Examining Sodium and Potassium Channel Conductances Involved in Hyperexcitability of Chemotherapy-Induced Peripheral Neuropathy: A Mathematical and Cell Culture-Based Study.

Parul Verma,Doraiswami Ramkrishna,Yang Yang,Dietrich Flockerzi,Muriel Eaton,Achim Kienle

doi:10.3389/fncom.2020.564980

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.

Highlights

Chemotherapy-induced peripheral neuropathy (CIPN) is a painful, dose-limiting side effect of chemotherapy cancer treatment that affects more than 85% of patients during treatment (Fallon, 2013) and 60% of patients 3 months post chemotherapy treatment (Seretny et al, 2014)
We apply a mathematical approach using numerical bifurcation theory to understand the role of sodium channel Nav1.7, sodium channel Nav1.8, delayed rectifier potassium channel, and A-type transient potassium channel in CIPN in a putative small dorsal root ganglia (DRG) neuron model
We found that, increasing g1.8 and decreasing gKDR can induce spontaneous firing in a simplified DRG neuron model

Summary

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is a painful, dose-limiting side effect of chemotherapy cancer treatment that affects more than 85% of patients during treatment (Fallon, 2013) and 60% of patients 3 months post chemotherapy treatment (Seretny et al, 2014). These patients report enduring “pin and needle” paresthesias (i.e., tingling, numbness) in the peripheral nervous system (hands and feet) (Park et al, 2013). To improve quality of life of cancer patients, it is imperative to find CIPN preventive agents. Since there is currently no FDA-approved treatment for CIPN, management of CIPN-induced pain includes many options such as antidepressants, anticonvulsants, anti-inflammatory, and opioid therapies

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