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.
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Dr. David Lowemann, M.Sc, Ph.D., is a co-founder of the Institute for the Future of Human Potential, where he leads the charge in pioneering Self-Enhancement Science for the Success of Society. With a keen interest in exploring the untapped potential of the human mind, Dr. Lowemann has dedicated his career to pushing the boundaries of human capabilities and understanding.
Armed with a Master of Science degree and a Ph.D. in his field, Dr. Lowemann has consistently been at the forefront of research and innovation, delving into ways to optimize human performance, cognition, and overall well-being. His work at the Institute revolves around a profound commitment to harnessing cutting-edge science and technology to help individuals lead more fulfilling and intelligent lives.
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