title: Nerve growth factor alters microtubule targeting agent-induced neurotransmitter release but not MTA-induced neurite retraction in sensory neurons.
abstract: Peripheral neuropathy is a dose-limiting side effect of anticancer treatment with the microtubule-targeted agents (MTAs), paclitaxel and epothilone B (EpoB); however, the mechanisms by which the MTAs alter neuronal function and morphology are unknown. We previously demonstrated that paclitaxel alters neuronal sensitivity, in vitro, in the presence of nerve growth factor (NGF). Evidence in the literature suggests that NGF may modulate the neurotoxic effects of paclitaxel. Here, we examine whether NGF modulates changes in neuronal sensitivity and morphology induced by paclitaxel and EpoB. Neuronal sensitivity was assessed using the stimulated release of calcitonin gene-related peptide (CGRP), whereas morphology of established neurites was evaluated using a high content screening system. Dorsal root ganglion cultures, maintained in the absence or presence of NGF, were treated from day 7 to day 12 in culture with paclitaxel (300nM) or EpoB (30nM). Following treatment, the release of CGRP was stimulated using capsaicin or high extracellular potassium. In the presence of NGF, EpoB mimicked the effects of paclitaxel: capsaicin-stimulated release was attenuated, potassium-stimulated release was slightly enhanced and the total peptide content was unchanged. In the absence of NGF, both paclitaxel and EpoB decreased capsaicin- and potassium-stimulated release and the total peptide content, suggesting that NGF may reverse MTA-induced hyposensitivity. Paclitaxel and EpoB both decreased neurite length and branching, and this attenuation was unaffected by NGF in the growth media. These differential effects of NGF on neuronal sensitivity and morphology suggest that neurite retraction is not a causative factor to alter neuronal sensitivity.
authors.affiliation: Indiana University School of Medicine, Department of Pharmacology and Toxicology, United States. Electronic address: sherry.pittman@bastyr.edu.
authors.forename: Sherry K
authors.initials: SK
authors.lastname: Pittman
authors.affiliation: Indiana University School of Medicine, Department of Pharmacology and Toxicology, United States; Indiana University School of Medicine, Stark Neuroscience Research Institute, United States. Electronic address: neilia.gracias@gmail.com.
authors.forename: Neilia G
authors.initials: NG
authors.lastname: Gracias
authors.affiliation: Indiana University School of Medicine, Department of Pharmacology and Toxicology, United States; Indiana University School of Medicine, Stark Neuroscience Research Institute, United States; Indiana University School of Medicine, Department of Anesthesiology, United States. Electronic address: jfehrenb@iu.edu.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Fehrenbacher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D034261:Epothilones / Q000494:pharmacology / Q000633:toxicity; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D008297:Male; D008870:Microtubules / Q000187:drug effects*; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects*; D009479:Neuropeptides / Q000096:biosynthesis; D018377:Neurotransmitter Agents / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology / Q000633:toxicity; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D020932:Nerve Growth Factor; D015740:Calcitonin Gene-Related Peptide; D017239:Paclitaxel; D011188:Potassium; D002211:Capsaicin; C093788:epothilone B
keywords: Chemotherapy-induced peripheral neuropathy; Epothilone B; Microtubule; Nerve growth factor; Neurite outgrowth; Neuropeptide; Paclitaxel; Retraction; Sensory neuron