Effect of Lidocaine Transdermal Patch as Add-On Therapy in Treatment of Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer Patients
Ontology highlight
ABSTRACT: Oxaliplatin (OXA) is a third-generation platinum-based chemotherapeutic drug with better efficacy for colorectal carcinoma (CRC). Oxaliplatin-induced peripheral neuropathy (OIPN) is one of the most frequent dose-limiting or even treatment-terminating side effects that impair optimal treatment regimens in a significant proportion of patients from 19% to over 85%. Thus, OIPN impacts the quality of life and the patient’s survival. OIPN is a clinical challenge and healthcare professionals are facing this challenge with a limited selection of analgesics and nonpharmacological therapies. Pregabalin is a structural derivative of GABA and is one of the effective treatment modalities for OIPN. It binds with high affinity to the alpha2-delta site of voltage-gated calcium channels in central nervous system tissues and inhibits neurotransmitter release, thus producing anti-nociceptive and anti-seizure effects.
DISEASE(S): Peripheral Nervous System Diseases,Oxaliplatin Induced Peripheral Neuropathy In Cancer Patients
Project description:Kv1.2 is a prominent voltage-gated potassium channel that influences action potential generation and propagation in the central nervous system. We explored multi-protein complexes containing Kv1.2 using mass spectrometry of immunoprecipitated samples. Proteins identified as candidate interactors were prioritized based on abundance, and were screened for functional effects on Kv1.2 channels using electrophysiology.
Project description:Electrical excitability—the ability to fire and propagate action potentials—is a signature feature of neurons. How neurons become excitable during development and whether excitability is an intrinsic property of neurons or requires signaling from glial cells remain unclear. Here, we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E2, which is necessary and sufficient to induce developing somatosensory neurons to express normal levels of genes required for neuronal function, including voltage gated sodium channels, and to fire action potential trains. In this RNA-Seq study, we discovered that treating cultured DRG neurons with Schwann cell-conditioned media or PGE2 increased the expression of several genes required for neuronal maturation and excitability, including voltage-gated sodium channels.
Project description:Voltage gated calcium channels play a central role in regulating the electrical and biochemical properties of neurons and muscle cells. Cells coordinate the expression of voltage gated calcium channels with the expression of other proteins that regulate membrane potential and calcium homeostasis. We report that the C-terminus of CaV 1.2, an L-type calcium channel (LTC) contains a C-terminal fragment that translocates to the nucleus and regulates transcription. This calcium channel associated transcription factor (CCAT) associates with transcriptional co-regulators such as p54nrb/NonO and binds to endogenous promoters. CCAT regulates the expression of gap junctions, sodium calcium exchangers, NMDA receptors, potassium channels and other proteins that regulate neuronal signaling. Electrical activity and developmental processes regulate the nuclear localization of CCAT, suggesting that the CCAT integrates information about the number of LTCs with information about the developmental history and electrical activity of a cell. These findings provide the first evidence that voltage gated calcium channels can directly activate transcription and suggest a novel mechanism linking voltage gated channels to the function and differentiation of excitable cells. Keywords: Genetic modification Analysis
2006-05-05 | GSE4180 | GEO
Project description:Targeted Sequencing of Salamander Voltage-Gated Sodium Channels
Project description:Increasing evidence suggests that loss of beta cell characteristics may cause insulin secretory deficiency in diabetes but the underlying mechanisms remain unclear. Here we show that Rfx6, whose mutation leads to neonatal diabetes in man, is essential to maintain key features of functionally mature beta cells in mice. Rfx6 loss in adult beta cells leads to glucose intolerance, impaired beta cell glucose sensing and to defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway including GLucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca2 channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of M-bM-^@M-^\disallowedM-bM-^@M-^] genes, a group usually specifically repressed in adult beta cells, and thus to the maintenance of beta cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to beta cell failure in man. Two ChIP-Seq experiments have been performed : 1) anti-HA ChIP-Seq on 3HA-Rfx6 transfected Min6b1 cells and 2) anti-HA ChIP-Seq on Min6b1 cells
Project description:The long-term goal of this project is to establish whether and how chronic nicotine exposure affects nervous system function. The biological targets of nicotine action are diverse members of the superfamily of neurotransmitter-gated ion channels called nicotinic acetylcholine receptors (nAChR). nAChR play multiple, critical roles in chemical signaling throughout the brain and body. They also must be involved in nicotine dependence, which drives tobacco product use responsible for tremendous economic and personal costs. To define changes in gene expression induced by nicotine exposure in a model neuronal cell lines expressing at least two nicotinic receptor subtypes. Nicotine exposure exerst at least some of its effects on nervous system function by altering gene expression. Cells of the SH-SY5Y human neuroblastoma will be exposed to an efficacious dose of nicotine or to control medium for two different periods.
Project description:The cellular and molecular actions of general anaesthetics to induce anaesthesia state and also cellular signalling changes for subsequent potential “long term” effects remain largely elusive although great efforts have been made to study these in vitro, ex vivo and in vivo settings. General anaesthetics were reported to act on voltage-gated ion channels and ligand-gated ion channels. Here we used single-cell RNA-sequencing complemented with whole-cell patch clamp and calcium transient techniques to examine the gene transcriptome and ion channels profiling of sevoflurane and propofol, both commonly used clinically, on human embryonic primary prefrontal cortex (PFC) mixed cell cultures. Both propofol and sevoflurane at clinically relevant dose/concentration promoted “microgliosis” but only sevoflurane changed microglia cell similarity. Propofol and sevoflurane each extensively but transiently altered transcriptome profiling 2 hours after anaesthetics exposure across microglia, excitatory neurons, interneurons, astrocytes and oligodendrocyte progenitor cells. Within the excitatory neurons and microglia, exemplary ion-gated and ligand-gated ion channels related genes response to either anaesthetic included SCN1A, CACNAB2, KCNA1, GABRR2 and GRINA1 amongst many others. Utilising scRNA-seq as a robust and high-throughput tool, our work may provide a comprehensive blueprint for future mechanistic studies of general anaesthetics in clinically relevant settings.
Project description:Voltage-gated sodium channels are responsible for the initiation and propagation of action potentials in excitable cells. While the channel is functional on its own, it is the transient and stable protein-protein interactions that modulate functional outcomes. AP-MS has been successfully applied to a number of ion channels. However to the best of our knowledge, no AP-MS study has been carried out on any member of the voltage-gated sodium channel family.
Project description:Voltage-gated potassium channels (VGKCs) comprise one of the largest, most diverse and complex families of ion channels. Approximately 70 genes encode the alpha subunits that form homomeric VGKC channels. In addition, these subunits can form functional heteromeric channels, thus exponentially increasing the diversity of VGKCs. The functional expression and physiological role of heteromeric K-channels have remained largely unexplored due to the lack of tools to probe their functions. Conotoxins have high affinity and specificity for heteromeric combinations of K-channels and show great promise for elucidating their functions. In this work, using conotoxin kM-RIIIJ as a pharmacological probe, we explore the expression and physiological functions of heteromeric Kv1.2 channels using constellation pharmacology. We report that heteromers of Kv1.2/1.1 are highly expressed in proprioceptive neurons found in the dorsal root ganglion (DRG). Inhibition of Kv1.2/1.1 heteromers leads to an influx of calcium ions, suggesting that these channels regulate neuronal excitability. We also present evidence that Kv1.2/1.1 heteromers counteract persistent sodium currents, and that inhibiting these channels leads to tonic firing of action potentials. Additionally, kM-RIIIJ induces impaired proprioception in mice, uncovering a previously unrecognized physiological role of heteromeric Kv1.2/1.1 channels in proprioceptive sensory neurons of the DRG.
Project description:The goal of this study was to analyze global gene expression in specific populations of somatosensory neurons in the periphery, including major, non-overlapping populations that include nociceptors, pruriceptors, and prorioceptors. The mammalian somatosensory nervous system encodes the perception of specific environmental stimuli. The dorsal root ganglion (DRG) contains distinct somatosensory neuron subtypes that innervate diverse peripheral tissues, mediating the detection of thermal, mechanical, proprioceptive, pruriceptive, and nociceptive stimuli. We purified discrete subtypes of mouse DRG somatosensory neurons by flow cytometry using fluorescently labeled mouse lines (SNS-Cre/TdTomato, Parv-Cre/TdTomato) in combination with Isolectin B4-FITC surface staining (IB4). This allowed identification of transcriptional differences between these major populations, revealing enrichment of voltage-gated ion channels, TRP channels, G-protein coupled receptors, transcription factors, and other functionally important classes of genes within specific somatosensory neuron subsets.