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bioRxiv · 10.1101/2020.04.23.057851

A mathematical investigation of chemotherapy-induced peripheral neuropathy

Verma, P.·Eaton, M.·Kienle, A.·Flockerzi, D.·Yang, Y.·Ramkrishna, D.
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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. A surrogate of neuropathic pain in an in vitro setting 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 suggests that the sodium channel Nav1.8 and the delayed rectifier potassium channel conductances are the most critical for hyperexcitability in normal firing small DRG neurons. Introducing paclitaxel into the model, our bifurcation analysis predicts that hyperexcitability is extreme for a medium dose of paclitaxel, which is validated by multi-electrode array recordings. Our findings using multi-electrode array experiments reveal that the Nav1.8 blocker A-803467 and the delayed rectifier potassium enhancer L-alpha-phosphatidyl-D-myo-inositol 4,5-diphosphate, dioctanoyl (PIP2) have a protective effect on the firing rate of DRG when administered separately together with paclitaxel as suggested by our bifurcation analysis.

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Verma, P., Eaton, M., Kienle, A., Flockerzi, D., Yang, Y., Ramkrishna, D.. 2020-04-25. A mathematical investigation of chemotherapy-induced peripheral neuropathy. https://doi.org/10.1101/2020.04.23.057851

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