(158c) A Mathematical Investigation of Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy is like a double-edged sword. On one hand, it has enabled a high survival rate for cancer patients, on the other, it can cause them severe discomfort due to several disabling side-effects. One of its common side-effects is chemotherapy-induced peripheral neuropathy (CIPN): a painful, numbing and tingling sensation felt in the palm and feet. Sometimes, this effect is prolonged and severely impacts the daily life of these patients by hindering their regular activities such as climbing the stairs, writing, etc. Currently, there are no established therapeutic agents to treat CIPN, which stems from an incomplete understanding of its pathophysiology. A chemotherapy drug attacks several parts of a neuron (nerve cell) via various avenues, leading to peripheral neuropathy. Several of these avenues are interlinked in a complex fashion. This seems to explain the failure of single potential therapeutic agents that target only one of these avenues. Hence, it is imperative to examine the system holistically. The aim of this study is to investigate the interaction of various voltage-gated ion channels and their role in inducing CIPN, in a comprehensive manner, using dynamical systems theory.

To this end, we analyzed a mathematical model to predict electrophysiology in a pain-sensing neuron. We focused on investigating the role of ion channels in inducing hyperexcitability, which is an abnormality in voltage dynamics, and is a potential indicator of peripheral neuropathy in vitro[1,2]. We used dynamical systems theory to understand the functioning of a pain-sensing neuron, and the conditions under which it becomes susceptible to hyperexcitability due to a change in either the expression of ion channels or the intensity of external stimulus. We found subcritical Hopf, limit point and period doubling bifurcations explaining different voltage dynamics displayed by the neuron. Furthermore, we found specific sodium and potassium ion channels that can potentially induce hyperexcitability since they were highly sensitive to the bifurcations. By selectively targeting them, we can possibly reverse hyperexcitability and hence provide a treatment strategy for CIPN. Through this work, we provide a novel and promising framework for identifying important parameters that can treat this debilitating side-effect and have prospects of improving the quality of life of cancer patients.

References:

1. Chung JM, Chung K. Importance of hyperexcitability of DRG neurons in neuropathic pain. Pain Practice. 2002, 2.2, 87-97.
2. Aromolaran KA, Goldstein PA. Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy: Cause and effect?. Molecular pain. 2017, 13, 1744806917714693.