Abstract
BackgroundPeripheral neuropathy is a common and dose-limiting side effect of many cancer chemotherapies. The taxane agents, including paclitaxel (Taxol®), are effective chemotherapeutic drugs but cause degeneration of predominantly large myelinated afferent sensory fibers of the peripheral nervous system in humans and animal models. Dorsal root ganglia (DRG) neurons are sensory neurons that have unipolar axons each with two branches: peripheral and central. While taxane agents induce degeneration of peripheral axons, whether they also cause degeneration of central nervous system axons is not clear. Using a mouse model of paclitaxel-induced neuropathy, we investigated the effects of paclitaxel on the central branches of sensory axons.ResultsWe observed that in the spinal cords of paclitaxel-intoxicated mice, degenerated axons were present in the dorsal columns, where the central branches of DRG axons ascend rostrally. In the peripheral nerves, degenerated myelinated fibers were present in significantly greater numbers in distal segments than in proximal segments indicating that this model exhibits the distal-to-proximal degeneration pattern generally observed in human peripheral nerve disorders.ConclusionsWe conclude that paclitaxel causes degeneration of both the peripheral and central branches of DRG axons, a finding that has implications for the site and mode of action of chemotherapy agents on the nervous system.
Highlights
Peripheral neuropathy is a common and dose-limiting side effect of many cancer chemotherapies
Given the degenerative effect of paclitaxel on peripheral sensory axons, we asked whether the central branches of Dorsal root ganglia (DRG) axons are affected
We sought to determine whether the chemotherapy agent paclitaxel causes degeneration of central nervous system axons, those that carry sensory information to higher brain regions
Summary
Peripheral neuropathy is a common and dose-limiting side effect of many cancer chemotherapies. The taxane agents, including paclitaxel (Taxol®), are effective chemotherapeutic drugs but cause degeneration of predominantly large myelinated afferent sensory fibers of the peripheral nervous system in humans and animal models. While taxane agents induce degeneration of peripheral axons, whether they cause degeneration of central nervous system axons is not clear. Using a mouse model of paclitaxel-induced neuropathy, we investigated the effects of paclitaxel on the central branches of sensory axons. Chemotherapy-induced peripheral neuropathy (CIPN) is often a factor in limiting cancer therapy with chemotherapeutic drugs, for effective taxane agents such as paclitaxel (Taxol®) [1, 2]. The incidence of CIPN is influenced by a number of factors including dose intensity, cumulative dose, duration of therapy, and co-administration of other neurotoxic chemotherapeutic drugs [3]. Some patients develop neuropathy after only a single administration of the drug, especially when in combination with other chemotherapeutic drugs [4]
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