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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

Degeneration of axons in the dorsal column of mice intoxicated with paclitaxel. Images are cross-sectioned semithin (1 µm) plastic sections of spinal cords stained for toluidine blue. a Control vehicle-treated (cremophor) spinal cord at lumbar level. No degenerated axons are observed. b Paclitaxel treated spinal cord. Degenerated myelin profiles are present in dorsal column of thoracic level where ascending central branches axons of DRG neurons reside. c Paclitaxel treated spinal cord. Degenerated myelin profiles are present in dorsal column of lumbar level where ascending central branches axons of DRG neurons reside. d High magnification of a showing no degenerated axons. e High magnification of b showing degenerated myelin profiles (arrows). f High magnification of c showing degenerated myelin profiles (arrows). Scale bar in c = 50 μm and applies to a–c. Scale bar in f = 10 μm and applies to d–f
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Fig1: Degeneration of axons in the dorsal column of mice intoxicated with paclitaxel. Images are cross-sectioned semithin (1 µm) plastic sections of spinal cords stained for toluidine blue. a Control vehicle-treated (cremophor) spinal cord at lumbar level. No degenerated axons are observed. b Paclitaxel treated spinal cord. Degenerated myelin profiles are present in dorsal column of thoracic level where ascending central branches axons of DRG neurons reside. c Paclitaxel treated spinal cord. Degenerated myelin profiles are present in dorsal column of lumbar level where ascending central branches axons of DRG neurons reside. d High magnification of a showing no degenerated axons. e High magnification of b showing degenerated myelin profiles (arrows). f High magnification of c showing degenerated myelin profiles (arrows). Scale bar in c = 50 μm and applies to a–c. Scale bar in f = 10 μm and applies to d–f

Mentions: Each DRG neuron has a unipolar axon with two branches: peripheral and central. Given the degenerative effect of paclitaxel on peripheral sensory axons, we asked whether the central branches of DRG axons are also affected. We examined representative sections of spinal cords at all levels, and degeneration was observed at all representative levels. In semithin 1 μm plastic sections, degenerated myelin profiles were present in the dorsal column, where central branches of DRG axons ascend rostrally (Fig. 1a–f). Within the spinal cord, degenerated myelin profiles, the footprint of degenerated myelinated axons, were restricted to the dorsal column. None were present in the ventral horn or lateral columns (Fig. 2A), indicating that the toxic effects of paclitaxel were restricted to ascending sensory axons (Fig. 1a–f). Further, the pattern of degeneration in the dorsal column spanned medial and lateral areas of the dorsal column.Fig. 1


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)

Degeneration of axons in the dorsal column of mice intoxicated with paclitaxel. Images are cross-sectioned semithin (1 µm) plastic sections of spinal cords stained for toluidine blue. a Control vehicle-treated (cremophor) spinal cord at lumbar level. No degenerated axons are observed. b Paclitaxel treated spinal cord. Degenerated myelin profiles are present in dorsal column of thoracic level where ascending central branches axons of DRG neurons reside. c Paclitaxel treated spinal cord. Degenerated myelin profiles are present in dorsal column of lumbar level where ascending central branches axons of DRG neurons reside. d High magnification of a showing no degenerated axons. e High magnification of b showing degenerated myelin profiles (arrows). f High magnification of c showing degenerated myelin profiles (arrows). Scale bar in c = 50 μm and applies to a–c. Scale bar in f = 10 μm and applies to d–f
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig1: Degeneration of axons in the dorsal column of mice intoxicated with paclitaxel. Images are cross-sectioned semithin (1 µm) plastic sections of spinal cords stained for toluidine blue. a Control vehicle-treated (cremophor) spinal cord at lumbar level. No degenerated axons are observed. b Paclitaxel treated spinal cord. Degenerated myelin profiles are present in dorsal column of thoracic level where ascending central branches axons of DRG neurons reside. c Paclitaxel treated spinal cord. Degenerated myelin profiles are present in dorsal column of lumbar level where ascending central branches axons of DRG neurons reside. d High magnification of a showing no degenerated axons. e High magnification of b showing degenerated myelin profiles (arrows). f High magnification of c showing degenerated myelin profiles (arrows). Scale bar in c = 50 μm and applies to a–c. Scale bar in f = 10 μm and applies to d–f
Mentions: Each DRG neuron has a unipolar axon with two branches: peripheral and central. Given the degenerative effect of paclitaxel on peripheral sensory axons, we asked whether the central branches of DRG axons are also affected. We examined representative sections of spinal cords at all levels, and degeneration was observed at all representative levels. In semithin 1 μm plastic sections, degenerated myelin profiles were present in the dorsal column, where central branches of DRG axons ascend rostrally (Fig. 1a–f). Within the spinal cord, degenerated myelin profiles, the footprint of degenerated myelinated axons, were restricted to the dorsal column. None were present in the ventral horn or lateral columns (Fig. 2A), indicating that the toxic effects of paclitaxel were restricted to ascending sensory axons (Fig. 1a–f). Further, the pattern of degeneration in the dorsal column spanned medial and lateral areas of the dorsal column.Fig. 1

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