scholarly journals Cancer Exacerbates Chemotherapy Induced Sensory Neuropathy

2019 ◽  
Author(s):  
Stephen N. Housley ◽  
Paul Nardelli ◽  
Dario Carrasco ◽  
Emily Pfahl ◽  
Lilya Matyunina ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Ion Channel ◽  
Neurological Disorders ◽  
Neuronal Excitability ◽  
Inflammatory Responses ◽  
Transcriptional Profiling ◽  
Sensory Neuropathy ◽  
Potential Contributor ◽  
Sensory Encoding ◽  
Linear Interactions

AbstractFor the constellation of neurological disorders known as chemotherapy induced peripheral neuropathy, mechanistic understanding, and treatment remain deficient. Here we present the first evidence in preclinical investigation of rats that chronic sensory neuropathy depends on non-linear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as a potential contributor to sensory neuron dysfunction. These original findings identify novel contributors to peripheral neuropathy, and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer.

scholarly journals PKA-RIIβ autophosphorylation modulates PKA activity and seizure phenotypes in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jingliang Zhang ◽  
Chenyu Zhang ◽  
Xiaoling Chen ◽  
Bingwei Wang ◽  
Weining Ma ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Neurological Disorders ◽  
Neuronal Excitability ◽  
Granule Cells ◽  
Critical Role ◽  
Intrinsic Excitability ◽  
Seizure Susceptibility ◽  
Seizure Onset ◽  
Potential Therapeutic Target ◽  
Seizure Model

AbstractTemporal lobe epilepsy (TLE) is one of the most common and intractable neurological disorders in adults. Dysfunctional PKA signaling is causally linked to the TLE. However, the mechanism underlying PKA involves in epileptogenesis is still poorly understood. In the present study, we found the autophosphorylation level at serine 114 site (serine 112 site in mice) of PKA-RIIβ subunit was robustly decreased in the epileptic foci obtained from both surgical specimens of TLE patients and seizure model mice. The p-RIIβ level was negatively correlated with the activities of PKA. Notably, by using a P-site mutant that cannot be autophosphorylated and thus results in the released catalytic subunit to exert persistent phosphorylation, an increase in PKA activities through transduction with AAV-RIIβ-S112A in hippocampal DG granule cells decreased mIPSC frequency but not mEPSC, enhanced neuronal intrinsic excitability and seizure susceptibility. In contrast, a reduction of PKA activities by RIIβ knockout led to an increased mIPSC frequency, a reduction in neuronal excitability, and mice less prone to experimental seizure onset. Collectively, our data demonstrated that the autophosphorylation of RIIβ subunit plays a critical role in controlling neuronal and network excitabilities by regulating the activities of PKA, providing a potential therapeutic target for TLE.

Neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors

Neurology ◽  
2019 ◽  
Vol 93 (2) ◽  
pp. e143-e148 ◽  
Author(s):  
Bhaskar Roy ◽  
Avash Das ◽  
Kumar Ashish ◽  
Dhrubajyoti Bandyopadhyay ◽  
Abhishek Maiti ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Sensory Neuropathy ◽  
Vascular Endothelial ◽  
High Grade ◽  
Patients With Cancer ◽  
Endothelial Growth Factor ◽  
Receptor Tyrosine Kinase Inhibitors

ObjectiveTo explore the association of peripheral neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) use in patients with cancer.MethodsPublished data search up to November 2018 reporting peripheral neuropathy in patients with cancer treated with VEGFR-TKIs was performed. The primary outcome was presence of peripheral neuropathy at the end of the trial. Random-effects meta-analysis was performed to estimate relative risk (RR) of individual treatment.ResultsThirty randomized clinical trials (RCTs) including 12,490 patients with cancer were included in this analysis. Eight studies compared VEGFR-TKIs with placebo and the remaining studies compared VEGFR-TKIs with the standard chemotherapeutic regimen. When compared against placebo, VEGFR-TKIs were associated with a higher risk of peripheral neuropathy (RR 1.76; 95% confidence interval [CI] 1.13–2.75, p = 0.01). Similarly, a stronger association was noted for sensory neuropathy with VEGFR-TKIs monotherapy (RR 1.61; 95% CI 1.09–2.37, p = 0.02). Risk of peripheral neuropathy with VEGFR-TKIs was higher even when they were compared against control (either placebo or standard chemotherapeutic agents) (RR 1.08; 95% CI 1.01–1.15, p = 0.03). High-grade neuropathy (RR 1.28; 95% CI 1.06–1.54, p <0.01) and high-grade sensory neuropathy (RR 1.38; 95% CI 1.09–1.74, p < 0.01) were noted more frequently with VEGFR-TKIs treatment compared against control.ConclusionsVEGFR-TKIs therapy appeared to be associated with an increased risk of neuropathy.

EP.112Congenital sensory neuropathy as a new associated finding in COG6 and PIGG neurological disorders

2019 ◽  
Vol 29 ◽  
pp. S200
Author(s):  
L. CostaComellas ◽  
D. Gómez Andrés ◽  
M. Alvarez-Molinero ◽  
M. Gratacós Viñola ◽  
A. Sanchez-Montáñez ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Sensory Neuropathy

scholarly journals Effectiveness assessment of riluzole in the prevention of oxaliplatin-induced peripheral neuropathy: RILUZOX-01: protocol of a randomised, parallel, controlled, double-blind and multicentre study by the UNICANCER-AFSOS Supportive Care intergroup

BMJ Open ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. e027770 ◽  
Author(s):  
Nicolas Kerckhove ◽  
Jérome Busserolles ◽  
Trevor Stanbury ◽  
Bruno Pereira ◽  
Valérie Plence ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Disease Free Survival ◽  
Sensory Neuropathy ◽  
Repeated Administration ◽  
Public Health Issue ◽  
Double Blind Study ◽  
Double Blind ◽  
Related Quality ◽  
Registration Number ◽  
Randomised Controlled

IntroductionMost patients (>70%) experience acute neuropathic symptoms shortly after oxaliplatin infusions. These symptoms are not always resolved between infusions. Overall, 30%–50% of patients suffer from chronic oxaliplatin-induced peripheral neuropathy (OIPN). This cumulative and dose-dependent sensory neuropathy limits compliance or results in oxaliplatin-based chemotherapies to be substituted with less neurotoxic agents. These treatment changes impair clinical outcomes, and may be associated with comorbidities, such as distress, depression and anxiety. Currently, no drug used to prevent or treat OIPN is sufficiently effective to be used routinely in clinical practice. There is, thus, an unmet therapeutic need to reduce the intensity of and/or prevent OIPN. We hypothesised that riluzole would be an excellent candidate to address this public health issue. Riluzole is approved for treating amyotrophic lateral sclerosis. In animals, there is a beneficial effect on sensorimotor and pain disorders, as well as related comorbidities, after repeated administration of oxaliplatin. In humans, riluzole has shown neuroprotective, anxiolytic and antidepressive effects.Methods and analysisRILUZOX-01 trial was designed as a randomised, controlled, double-blind study to evaluate the efficacy of riluzole to prevent OIPN. Patients with colorectal cancer and initiating adjuvant oxaliplatin-based chemotherapy are eligible. Patients (n=210) will be randomly assigned to either riluzole or placebo, concomitantly with chemotherapy. The primary endpoint is the change in OIPN intensity, assessed by the sensory scale of the QLQ-CIPN20, after six 2-week cycles of chemotherapy. Secondary endpoints include incidence and severity of neuropathy, grade of sensory neuropathy, intensity and features of neuropathic pain, health-related quality of life, disease-free survival, overall survival and safety.Ethics and dessiminationThe study was approved by a French ethics committee (ref:39/18_1, ‘Comité de Protection des Personnes’ Ouest-IV, France) and plans to start enroling patients in September 2019. The trial is registered in EudraCT and clinicaltrials.gov.Trial registration numberN°2017-002320-25;NCT03722680

scholarly journals Mechanisms of Chemotherapy-Induced Peripheral Neuropathy

2019 ◽  
Vol 20 (6) ◽  
pp. 1451 ◽  
Author(s):  
Renata Zajączkowska ◽  
Magdalena Kocot-Kępska ◽  
Wojciech Leppert ◽  
Anna Wrzosek ◽  
Joanna Mika ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Cancer Patients ◽  
Health Care Providers ◽  
Antineoplastic Agents ◽  
Proteasome Inhibitors ◽  
Sensory Neuropathy ◽  
Vinca Alkaloids ◽  
Care Providers ◽  
Underlying Mechanisms ◽  
The Moment

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. Clinically, CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers, especially because, at the moment, there is no single effective method of preventing CIPN; moreover, the possibilities of treating this syndrome are very limited. There are six main substance groups that cause damage to peripheral sensory, motor and autonomic neurons, which result in the development of CIPN: platinum-based antineoplastic agents, vinca alkaloids, epothilones (ixabepilone), taxanes, proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). Among them, the most neurotoxic are platinum-based agents, taxanes, ixabepilone and thalidomide; other less neurotoxic but also commonlyused drugs are bortezomib and vinca alkaloids. This paper reviews the clinical picture of CIPN and the neurotoxicity mechanisms of the most common antineoplastic agents. A better understanding of the risk factors and underlying mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies.

scholarly journals The Anti-Tumor Agent Sodium Selenate Decreases Methylated PP2A, Increases GSK3βY216 Phosphorylation, Including Tau Disease Epitopes and Reduces Neuronal Excitability in SHSY-5Y Neurons

2019 ◽  
Vol 20 (4) ◽  
pp. 844 ◽  
Author(s):  
Wesal Habbab ◽  
Imad Aoudé ◽  
Freshteh Palangi ◽  
Sara Abdulla ◽  
Tariq Ahmed
Keyword(s):  
Neurological Disorders ◽  
Neuronal Excitability ◽  
Active Form ◽  
Close Correlation ◽  
Maximum Effect ◽  
Sodium Selenate ◽  
Dependent Manner ◽  
Maximum Increase ◽  
Electrophysiological Studies ◽  
Catalytically Active

Selenium application as sodium selenate was repeatedly shown to have anti-carcinogenic properties by increasing levels of the serine/ threonine protein phosphatase 2A (PP2A) in cancer cells. PP2A has a prominent role in cell development, homeostasis, and in neurons regulates excitability. PP2A, GSK3β and Tau reside together in a complex, which facilitates their interaction and (dys)-function as has been reported for several neurological disorders. In this study we recorded maximum increase in total PP2A at 3 µM sodium selenate in a neuron cell line. In conjunction with these data, whole-cell electrophysiological studies revealed that this concentration had maximum effect on membrane potentials, conductance and currents. Somewhat surprisingly, the catalytically active form, methylated PP2A (mePP2A) was significantly decreased. In close correlation to these data, the phosphorylation state of two substrate proteins, sensitive to PP2A activity, GSK3β and Tau were found to be increased. In summary, our data reveal that sodium selenate enhances PP2A levels, but reduces catalytic activity of PP2A in a dose dependent manner, which fails to reduce Tau and GSK3β phosphorylation under physiological conditions, indicating an alternative route in the rescue of cell pathology in neurological disorders.

scholarly journals Microglia Control Neuronal Network Excitability via BDNF Signalling

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Francesco Ferrini ◽  
Yves De Koninck
Keyword(s):  
Neural Network ◽  
Nitric Oxide ◽  
Neurological Disorders ◽  
Neuronal Excitability ◽  
Current Knowledge ◽  
Glycine Receptor ◽  
Network Activity ◽  
Biophysical Mechanism ◽  
Neural Dysfunctions ◽  
Novel Therapeutic

Microglia-neuron interactions play a crucial role in several neurological disorders characterized by altered neural network excitability, such as epilepsy and neuropathic pain. While a series of potential messengers have been postulated as substrates of the communication between microglia and neurons, including cytokines, purines, prostaglandins, and nitric oxide, the specific links between messengers, microglia, neuronal networks, and diseases have remained elusive. Brain-derived neurotrophic factor (BDNF) released by microglia emerges as an exception in this riddle. Here, we review the current knowledge on the role played by microglial BDNF in controlling neuronal excitability by causing disinhibition. The efforts made by different laboratories during the last decade have collectively provided a robust mechanistic paradigm which elucidates the mechanisms involved in the synthesis and release of BDNF from microglia, the downstream TrkB-mediated signals in neurons, and the biophysical mechanism by which disinhibition occurs, via the downregulation of the K+-Cl−cotransporter KCC2, dysrupting Cl−homeostasis, and hence the strength ofGABAA- and glycine receptor-mediated inhibition. The resulting altered network activity appears to explain several features of the associated pathologies. Targeting the molecular players involved in this canonical signaling pathway may lead to novel therapeutic approach for ameliorating a wide array of neural dysfunctions.

Endogenous ion channel complexes: the NMDA receptor

2011 ◽  
Vol 39 (3) ◽  
pp. 707-718 ◽  
Author(s):  
René A.W. Frank
Keyword(s):  
Nmda Receptor ◽  
Ion Channel ◽  
Present Article ◽  
Neuronal Excitability ◽  
Structure And Function ◽  
Current Understanding ◽  
Ionotropic Receptors ◽  
Receptor Complexes ◽  
Aspartate Receptor ◽  
And Function

Ionotropic receptors, including the NMDAR (N-methyl-D-aspartate receptor) mediate fast neurotransmission, neurodevelopment, neuronal excitability and learning. In the present article, the structure and function of the NMDAR is reviewed with the aim to condense our current understanding and highlight frontiers where important questions regarding the biology of this receptor remain unanswered. In the second part of the present review, new biochemical and genetic approaches for the investigation of ion channel receptor complexes will be discussed.

Structure and Function of TMEM16 Proteins (Anoctamins)

2014 ◽  
Vol 94 (2) ◽  
pp. 419-459 ◽  
Author(s):  
Nicoletta Pedemonte ◽  
Luis J. V. Galietta
Keyword(s):  
Ion Transport ◽  
Ion Channel ◽  
Neuronal Excitability ◽  
Genetic Diseases ◽  
Smooth Muscle Contraction ◽  
Dual Function ◽  
Anoctamin 1 ◽  
Genetic Ablation ◽  
Cell Functions ◽  
Outer Leaflet

TMEM16 proteins, also known as anoctamins, are involved in a variety of functions that include ion transport, phospholipid scrambling, and regulation of other membrane proteins. The first two members of the family, TMEM16A (anoctamin-1, ANO1) and TMEM16B (anoctamin-2, ANO2), function as Ca2+-activated Cl−channels (CaCCs), a type of ion channel that plays important functions such as transepithelial ion transport, smooth muscle contraction, olfaction, phototransduction, nociception, and control of neuronal excitability. Genetic ablation of TMEM16A in mice causes impairment of epithelial Cl−secretion, tracheal abnormalities, and block of gastrointestinal peristalsis. TMEM16A is directly regulated by cytosolic Ca2+as well as indirectly by its interaction with calmodulin. Other members of the anoctamin family, such as TMEM16C, TMEM16D, TMEM16F, TMEM16G, and TMEM16J, may work as phospholipid scramblases and/or ion channels. In particular, TMEM16F (ANO6) is a major contributor to the process of phosphatidylserine translocation from the inner to the outer leaflet of the plasma membrane. Intriguingly, TMEM16F is also associated with the appearance of anion/cation channels activated by very high Ca2+concentrations. Furthermore, a TMEM16 protein expressed in Aspergillus fumigatus displays both ion channel and lipid scramblase activity. This finding suggests that dual function is an ancestral characteristic of TMEM16 proteins and that some members, such as TMEM16A and TMEM16B, have evolved to a pure channel function. Mutations in anoctamin genes ( ANO3, ANO5, ANO6, and ANO10) cause various genetic diseases. These diseases suggest the involvement of anoctamins in a variety of cell functions whose link with ion transport and/or lipid scrambling needs to be clarified.

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