Abstract
Oxaliplatin is an agent that is used extensively in gastrointestinal cancer chemotherapy. The agent's major dose-limiting toxicity is peripheral neuropathy that can manifest as a chronic or an acute syndrome. Oxaliplatin-induced acute neuropathy is purportedly caused by an alteration of the biophysical properties of voltage-gated sodium channels. However, sodium channel blockers have not been successful at preventing acute neuropathy in the clinical setting. We report intra-axonal recordings from the isolated rat sciatic nerve preparation under the effect of oxaliplatin. The depolarization phase of single action potentials remains intact with a duration of 0.52 ± 0.02 ms (n=68) before and 0.55 ± 0.01 ms (n=68) after 1-5 h of exposure to 150 μM oxaliplatin (unpaired t-test, P > 0.05) whereas there is a significant broadening of the repolarization phase (2.16 ± 0.10 ms, n=68, before and 5.90 ± 0.32 ms after, n=68, unpaired t-test, P < 0.05). Apart from changes in spike shape, oxaliplatin also had drastic concentration- and time-dependent effects on the firing responses of fibers to short stimuli. In the intra-axonal recordings, three groups of firing patterns were indentified. The first group shows bursting (internal frequency 90 - 130 Hz, n=88), the second shows a characteristic plateau (at -19.27±2.84 mV, n=31, with durations ranging from 45 - 140 ms depending on the exposure time), and the third combines a plateau and a bursting period. Our results implicate the voltage-gated potassium channels as additional oxaliplatin targets, opening up new perspectives for the pharmacological prevention of peripheral neuropathy.
Keywords: Action potential, Colorectal cancer, Hyperexcitability, Intra-axonal recordings, Peripheral neuropathy, Oxaliplatin, Sciatic nerve fiber
Anti-Cancer Agents in Medicinal Chemistry
Title:Oxaliplatin-induced Hyperexcitation of Rat Sciatic Nerve Fibers: An Intra-axonal Study
Volume: 13 Issue: 2
Author(s): Alexia Kagiava, Efstratios K. Kosmidis and George Theophilidis
Affiliation:
Keywords: Action potential, Colorectal cancer, Hyperexcitability, Intra-axonal recordings, Peripheral neuropathy, Oxaliplatin, Sciatic nerve fiber
Abstract: Oxaliplatin is an agent that is used extensively in gastrointestinal cancer chemotherapy. The agent's major dose-limiting toxicity is peripheral neuropathy that can manifest as a chronic or an acute syndrome. Oxaliplatin-induced acute neuropathy is purportedly caused by an alteration of the biophysical properties of voltage-gated sodium channels. However, sodium channel blockers have not been successful at preventing acute neuropathy in the clinical setting. We report intra-axonal recordings from the isolated rat sciatic nerve preparation under the effect of oxaliplatin. The depolarization phase of single action potentials remains intact with a duration of 0.52 ± 0.02 ms (n=68) before and 0.55 ± 0.01 ms (n=68) after 1-5 h of exposure to 150 μM oxaliplatin (unpaired t-test, P > 0.05) whereas there is a significant broadening of the repolarization phase (2.16 ± 0.10 ms, n=68, before and 5.90 ± 0.32 ms after, n=68, unpaired t-test, P < 0.05). Apart from changes in spike shape, oxaliplatin also had drastic concentration- and time-dependent effects on the firing responses of fibers to short stimuli. In the intra-axonal recordings, three groups of firing patterns were indentified. The first group shows bursting (internal frequency 90 - 130 Hz, n=88), the second shows a characteristic plateau (at -19.27±2.84 mV, n=31, with durations ranging from 45 - 140 ms depending on the exposure time), and the third combines a plateau and a bursting period. Our results implicate the voltage-gated potassium channels as additional oxaliplatin targets, opening up new perspectives for the pharmacological prevention of peripheral neuropathy.
Export Options
About this article
Cite this article as:
Kagiava Alexia, K. Kosmidis Efstratios and Theophilidis George, Oxaliplatin-induced Hyperexcitation of Rat Sciatic Nerve Fibers: An Intra-axonal Study, Anti-Cancer Agents in Medicinal Chemistry 2013; 13 (2) . https://dx.doi.org/10.2174/1871520611313020023
DOI https://dx.doi.org/10.2174/1871520611313020023 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
CDK Inhibitors: From the Bench to Clinical Trials
Current Drug Targets JAK Inhibitors: Pharmacology and Clinical Activity in Chronic Myeloprolipherative Neoplasms
Current Medicinal Chemistry Pharmacogenetics of Oxazaphosphorines and its Clinical Implications
Current Pharmacogenomics Pharmacogenomics of Cytochrome P450 Enzymes in Tumours
Current Pharmacogenomics Prodrugs in Genetic Chemoradiotherapy
Current Pharmaceutical Design Genetic Mechanisms and Aberrant Gene Expression during the Development of Gastric Intestinal Metaplasia and Adenocarcinoma
Current Genomics Therapeutic Strategies for Targeting BRAF in Human Cancer
Reviews on Recent Clinical Trials p42.3 in Gastric Carcinoma: A Novel Biomarker and Promising Therapeutic Target
Letters in Drug Design & Discovery Evaluation of Variances in VEGF-A-D and VEGFR-1-3 Expression in the Ishikawa Endometrial Cancer Cell Line Treated with Salinomycin and Anti-Angiogenic/Lymphangiogenic Effect
Current Pharmaceutical Biotechnology Drug Discovery and Protein Tyrosine Phosphatases
Current Medicinal Chemistry Himalayan Plants as a Source of Anti-Cancer Agents: A Review
The Natural Products Journal Lapatinib as a Chemotherapeutic Drug
Recent Patents on Anti-Cancer Drug Discovery Randomised Trials in Surgery: The Burden of Evidence
Reviews on Recent Clinical Trials Developments in the Application of 1,2,3-Triazoles in Cancer Treatment
Recent Patents on Anti-Cancer Drug Discovery DNA-Damaging Anticancer Drugs – A Perspective for DNA Repair- Oriented Therapy
Current Medicinal Chemistry Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets
Anti-Cancer Agents in Medicinal Chemistry Non-Genotoxic p53-Activators and their Significance as Antitumor Therapy of Future
Current Medicinal Chemistry Recent Advances in Cancer Therapy: An Overview
Current Pharmaceutical Design Pro-apoptotic Activity of BH3-only Proteins and BH3 Mimetics: from Theory to Potential Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Inflammation and Cancer: In Medio Stat Nano
Current Medicinal Chemistry