Chemotherapy-induced Neuropathy Research Articles

Routine early screening for chemotherapy-induced hearing loss and other neuropathies in patients undergoing cancer treatment: a pilot study

<h3>Objectives:</h3> Neuropathies are well-recognized and potentially long-lasting complications of chemotherapy. The purpose of this study was to evaluate the feasibility and potential utility of routinely screening in patients undergoing cancer treatment for chemotherapy-induced neuropathies including: hearing loss (CIHL), peripheral neuropathy (CIPN), and cognitive impairment (CICI). <h3>Methods:</h3> After obtaining Institutional Review Board (IRB) approval five registered nurses were trained to conduct this prospective observational cohort study. Patients were recruited and consented after being scheduled to receive taxane or platinum based chemotherapy regimens. Prior to each chemotherapy infusion, subjects were invited to undergo on-site, portable automatic iPad-based air-conduction hearing testing and complete questionnaires assessing symptoms associated with peripheral neuropathy (CIPNAT: Chemotherapy-induced peripheral neuropathy assessment tool) and cognitive impairment (AFI: Attentional function index). Descriptive statistics were used to summarize study data. <h3>Results:</h3> A total of 20 subjects were enrolled. Each subject was able and willing to complete screenings and assessments prior to their chemotherapy infusion. Over 6 months, 2 subjects subjectively reported tinnitus and/or hearing impairment, which subsequently discontinued their chemotherapy. Both were unable to complete auditory testing due to tinnitus-associated pain induced by testing. In addition, objective evidence of auditory impairment was detected in another 7/16 subjects who denied subjective auditory symptoms. No improvements in CIHL were observed after subjects (n=6) had a treatment delay. A total of 65 percent (n=13) of subjects reported subjectively experiencing at least one symptom of peripheral neuropathy (CIPN). This was observed as early as the first cycle of chemotherapy (n=6), after which the proportion of subjects experiencing CIPN increased. After the third treatment, the total number of subjects (n=10) experiencing CIPN reported a decrease as dose reductions and/or treatment delays were initiated. All subjects (20/20) reported evidence of cognitive impairment (CICI) that progressively worsened over their treatment course. No improvements in CIHL or CICI were observed following dose reductions/delays or pyridoxine use. <h3>Conclusions:</h3> Routine on-site screening for chemotherapy-induced neuropathies in patients receiving chemotherapy for cancer treatment is feasible. Importantly, these screenings can uncover otherwise unappreciated complications, such as hearing loss and impaired cognition. Given that neither CIHL or CICI improved following treatment delays or pyridoxine use, routine screening may allow for the early implementation of therapies to blunt the impact of long-lasting side effects which lead to decreased quality of life.

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.

Spinal Cord Stimulator for Treating Chemotherapy-induced Peripheral Neuropathy

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is not only one of the most common adverse experiences of cancer survivors, but it is also one which has the greatest effect on quality of life. Ultimately, CIPN can lead to unwanted modification of treatment such as chemotherapy dose reductions or termination of treatment altogether. CASE REPORT: We present a case of a 47-year-old man with severe bilateral CIPN resistant to conservative management, who was successfully treated with spinal cord stimulation. CONCLUSION: Spinal cord stimulation can be an effective treatment for CIPN resistant to conservative management. KEY WORDS: Spinal cord stimulator, chemotherapy induced neuropathy, peripheral neuropathy

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.

Investigating the prevalence and risk of chemotherapy-induced neuropathy among cancer patients.

12078 Background: Neuropathy is a common side effect of some chemotherapies. Clinical and other factors may confer neuropathy risk, but rates and risk factors across neuropathy-causing chemotherapies are incompletely understood. Methods: We examined 15 chemotherapy drugs known to confer neuropathy. Within a broad population of cancer patients who underwent treatment with these agents at the University of Chicago Medicine between 2012-2018, we determined prevalence of chemotherapy-induced neuropathy, defined as patients with initiation of a neuropathy treatment medication (amitriptyline, carbamazepine, duloxetine, gabapentin, or pregabalin) after starting chemotherapy. We then analyzed chemotherapy-induced neuropathy risk for different drugs and based on clinical demographic factors. Results: We analyzed 7,866 patients (65.3% White, 53.7% Female, 27.6% Black/African-American, 5.6% Hispanic or Latino, 3.1% Asian/Mideast Indian, 2.4% More than one Race, 0.2% American Indian or Alaska Native, 0.2% Native Hawaiian/Other Pacific Islander). The overall prevalence of chemotherapy-induced neuropathy was 24.3% across our patient population. Black/African-American patients had an increased risk of chemotherapy-induced neuropathy compared to the rest of the patient cohort (OR 1.4, 95% CI 1.3-1.6, P = 1.6e-10). Females also exhibited an increased risk of chemotherapy-induced neuropathy compared to males (OR 1.2, 95% CI 1.1-1.3, P = 1.5e-3). Conclusions: Certain chemotherapy agents confer substantial risk of chemotherapy-induced neuropathy, and risk is increased in Blacks and females. Future work will investigate additional risk-modifying factors including the potential role of germline polymorphisms on chemotherapy neuropathy risk.[Table: see text]

MORPHOLOGICAL MANIFESTATIONS OF EXPERIMENTAL PACLITAXEL-INDUCED SICK NERVE NEUROPATHY UNDER CORRECTION OF 2-ETHYL-6-METHYLIDE-3-HYCYDYR-3-HYDYCIDE-3

Paclitaxel is an effective chemotherapeutic agent for many cancers, but 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 as of today, there are no proven effective drugs for the prevention or treatment of paclitaxel-induced neuropathic pain (IDP) in particular, or peripheral chemotherapy-induced neuropathy (PIH) in general. 2-ethyl-6-methyl-3-hydroxypyridine succinate (HS) is a derivative of succinic acid with neuroprotective, antihypoxic, membrane-protective, nootropic, sedative action. The experiment was performed on 80 white rats injected intraperitoneally with paclitaxel (Actavis, Romania), pre-dissolved in isotonic saline at a dose of 2 mg / kg body weight four times a day until a total dose of 8 mg / kg. Forty of these animals were then injected intraperitoneally with 2-ethyl-6-methyl-3-hydroxypyridine succinate at a dose of 10 mg / kg (the other 40 rats received intraperitoneal water for injection). Morphological studies were performed on the 1st, 7th, 15th, 28th, 60th, 90th and 120th days after the last administration of the drug. We investigated the pharmacological potential of HS in the prevention and treatment of PNH at the level of the sciatic nerve (CH). Our results allow us to conclude that the introduction of HS creates a protective effect against paclitaxel-induced peripheral neuropathy (PIPN) by affecting both the axial cylinder and the myelin sheath of HF. Due to the known pathophysiological mechanisms of neuropathy, this method can be a promising therapeutic tool for the prevention and treatment of PIPN.

Clinical Scales for Diabetic Neuropathy and Chemotherapy-induced Neuropathy

Diabetic neuropathy and chemotherapy-induced peripheral neuropathy are complex disorders affecting different nerve fiber group and remain as major source of morbidity and decreased quality of life of the patients. Given the recent advance in understanding the pathophysiological mechanism of these neuropathies and the development of new drugs, it is imperative to set proper scales to rate the severity of symptoms or signs. Moreover, well-designed, highly sensitive and valid scales could get scientific reliability and clinical utility if they are combined with objective neurophysiological measures. This review will discuss about the reliable and validated scales used in these common toxic and metabolic neuropathies.

Effects of paclitaxel in mitochondrial function and cellular phenotype in human peripheral blood mononuclear cells and monocytes

Chemotherapy-induced neuropathy (CIPN) is a common complication of paclitaxel. CIPN affects the quality of life of cancer survivors and frequently leads to discontinuation of treatment. Paclitaxel affects neuronal microtubules and induces neuronal mitochondrial dysfunction. However, there is limited clinical information regarding paclitaxel's effects on monocytes. Preclinical studies suggest that paclitaxel-induced neuronal damage is driven by monocytes/macrophages. Therefore, we evaluated whether paclitaxel selectively induces mitochondrial dysfunction and a pro-inflammatory phenotype in human circulating monocytes. We conducted studies in human primary peripheral blood mononuclear cells (PBMCs) from cancer patients being treated with paclitaxel, and in vitro analysis in PBMC cells and monocytes, and THP-1 monocytes in the presence of paclitaxel (0.1, 1, 10 uM). We used flow cytometric markers to study mitochondrial reactive oxygen species (ROS) and mitochondrial membrane potential, namely MitoSox and DIOC6(3) respectively. We also measured mRNA levels of pro- and anti-inflammatory molecules using qRT-PCR. In vitro paclitaxel induced a depolarization state in mitochondria in THP-1, human primary monocytes, and primary human PBMCs, but it did not change MitoSox. Monocytes in PBMCs cells from patients treated with paclitaxel showed significative depolarization state in mitochondria when compared to cells from control patients. In THP-1 cells, paclitaxel enhanced mRNA levels of the pro-inflammatory cytokines IL-8 and TNF alpha. In human primary PBMCs, paclitaxel reduced the anti-inflammatory factors CD163 and IL-10, and enhanced the TNF alpha, COX-2 and MCP-1 mRNA levels. Our study provides evidence that paclitaxel can induce mitochondrial dysfunction in isolated human monocytes and in monocytes present in total PBMCs cells. The observed depolarizing changes are indicative of a pro-mitophagy state, which is in accordance with the paclitaxel-induced pro-inflammatory phenotype in these cells. Early detection of mitochondria dysfunction in human monocytes could be a predictable sign to CIPN development in cancer patients. Our research was supported by the Early-Career Investigator Award W81XWH-16-1-0438 of the Department of Defense, The Pershing Square Sohn Cancer Research Alliance, Weill Cornell Medicine Funds, Department of Anesthesiology-Wake Forest School of Medicine Funds, Comprehensive Cancer Center-Wake Forest School of Medicine Funds, NIDA R21CA248106, National Center for Advancing Translational Sciences (NCATS)-NIH through Grant Award Number UL1TR001420. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

PEA-OXA Mitigates Oxaliplatin-Induced Painful Neuropathy through NF-κB/Nrf-2 Axis.

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics, such as oxaliplatin (L-OHP). The aim of the present work was to evaluate the potential beneficial effects of 2-pentadecyl-2-oxazoline (PEA-OXA) in a murine model of oxaliplatin-induced peripheral neuropathy (OIPN). OIPN was induced by an intraperitoneally injection of L-OHP in rats on five consecutive days (D0–4) for a final cumulative dose of 10 mg/kg. PEA-OXA and ultramicronized palmitoylethanolamide (PEAum), both 10 mg/kg, were given orally 15–20 min prior (L-OHP) and sacrifice was made on day 25. Our results demonstrated that PEA-OXA, more than PEAum, reduced the development of hypersensitivity in rats; this was associated with the reduction in hyperactivation of glia cells and the increased production of proinflammatory cytokines in the dorsal horn of the spinal cord, accompanied by an upregulation of neurotrophic factors in the dorsal root ganglia (DRG). Moreover, we showed that PEA-OXA reduced L-OHP damage via a reduction in NF-κB pathway activation and a modulation of Nrf-2 pathways. Our findings identify PEA-OXA as a therapeutic target in chemotherapy-induced painful neuropathy, through the biomolecular signaling NF-κB/Nrf-2 axis, thanks to its abilities to counteract L-OHP damage. Therefore, we can consider PEA-OXA as a promising adjunct to chemotherapy to reduce chronic pain in patients.

Behavior and electrophysiology studies of the peripheral neuropathy induced by individual and co-administration of paclitaxel and oxaliplatin in rat

AimsAntitumor agents, as taxanes and platinum compounds, induce peripheral neuropathies which can hamper their use for cancer treatment. The study of chemotherapy-induced neuropathies in humans is difficult because of ethical reasons, differences among administration protocols and intrinsic characteristics of patients. The aim of the present study is to compare the neuropathic signs induced by individual or combined administration of paclitaxel and oxaliplatin. Main methodsOxaliplatin and paclitaxel were administered individually and combined to induce peripheral neuropathy in rats, sensory neuropathic signs were assessed in the hind limbs and orofacial area. The in vitro skin-saphenous nerve preparation was used to record the axonal activity of Aδ sensory neurons. Key findingsAnimals treated with the combination developed mechanical allodynia in the paws and muscular hyperalgesia in the orofacial area, which was similar to that in animals treated with monotherapy, the latter also developed cold allodynia in the paws. Aδ-fibers of the rats treated with the combination were hyperexcited and presented hypersensitivity to pressure stimulation of the innervated skin, also similar to that recorded in the fibers of the animals treated with monotherapy. SignificanceOur work objectively demonstrates that the combination of a platinum compound with a taxane does not worsen the development of sensorial neuropathies in rats, which is an interesting data to take into account when the combination of antitumor drugs is necessary. Co-administration of antitumor drugs is more effective in cancer treatment without increasing the risk of the disabling neuropathic side effects.

When POTS is the tip of the iceberg: Rare cases of dysautonomia as a possible manifestation of another disorder.

Postural tachycardia syndrome (POTS) is a heterogenous disorder of the autonomic nervous system that is commonly associated with small fiber neuropathy, Ehlers-Danlos Syndrome and autoimmune disorders, but association with rare conditions may also occur. Reported here are clinical features, diagnostic tests and treatment outcomes of 6 unique patients who presented with POTS and were subsequently diagnosed with Fabry disease, McArdle disease, Complex V mitochondrial disease, carcinoid tumor, Hodgkin's lymphoma and chemotherapy-induced neuropathy. All patients (age range 15-57 years, 3 females, 3 males) presented with orthostatic intolerance of at least 6 months duration, and all patients had co-morbid small fiber neuropathy. Five patients presented with symptoms of POTS months to years before the underlying or associated medical condition was discovered, and three out of six patients experienced either complete resolution or significant improvement of POTS after treatment of the underlying or associated medical condition. In rare cases, POTS can present as a possible manifestation of genetic, neoplastic or neurotoxic disorders. Unusual clinical features that fall outside of the typical spectrum of dysautonomia can point toward the presence of another disorder and help guide further diagnostic investigation.

Topical Cannabinoids for Treating Chemotherapy-Induced Neuropathy: A Case Series.

BackgroundChemotherapy-induced peripheral neuropathy is a common and often severe side effect from many chemotherapeutic agents, with limited treatment options. There is no literature on the use of topical cannabinoids for chemotherapy-induced neuropathy.Case PresentationsThe current manuscript presents a case series of patients presenting in oncology clinics at Sutter Health, CA and Mayo Clinic, Rochester, MN from April 2019 to December 2020 with chemotherapy-induced peripheral neuropathy who used topical creams containing the cannabinoids delta-nine-tetrahydrocannabinol (THC) and/or cannabidiol (CBD).ConclusionsThis case series suggests that topical cannabinoids may be helpful for patients with chemotherapy-induced peripheral neuropathy. This paper also discusses the potential mechanisms of action by which topical cannabinoids might alleviate established CIPN symptoms. A randomized placebo-controlled trial using a standardized product is planned to study the actual efficacy of such treatment.

Psychological Disorders, Cognitive Impairment, and Quality of Life with Chemotherapy-induced Neuropathy in Colon and Rectal Carcinoma Patients

Purpose: To evaluate mental health, cognitive function, and living quality of colon and rectal carcinoma patients with oxaliplatin-induced neurotoxicity. Methods: Fifty recurrence-free colorectal cancer (CRC) patients with oxaliplatin chemotherapy while 50 control patients without oxaliplatin chemotherapy were enrolled in this study. Subjective and objective aspects of oxaliplatin chemotherapy symptoms were assessed with oxaliplatin neurotoxicity classification. Psychological assessment was measured via the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS). Cognitive function was measured via Montreal Cognitive Assessment (MoCA). Quality of Life (QOL) was assessed using the World Health Organization’s Quality of Life (WHOQOL-BREF) shortened instrument. Results: Of the patients with oxaliplatin chemotherapy, 41 patients had depression and 42 patients had anxiety. Patients with oxaliplatin chemotherapy scored higher on average on both the SDS (64.36 ± 7.22) and SAS (67.49 ± 9.41) compared to those without oxaliplatin chemotherapy (SDS, 57.86 ± 5.27, p=0.006; SAS, 61.57 ± 10.06, p = 0.004). Patients with oxaliplatin chemotherapy, on average, scored lower on the MoCA (23.46 ± 3.17) compared to patients without oxaliplatin chemotherapy (27.49 ± 2.03, p &lt; 0.05). In addition, patients with oxaliplatin chemotherapy scored significantly lower on measures of physical health (18.9 ± 7.8 vs. 37.8 ± 6.2, p&lt;0.05), psychological health (19.3 ± 8.2vs. 39.8 ± 8.1, p&lt;0.05), and social relationship (50.2 ± 10.1 vs. 70.6 ± 10.5, p&lt;0.05) compared to patients without oxaliplatin chemotherapy. Multivariate linear regression analysis demonstrated that anxiety and cognitive impairment performance significantly predicted for global Quality of Life (QOL). Conclusions: colorectal cancer (CRC)patients with oxaliplatin chemotherapy experience mood disorders, cognitive impairment, and reduced Quality of Life (QOL). The clinical symptoms severity of oxaliplatin cemotherapy plays an important role in mood change and cognitive function. Decreased Quality of Life (QOL) was associated with anxiety and cognitive impairment.

Changes in blood-spinal cord barrier permeability and neuroimmune interactions in the underlying mechanisms of chronic pain.

Advancing our understanding of the underlying mechanisms of chronic pain is instrumental to the identification of new potential therapeutic targets. Neuroimmune communication throughout the pain pathway is of crucial mechanistic importance and has been a major focus of preclinical chronic pain research over the last 2 decades. In the spinal cord, not only do dorsal horn neurons partake in mechanistically important bidirectional communication with resident immune cells such as microglia, but in some cases, they can also partake in bidirectional crosstalk with immune cells, such as monocytes/macrophages, which have infiltrated into the spinal cord from the circulation. The infiltration of immune cells into the spinal cord can be partly regulated by changes in permeability of the blood-spinal cord barrier (BSCB). Here, we discuss evidence for and against a mechanistic role for BSCB disruption and associated changes in neuroimmune crosstalk in preclinical chronic pain. We also consider recent evidence for its potential involvement in the vincristine model of chemotherapy-induced painful neuropathy. We conclude that current knowledge warrants further investigation to establish whether preventing BSCB disruption, or targeting the changes associated with this disruption, could be used for the development of novel approaches to treating chronic pain.

Vibration Perception Threshold and Heart Rate Variability as methods to assess chemotherapy-induced neuropathy in women with breast cancer – a pilot study

PurposeChemotherapy-induced peripheral neuropathy (CIPN) is a recognized adverse effect of standard (neo)adjuvant chemotherapy in breast cancer (BC) treatment. However, there is no consensus on a validated method for assessing CIPN. Heart rate variability (HRV) and vibration perception threshold (VPT) could be used as objective measures to describe CIPN. The aim of this pilot study was to investigate whether subjectively reported CIPN was associated with altered HRV and VPT in BC patients. MethodsWe performed a cross-sectional pilot study evaluating 30 BCE patients previously treated with chemotherapy, 26 BCE patients who did not receive chemotherapy, and 22 controls without breast cancer. Self-reported CIPN was registered for the BC patients. All participants were subjected to multi-frequency vibration analyses to determine VPT along with short ECG measurements to determine HRV measures. ResultsSelf-reported CIPN was registered in 14 (46.6%) BC patients treated with chemotherapy. The VPT at 64 Hz (P = 0.022) and mean HR (P = 0.022) were significantly higher and the HRV measures SDNN (P = 0.023), RMSSD (P = 0.007), LF (P = 0.050) and HF (P = 0.045) were significantly lower in BC patients reporting CIPN compared to controls when adjusted for age. VPT at 64 Hz and 125 Hz were significantly higher in BC patients not reporting CIPN compared to controls when adjusted for age. ConclusionWe found elevated VPT and mean HR along with decreased HRV parameters in 14 BCE patients reporting CIPN. These findings support the need for further investigation into whether HRV and vibration analysis could contribute to an objective assessment of CIPN.

A review on pain-relieving activity of berberine.

As isoquinoline alkaloid naturally occurs in Coptis and Berberis species, berberine (BER) has shown anti-oxidant, anti-tumour, anti-bacterial and hepatoprotective activities and beneficial effects against digestive, cardiovascular and neurological conditions. Also, BER antiinflammatory, pain-relieving and anti-cholinesterase activities were widely studied. The present overview discusses the analgesic effects of BER. Based on the literature, BER exerted pain-relieving activity against diabetic and chemotherapy-induced neuropathy, and sciatic nerve injury-induced pain via down-regulation of transient receptor potential vanilloid 1, suppression of NF-κB and modulation of μ and δ opioid receptors. Besides, BER could repress inflammatory markers tumour necrosis factor-α, interleukin-6 and IL-1β, as well as prostaglandin E2, inducible nitric oxide synthase and cyclooxygenase-2. The modulatory effects of BER on dopamine and N-methyl d-aspartate systems were also noted. Moreover, BER could induce Nrf2 expression but inhibits p38-MAPK and STAT3 phosphorylation. Noteworthy, anti-cholinesterase activity, which may potentially contribute to BER analgesic properties, warrants particular attention.

Assessment of Pediatric Chemotherapy-Induced Peripheral Neuropathy Using a New Patient-Reported Outcome Measure: The P-CIN.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is commonly experienced by children receiving neurotoxic chemotherapy. No validated pediatric CIPN patient-reported outcome (PRO) measures exist. Purpose: To test sensitivity, internal consistency reliability, content and convergent validity, and feasibility of the Pediatric Chemotherapy-Induced Neuropathy (P-CIN), an electronic PRO measure for assessing CIPN in children who received neurotoxic chemotherapy. Method: Five experts evaluated content validity of the 14-item P-CIN. Children 5 to 17 years old with CIPN (N = 79) completed the P-CIN via tablet computer; a subset (n = 26) also underwent neurological examinations using the Pediatric-Modified Total Neuropathy Score. Following preliminary analyses, one item was deleted and three others modified. The revised P-CIN was retested with patients (n = 6) who also completed the Bruininks-Oseretsky Test of Motor Proficiency motor function assessment. Means, item response ranges, standard deviations, content validity indexes, Cronbach's alphas, and correlation coefficients were calculated. Results: Mean participant age was 11.25 (SD = 4.0) years. Most had acute leukemia (62.5%) and received vincristine (98.7%). Content validity index coefficients ranged from .80 to 1.0 (p = .05). For 9 of 14 items, responses ranged from 0 to 4 or 5; response ranges for toe numbness, pick up a coin, and three of four pain items were 0 to 3. After deleting one item, Cronbach's alpha coefficient was .83. P-CIN scores were strongly associated with Pediatric-Modified Total Neuropathy Score (r = .52, p < .01) and Bruininks-Oseretsky Test of Motor Proficiency (r = -.83, p = .04) scores. Sixty-eight percent of children 6 to 17 years old completed P-CIN independently. Discussion: Preliminary evidence suggests that the 13-item P-CIN is internally consistent, is valid, and can be completed independently by children ≥ 6 years. However, we recommend additional testing.

Inhaled Cannabis Suppresses Chemotherapy-Induced Neuropathic Nociception by Decoupling the Raphe Nucleus: A Functional Imaging Study in Rats

BackgroundEfficacy of inhaled cannabis for treating pain is controversial. Effective treatment for chemotherapy-induced neuropathy represents an unmet medical need. We hypothesized that cannabis reduces neuropathic pain by reducing functional coupling in the raphe nuclei. MethodsWe assessed the impact of inhalation of vaporized cannabis plant (containing 10.3% Δ9-tetrahydrocannabinol/0.05% cannabidiol) or placebo cannabis on brain resting-state blood oxygen level–dependent functional connectivity and pain behavior induced by paclitaxel in rats. Rats received paclitaxel to produce chemotherapy-induced peripheral neuropathy or its vehicle. Behavioral and imaging experiments were performed after neuropathy was established and stable. Images were registered to, and analyzed using, a 3D magnetic resonance imaging rat atlas providing site-specific data on more than 168 different brain areas. ResultsPrior to vaporization, paclitaxel produced cold allodynia. Inhaled vaporized cannabis increased cold withdrawal latencies relative to prevaporization or placebo cannabis, consistent with Δ9-tetrahydrocannabinol-induced antinociception. In paclitaxel-treated rats, the midbrain serotonergic system, comprising the dorsal and median raphe, showed hyperconnectivity to cortical, brainstem, and hippocampal areas, consistent with nociceptive processing. Inhalation of vaporized cannabis uncoupled paclitaxel-induced hyperconnectivity patterns. No such changes in connectivity or cold responsiveness were observed following placebo cannabis vaporization. ConclusionsInhaled vaporized cannabis plant uncoupled brain resting-state connectivity in the raphe nuclei, normalizing paclitaxel-induced hyperconnectivity to levels observed in vehicle-treated rats. Inhaled vaporized cannabis produced antinociception in both paclitaxel- and vehicle-treated rats. Our study elucidates neural circuitry implicated in the therapeutic effects of Δ9-tetrahydrocannabinol and supports a role for functional imaging studies in animals in guiding indications for future clinical trials.

The Neuroprotective Effect of Mesna on Cisplatin-Induced Neurotoxicity: Behavioral, Electrophysiological, and Molecular Studies.

Peripheral neuropathy and cognitive impairments following cisplatin administration may interfere with the clinical usage of the drug. Mesna is a chemoprotective agent with anti-inflammatory and anti-oxidant effects. Our study aimed to investigate the protective effects of mesna against cisplatin-induced neurotoxicity. Neurotoxicity was induced by the administration of 2.5mg/kg cisplatin twice a week for four consecutive weeks in male Wistar rats. The neuroprotective effect of mesna (150mg/kg/day) was evaluated through behavioral, electrophysiological, and molecular studies. Cisplatin treatment caused passive avoidance memory impairment, increased anxiety-like behaviors, altered thermal sensitivity, and decreased muscle strength in a grip strength test. Our electrophysiological studies indicated that administration of cisplatin induced peripheral sensory neuropathy and decreased the amplitudes of the compound action potential of sensory nerves. Cisplatin administration increased MDA and 4-HNE levels and decreased anti-oxidant (SOD and GPx) enzymes. Proinflammatory cytokines (IL-1β and TNF-α) and metalloproteinase-2 and 9 (MMP-2/9) were increased by cisplatin treatment. Morphological alterations were observed in the dorsal root ganglion (DRG) of cisplatin-treated rats. Cognitive impairments, anxiety, muscle strength, and thermal sensitivity changes induced by cisplatin were improved with mesna treatment. The reduced conduction velocity in sensory nerves was recovered in the cisplatin+mesna group. Mesna partially alleviated redox imbalance, reduced the proinflammatory cytokines, and MMP-2/9 levels. Mesna administration also relieved the morphological changes in DRG of cisplatin-treated rats. In conclusion, our results revealed that mesna can alleviate cisplatin-induced central and peripheral nervous system toxicity. These results support the concept that chemotherapy-induced neuropathy can be partially inhibited via mesna.

Platinum-Based Drugs Cause Mitochondrial Dysfunction in Cultured Dorsal Root Ganglion Neurons.

Cisplatin and oxaliplatin are treatment options for a variety of cancer types. While highly efficient in killing cancer cells, both chemotherapeutics cause severe side effects, e.g., peripheral neuropathies. Using a cell viability assay, a mitochondrial stress assay, and live-cell imaging, the effects of cis- or oxaliplatin on the mitochondrial function, reactive oxygen species (ROS) production, and mitochondrial and cytosolic calcium concentration of transient receptor potential ankyrin 1 (TRPA1)- or vanilloid 1 (TRPV1)-positive dorsal root ganglion (DRG) neurons of adult Wistar rats were determined. Mitochondrial functions were impaired after exposure to cis- or oxaliplatin by mitochondrial respiratory chain complex I-III inhibition. The basal respiration, spare respiratory capacity, and the adenosine triphosphate (ATP)-linked respiration were decreased after exposure to 10 µM cis- or oxaliplatin. The ROS production showed an immediate increase, and after reaching the peak, ROS production dropped. Calcium imaging showed an increase in the cytosolic calcium concentration during exposure to 10 µM cis- or oxaliplatin in TRPA1- or TRPV1-positive DRG neurons while the mitochondrial calcium concentration continuously decreased. Our data demonstrate a significant effect of cis- and oxaliplatin on mitochondrial function as an early event of platinum-based drug exposure, suggesting mitochondria as a potential target for preventing chemotherapy-induced neuropathy.