Recommended Citation
Verma, Parul; Eaton, Muriel; Kienle, Achim; Flockerzi, Dietrich; Yang, Yang; and Ramkrishna, Doraiswami, "Examining Sodium and Potassium Channel Conductances Involved in Hyperexcitability of Chemotherapy-Induced Peripheral Neuropathy: A Mathematical and Cell Culture-Based Study" (2020). Purdue University Libraries Open Access Publishing Fund. Paper 140.
http://dx.doi.org/10.3389/fncom.2020.564980
DOI
10.3389/fncom.2020.564980
Date of this Version
10-14-2020
Keywords
chemotherapy-induced peripheral neuropathy, ion channel, bifurcation theory, hyperexcitability, paclitaxel, DRG neuron, multielectrode array
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent, painful side effect which arises due to a number of chemotherapy agents. CIPN can have a prolonged effect on quality of life. Chemotherapy treatment is often reduced or stopped altogether because of the severe pain. Currently, there are no FDA-approved treatments for CIPN partially due to its complex pathogenesis in multiple pathways involving a variety of channels, specifically, voltage-gated ion channels. One aspect of neuropathic pain in vitro is hyperexcitability in dorsal root ganglia (DRG) peripheral sensory neurons. Our study employs bifurcation theory to investigate the role of voltage-gated ion channels in inducing hyperexcitability as a consequence of spontaneous firing due to the common chemotherapy agent paclitaxel. Our mathematical investigation of a reductionist DRG neuron model comprised of sodium channel Nav1.7, sodium channel Nav1.8, delayed rectifier potassium channel, A-type transient potassium channel, and a leak channel suggests that Nav1.8 and delayed rectifier potassium channel conductances are critical for hyperexcitability of small DRG neurons. Introducing paclitaxel into the model, our bifurcation analysis predicts that hyperexcitability is highest for a medium dose of paclitaxel, which is supported by multi-electrode array (MEA) recordings. Furthermore, our findings using MEA reveal that Nav1.8 blocker A-803467 and delayed rectifier potassium enhancer L-alpha-phosphatidyl-D-myo-inositol 4,5-diphosphate, dioctanoyl (PIP2) can reduce paclitaxel-induced hyperexcitability of DRG neurons. Our approach can be readily extended and used to investigate various other contributors of hyperexcitability in CIPN.
Comments
This is the publisher PDF of Verma P, Eaton M, Kienle A, Flockerzi D, Yang Y and Ramkrishna D (2020) Examining Sodium and Potassium Channel Conductances Involved in Hyperexcitability of Chemotherapy-Induced Peripheral Neuropathy: A Mathematical and Cell Culture-Based Study. Front. Comput. Neurosci. 14:564980. This article is distributed under a CC-BY license, and is available at DOI: 10.3389/fncom.2020.564980.