity in the MOR β-arrestin pathway and other subtypes. The in vivo pain relief efficacy of Compound 17a was confirmed in a dose-dependent manner with spinal nerve ligation and cisplatin-induced peripheral neuropathy rodent neuropathic pain models.

Cannabigerol (CBG) attenuates mechanical hypersensitivity elicited by chemotherapy-induced peripheral neuropathy.

Cannabigerol (CBG) is a non-psychoactive phytocannabinoid produced by the plant Cannabis sativa with affinity to various receptors involved in nociception. As a result, CBG is marketed as an over-the-counter treatment for many forms of pain. However, there is very little research-based evidence for the efficacy of CBG as an anti-nociceptive agent. To begin to fill this knowledge gap, we assessed the anti-nociceptive effects of CBG in C57BL/6 mice using three different models of pain; cisplatin-induced peripheral neuropathy, the formalin test, and the tail-flick assay. Using the von Frey test, we found that CBG-attenuated mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy in both male and female mice. Additionally, we observed that this CBG-induced reduction in mechanical hypersensitivity was attenuated by the α2 -adrenergic receptor antagonist atipamezole (3mg/kg, i.p.) and the CB1 R antagonist, AM4113 (3mg/kg, i.p.), and blocked by the CB2 R antagonist/inverse agonist, SR144528 (10mg/kg, i.p.). We found that the TRPV1 antagonist, SB705498 (20 mg/kg, i.p.) was unable to prevent CBG actions. Furthermore, we show that CBG:CBD oil (10mg/kg, i.p.) was more effective than pure CBG (10mg/kg) at reducing mechanical hypersensitivity in neuropathic mice. Lastly, we show that pure CBG and CBG:CBD oil were ineffective at reducing nociception in other models of pain, including the formalin and tail flick assays. Our findings support the role of CBG in alleviating mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy, but highlight that these effects may be limited to specific types of pain. There are few effective treatments for neuropathic pain and neuropathic pain is projected to increase with the aging population. We demonstrate that CBG (cannabigerol) and CBG:CBD oil attenuate neuropathy-induced mechanical hypersensitivity mice. Second, we identify receptor targets that mediate CBG-induced reduction in mechanical hypersensitivity in neuropathic mice. Third, we demonstrate that an acute injection of CBG is anti-nociceptive specifically for neuropathic pain rather than other forms of pain, including persistent pain and thermal pain.

Pro-Inflammatory Signalling PRRopels Cisplatin-Induced Toxicity.

Cisplatin is a platinum-based chemotherapeutic that has long since been effective against a variety of solid-cancers, substantially improving the five-year survival rates for cancer patients. Its use has also historically been limited by its adverse drug reactions, or cisplatin-induced toxicities (CITs). Of these reactions, cisplatin-induced nephrotoxicity (CIN), cisplatin-induced peripheral neuropathy (CIPN), and cisplatin-induced ototoxicity (CIO) are the three most common of several CITs recognised thus far. While the anti-cancer activity of cisplatin is well understood, the mechanisms driving its toxicities have only begun to be defined. Most of the literature pertains to damage caused by oxidative stress that occurs downstream of cisplatin treatment, but recent evidence suggests that the instigator of CIT development is inflammation. Cisplatin has been shown to induce pro-inflammatory signalling in CIN, CIPN, and CIO, all of which are associated with persisting markers of inflammation, particularly from the innate immune system. This review covered the hallmarks of inflammation common and distinct between different CITs, the role of innate immune components in development of CITs, as well as current treatments targeting pro-inflammatory signalling pathways to conserve the use of cisplatin in chemotherapy and improve long-term health outcomes of cancer patients.

Impact of adverse health outcomes (AHOs) on self-reported physical and mental health in U.S. testicular cancer survivors (TCS).

12080 Background: No study has systematically evaluated the impact of AHOs on PROMIS-validated measures of physical and mental health in TCS. Patient-reported outcomes are increasingly recognized as crucial in TCS follow-up, given their young age at diagnosis and high cure rates. Methods: Eligible TCS (age &lt; 60 yr at diagnosis, given first-line cisplatin-based chemotherapy (CHEM)) completed comprehensive health surveys, prescription drug usage, and PROMIS global physical health and global mental health measures. PROMIS scores were compared to US subpopulation norms for similar-age men. 2017-2018 NHANES data were compared with select survey responses. Linear regression examined the relationship between individual AHOs (pain, obesity, cisplatin-induced peripheral neuropathy (CIPN)), cisplatin-related AHOs (CIPN, hearing loss, vertigo, tinnitus, renal disease), cardiovascular (CVD) AHOs (7 AHO), and all AHOs taken together (24 AHOs), with PROMIS global physical and mental health measures. Regression models were adjusted for age, cisplatin dose, time since CHEM, education, income, smoking, and alcohol. Results: Among 213 TCS (median age at evaluation: 46 yr; IQR: 38-52 yr; median time since CHEM completion: 10.6 yr; IQR: 6.8-16.6 yr), the most common AHOs were tinnitus (60%), self-reported hearing loss (60%), CIPN (55%), and Raynaud Phenomenon (43%). The median number of AHOs was 5 (IQR: 3-7), and 12% of TCS had ≥10 AHOs. Only 1.4% of TCS had no AHOs. Compared to NHANES men without cancer, controlling for age, education, and race, fewer TCS currently smoked (3% vs. 22%; P&lt;.001) and fewer were obese (31% vs. 43%, P=.026) but alcohol intake was comparable. However, TCS had significantly lower physical (mean: 48.5 vs. 51.2, P&lt;.001) and mental health (mean: 48.4 vs. 50.8, P&lt;.001) than US men. Increasing numbers of AHOs were significantly associated with decreasing physical ( P&lt;.001) and mental health ( P&lt;.001) after adjustment. The magnitude of effect was strongest for the number of cisplatin-related AHOs with both physical (β: -1.3; 95% CI: -1.9, -0.7; P&lt;.001) and mental health (β: -1.3; 95% CI: -2.1, -0.4; P=.003) after adjustment. In individual AHO adjusted models, CIPN (β: -1.8; 95% CI: -3.3, -0.4), pain (β: -5.0; 95% CI: -6.8, -3.2) and obesity (β: -2.7; 95% CI: -4.3, -1.1) were significantly associated with decreased physical health. Only pain (β: -5.9; 95% CI: -8.4, -3.4) and CIPN (β: -2.0; 95% CI: -4.0, -0.1), but not obesity, were associated with decreased mental health. Conclusions: At a median of 11 years after CHEM completion, 50% of TCS have ≥5 AHOs, and over 1 in 10 have ≥10 AHOs. AHO following cisplatin chemotherapy have major deleterious impacts on patient-reported measures of physical and mental health. Future survivorship research should focus on developing preventive and interventional strategies to care for TCS most vulnerable for impaired physical and mental health after CHEM.