(720a) Integrative Mathematical Model to Investigate Chemotherapy Induced Peripheral Neuropathy through a Mechanistic Study of Neuronal Dynamics

Chemotherapy Induced Peripheral Neuropathy (CIPN) is a prevalent and painful side effect which arises due to a number of chemotherapy drugs, such as vincristine, paclitaxel, and cisplatin. CIPN can be prolonged, and sometimes, chemotherapy treatment is stopped altogether because of the severe pain. Clinical trials have not been able to establish a treatment for CIPN until now. This is because peripheral neuropathy manifests due to damage to neurons in several ways, such as alteration in calcium signaling, voltage-gated ion channels, fast axonal transport, and occurrence of oxidative stress and inflammation¹. Due to alteration in voltage-gated channels, the dynamics of neuronal spiking and excitability change. Furthermore, alteration in intracellular biochemical reaction kinetics induces the release of cytokines, reactive oxygen species, and other trigger molecules which ultimately lead to axonal degeneration in a neuron. All these events are interlinked in a complex fashion. For example, calcium is involved both in intracellular signaling and in voltage-gated channels. Currently, single potential drugs target only one of these events and seem to fail because of this complexity. Hence, it is imperative to integrate these interlinked events together to identify potential therapeutic cures for CIPN.

To this end, we are developing a mathematical model to predict electrophysiology and intracellular dynamics in a neuron with and without perturbation due to the administration of a chemotherapy drug: paclitaxel. Several models have been developed in the past for electrophysiology² and intracellular dynamics, specifically, intracellular calcium dynamics³. For electrophysiology, voltage dynamics is modeled typically as a function of voltage-gated sodium, potassium and calcium channels induced current, taking into account dynamics of activation and inactivation of these channels. Intracellular calcium dynamics is modeled as a function of Inositol 1,4,5-Triphosphate (IP3) receptor-mediated calcium release from the endoplasmic reticulum in the presence of calcium buffers and ATP pumps. We modify these models to make them suitable for our system, and we couple them together. Further, we seek to perform sensitivity analysis to identify model parameters which are primarily responsible for altered dynamics upon administration of paclitaxel. A combination of drugs targeting those parameters can potentially reverse CIPN. This integrative mathematical modeling approach to explore therapeutic cures for CIPN is novel and is a promising step towards establishing a collaborative effort among clinicians, experimentalists, and mathematicians, which can lead to determining a robust solution to this long-standing problem.

References:

1. Carozzi, V. A., A. Canta, and A. Chiorazzi. "Chemotherapy-induced peripheral neuropathy: what do we know about mechanisms?." Neuroscience letters 596 (2015): 90-107.
2. Dayan, Peter, and Laurence F. Abbott. Theoretical neuroscience. Vol. 806. Cambridge, MA: MIT Press, 2001.
3. Sneyd, J., and M. Falcke. "Models of the inositol trisphosphate receptor." Progress in biophysics and molecular biology 89.3 (2005): 207-245.