Limits...
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

Electron microscope images of degenerated of axons in the dorsal column. A EM image showing healthy and no degenerated axons (arrows) and myelin ovoids in the ventral horn of lumbar region of mice intoxicated with paclitaxel. B Low magnification EM image showing degenerated axons (arrows) and myelin ovoids in the dorsal column of lumbar region. C High magnification EM images of lumbar level showing degenerated axons at various stages of degeneration. Arrowhead points to degenerated axoplasm filled with organelles. Arrow points to degenerated myelin profile that has already collapsed following degeneration of axoplasm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4940970&req=5

Fig2: Electron microscope images of degenerated of axons in the dorsal column. A EM image showing healthy and no degenerated axons (arrows) and myelin ovoids in the ventral horn of lumbar region of mice intoxicated with paclitaxel. B Low magnification EM image showing degenerated axons (arrows) and myelin ovoids in the dorsal column of lumbar region. C High magnification EM images of lumbar level showing degenerated axons at various stages of degeneration. Arrowhead points to degenerated axoplasm filled with organelles. Arrow points to degenerated myelin profile that has already collapsed following degeneration of axoplasm

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)

Electron microscope images of degenerated of axons in the dorsal column. A EM image showing healthy and no degenerated axons (arrows) and myelin ovoids in the ventral horn of lumbar region of mice intoxicated with paclitaxel. B Low magnification EM image showing degenerated axons (arrows) and myelin ovoids in the dorsal column of lumbar region. C High magnification EM images of lumbar level showing degenerated axons at various stages of degeneration. Arrowhead points to degenerated axoplasm filled with organelles. Arrow points to degenerated myelin profile that has already collapsed following degeneration of axoplasm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940970&req=5

Fig2: Electron microscope images of degenerated of axons in the dorsal column. A EM image showing healthy and no degenerated axons (arrows) and myelin ovoids in the ventral horn of lumbar region of mice intoxicated with paclitaxel. B Low magnification EM image showing degenerated axons (arrows) and myelin ovoids in the dorsal column of lumbar region. C High magnification EM images of lumbar level showing degenerated axons at various stages of degeneration. Arrowhead points to degenerated axoplasm filled with organelles. Arrow points to degenerated myelin profile that has already collapsed following degeneration of axoplasm
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