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Paclitaxel causes degeneration of both central and peripheral axon branches of dorsal root ganglia in mice.

Tasnim A, Rammelkamp Z, Slusher AB, Wozniak K, Slusher BS, Farah MH - BMC Neurosci (2016)

Bottom Line: Peripheral neuropathy is a common and dose-limiting side effect of many cancer chemotherapies.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.We 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.

View Article: PubMed Central - PubMed

Affiliation: Neuromuscular Division, Department of Neurology, Johns Hopkins University School of Medicine, The John G. Rangos Sr. Building, Room 239, 855 N. Wolfe Street, Baltimore, MD, 21205, USA.

ABSTRACT

Background: 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. 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.

Results: We 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.

Conclusions: We 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.

No MeSH data available.


Related in: MedlinePlus

Paclitaxel causes distal to proximal axonal degeneration in mice. Mice were treated with i.v. 30 mg/kg paclitaxel 3 times a week for 2 weeks. a–c are cross-sectioned semithin (1 µm) plastic sections stained for toluidine blue. a Vehicle-treated (cremophor) mice at the mid-thigh level of sciatic nerve. No degenerated axons are observed. b Paclitaxel-treated mice at the mid-thigh level of sciatic nerve. Degenerated myelin profiles were present across the nerve crossed section. Arrows point to large (black arrow) and small (white arrow) degenerated myelinated axons. c Paclitaxel-treated mice at 7–8 mm distal to the sciatic nerve segment in a. Greater numbers of degenerated myelin profiles are present across the distal segment of the nerve, indicating distal to proximal degeneration pattern. d Quantification of degenerating myelinated fibers in the whole cross-sectional area of nerve segments. N = 3 per nerve segment. Values are mean ± SEM. e Electron micrograph of distal nerve intoxicated with paclitaxel showing occasional swollen unmyelinated axon (arrow) and degeneration of myelinated axon (*). f Quantification of Remak bundles. N = 3 mice per treatment. There was no statistical difference between vehicle- and paclitaxel-treated nerves. Scale bar in c = 20 μm and applies to a–c. Scale bar in e = 500 nm
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Fig3: Paclitaxel causes distal to proximal axonal degeneration in mice. Mice were treated with i.v. 30 mg/kg paclitaxel 3 times a week for 2 weeks. a–c are cross-sectioned semithin (1 µm) plastic sections stained for toluidine blue. a Vehicle-treated (cremophor) mice at the mid-thigh level of sciatic nerve. No degenerated axons are observed. b Paclitaxel-treated mice at the mid-thigh level of sciatic nerve. Degenerated myelin profiles were present across the nerve crossed section. Arrows point to large (black arrow) and small (white arrow) degenerated myelinated axons. c Paclitaxel-treated mice at 7–8 mm distal to the sciatic nerve segment in a. Greater numbers of degenerated myelin profiles are present across the distal segment of the nerve, indicating distal to proximal degeneration pattern. d Quantification of degenerating myelinated fibers in the whole cross-sectional area of nerve segments. N = 3 per nerve segment. Values are mean ± SEM. e Electron micrograph of distal nerve intoxicated with paclitaxel showing occasional swollen unmyelinated axon (arrow) and degeneration of myelinated axon (*). f Quantification of Remak bundles. N = 3 mice per treatment. There was no statistical difference between vehicle- and paclitaxel-treated nerves. Scale bar in c = 20 μm and applies to a–c. Scale bar in e = 500 nm

Mentions: CIPN is thought to affect distal axons first as symptoms initially appear at distal sites [1, 2]. We examined whether our model exhibits a distal-to-proximal degeneration pattern by counting degenerated axons in the sciatic nerves of paclitaxel-intoxicated mice at two segments, distal and proximal. Degenerated myelin profiles were present all over the cross-sectional areas of the nerves at both proximal (Fig. 3b) and distal (Fig. 3c) segments of paclitaxel-intoxicated nerves. On average, 4–5 % of fibers examined were degenerated. However, greater numbers of degenerated fibers were present in the distal segments as compared to that in the proximal segments (Fig. 3d), indicating that this model of paclitaxel-induced neuropathy exhibits the well-described patterns of distal-to-proximal degeneration seen in peripheral neuropathies [13, 15]. Degenerated axons appeared to be of large- and medium-sized fiber classes (Fig. 3c, d). In intoxicated nerves examined under the electron microscope, very few swollen unmyelinated axons were present, and the vast majority of unmyelinated axons appeared normal (Fig. 3e, f), consistent with observations that in humans, paclitaxel has minimal adverse effects on unmyelinated axons [1, 2].Fig. 3


Paclitaxel causes degeneration of both central and peripheral axon branches of dorsal root ganglia in mice.

Tasnim A, Rammelkamp Z, Slusher AB, Wozniak K, Slusher BS, Farah MH - BMC Neurosci (2016)

Paclitaxel causes distal to proximal axonal degeneration in mice. Mice were treated with i.v. 30 mg/kg paclitaxel 3 times a week for 2 weeks. a–c are cross-sectioned semithin (1 µm) plastic sections stained for toluidine blue. a Vehicle-treated (cremophor) mice at the mid-thigh level of sciatic nerve. No degenerated axons are observed. b Paclitaxel-treated mice at the mid-thigh level of sciatic nerve. Degenerated myelin profiles were present across the nerve crossed section. Arrows point to large (black arrow) and small (white arrow) degenerated myelinated axons. c Paclitaxel-treated mice at 7–8 mm distal to the sciatic nerve segment in a. Greater numbers of degenerated myelin profiles are present across the distal segment of the nerve, indicating distal to proximal degeneration pattern. d Quantification of degenerating myelinated fibers in the whole cross-sectional area of nerve segments. N = 3 per nerve segment. Values are mean ± SEM. e Electron micrograph of distal nerve intoxicated with paclitaxel showing occasional swollen unmyelinated axon (arrow) and degeneration of myelinated axon (*). f Quantification of Remak bundles. N = 3 mice per treatment. There was no statistical difference between vehicle- and paclitaxel-treated nerves. Scale bar in c = 20 μm and applies to a–c. Scale bar in e = 500 nm
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Fig3: Paclitaxel causes distal to proximal axonal degeneration in mice. Mice were treated with i.v. 30 mg/kg paclitaxel 3 times a week for 2 weeks. a–c are cross-sectioned semithin (1 µm) plastic sections stained for toluidine blue. a Vehicle-treated (cremophor) mice at the mid-thigh level of sciatic nerve. No degenerated axons are observed. b Paclitaxel-treated mice at the mid-thigh level of sciatic nerve. Degenerated myelin profiles were present across the nerve crossed section. Arrows point to large (black arrow) and small (white arrow) degenerated myelinated axons. c Paclitaxel-treated mice at 7–8 mm distal to the sciatic nerve segment in a. Greater numbers of degenerated myelin profiles are present across the distal segment of the nerve, indicating distal to proximal degeneration pattern. d Quantification of degenerating myelinated fibers in the whole cross-sectional area of nerve segments. N = 3 per nerve segment. Values are mean ± SEM. e Electron micrograph of distal nerve intoxicated with paclitaxel showing occasional swollen unmyelinated axon (arrow) and degeneration of myelinated axon (*). f Quantification of Remak bundles. N = 3 mice per treatment. There was no statistical difference between vehicle- and paclitaxel-treated nerves. Scale bar in c = 20 μm and applies to a–c. Scale bar in e = 500 nm
Mentions: CIPN is thought to affect distal axons first as symptoms initially appear at distal sites [1, 2]. We examined whether our model exhibits a distal-to-proximal degeneration pattern by counting degenerated axons in the sciatic nerves of paclitaxel-intoxicated mice at two segments, distal and proximal. Degenerated myelin profiles were present all over the cross-sectional areas of the nerves at both proximal (Fig. 3b) and distal (Fig. 3c) segments of paclitaxel-intoxicated nerves. On average, 4–5 % of fibers examined were degenerated. However, greater numbers of degenerated fibers were present in the distal segments as compared to that in the proximal segments (Fig. 3d), indicating that this model of paclitaxel-induced neuropathy exhibits the well-described patterns of distal-to-proximal degeneration seen in peripheral neuropathies [13, 15]. Degenerated axons appeared to be of large- and medium-sized fiber classes (Fig. 3c, d). In intoxicated nerves examined under the electron microscope, very few swollen unmyelinated axons were present, and the vast majority of unmyelinated axons appeared normal (Fig. 3e, f), consistent with observations that in humans, paclitaxel has minimal adverse effects on unmyelinated axons [1, 2].Fig. 3

Bottom Line: Peripheral neuropathy is a common and dose-limiting side effect of many cancer chemotherapies.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.We 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.

View Article: PubMed Central - PubMed

Affiliation: Neuromuscular Division, Department of Neurology, Johns Hopkins University School of Medicine, The John G. Rangos Sr. Building, Room 239, 855 N. Wolfe Street, Baltimore, MD, 21205, USA.

ABSTRACT

Background: 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. 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.

Results: We 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.

Conclusions: We 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.

No MeSH data available.


Related in: MedlinePlus