Animal Models of Chemotherapy-Evoked Painful Peripheral Neuropathies

Abstract

Summary:This review examines recent preclinical research on toxic peripheral neuropathy and potential therapeutic developments. Chemotherapy-induced peripheral neurotoxicity is a major clinical problem because it represents the dose-limiting side effects of a significant number of antineoplastic drugs. Patients are unable to complete full or optimal treatment schedules. The incidence of chemotherapy-induced peripheral neuropathy varies depending on the drugs and schedules used, and this can be quite high, particularly when neurophysiological methods are used to make a diagnosis. However, even when chemotherapy-induced peripheral neuropathy is not a doselimiting side effect, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. As such, improved understanding of the pathophysiology of chemotherapy-induced neurotoxicity need for animal models is clinically relevant and will assist in the development of future neuroprotective strategies and also in the design of novel chemotherapies with improved toxicity profiles. In this review, the features of animal models of chemotherapy-induced painful neuropathy developed for 20 years, due to the administration of the most widely used drugs, such as platinum drugs, taxanes, and vinca alkaloids, will be discussed. In a second part, data available on neuroprotectants and treatment strategies, evaluated using these previous animal models in the attempt to prevent neuropathic pain, will be summarized.

Comparison of Neuropathy-Inducing Effects of Eribulin Mesylate, Paclitaxel, and Ixabepilone in Mice

“…Similar to the human situation, chemotherapy-induced neuropathy rodent models are characterized by neurophysiologic deficits and morphologic A B C D Figure 6. alterations in DRG and myelinated nerve fibers (23,(34)(35)(36). Somewhat surprisingly, in spite of the existence of such models, to our knowledge, there has never been a systematic comparison of the various microtubule-targeting agents in preclinical models.…”

“…As the understanding of the interactions of tubulin-targeting agents at the molecular level increases, differences in activity and side effects may become clearer. Differences in microtubulebinding properties may have significant effects on the toxicity profile of each agent (10,36).…”

Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain

“…Pain is the key symptom of this condition and rated as a 7 of 10 in severity by patients (4) who assigned "throbbing," "sharp," and "burning" properties to the pain (6). For those who are able to complete their chemotherapy treatment, pain remains poorly controlled by available analgesics (6), thus prompting preclinical studies aimed at understand the mechanisms underlying the neurotoxicity and its associated pain (7).…”

“…The hypersensitivity was well established following completion of the first cycle (day 4), maintained through the second cycle (day [7][8][9][10][11], and persisted for 6 days after completion of the second cycle (day 17). The mechanical hypersensitivity then gradually recovered and thresholds reached baseline values by 24 days after the first VCR administration ( Figure 1A), resembling the recovery seen in many patients in the clinic (1).…”

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

“…Preclinical studies utilizing rodent models of oxaliplatin‐induced peripheral neuropathy suggest a variety of mechanism‐based treatments for clinical oxaliplatin‐induced neuropathic pain such as the anticonvulsant gabapentin (Authier et al. 2009). However, gabapentin, either in tandem with oxaliplatin treatment or during established neuropathy, failed to demonstrate efficacy in clinical trials (Mitchell et al.…”