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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

Macrophages infiltration along degenerated axons in nerve intoxicated with paclitaxel. Longitudinal frozen sectioned nerve segment stained for CD68 and MBP. a MBP staining of nerve segment intoxicated with paclitaxel. The vast majority of fibers appear normal with the exception of a single fiber that show degenerated myelin (arrow). b CD68 staining. Macrophages (CD68-positive cells) infiltrate along a degenerating fiber, while not associating with other normal fibers (arrow). c Merged image of a and b. Scale bar 50 μm
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Fig4: Macrophages infiltration along degenerated axons in nerve intoxicated with paclitaxel. Longitudinal frozen sectioned nerve segment stained for CD68 and MBP. a MBP staining of nerve segment intoxicated with paclitaxel. The vast majority of fibers appear normal with the exception of a single fiber that show degenerated myelin (arrow). b CD68 staining. Macrophages (CD68-positive cells) infiltrate along a degenerating fiber, while not associating with other normal fibers (arrow). c Merged image of a and b. Scale bar 50 μm

Mentions: Macrophages infiltrate sciatic nerves in animals intoxicated with paclitaxel [11, 12]. In peripheral neuropathies, macrophages generally associate with degenerated fibers by invading basal lamina and ingesting axonal and myelin debris [13, 16]. We asked whether paclitaxel induced a similar pattern of macrophage invasion in intoxicated nerves. In longitudinal sections, we stained for myelin basic protein (MBP) to identify both healthy and degenerated, fragmented myelinated axons in conjunction with CD68, a lysosomal protein present in activated and phagocytic macrophages [17]. We found macrophages infiltrating degenerating fibers in the midst of normal-looking fibers (Fig. 4).Fig. 4


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)

Macrophages infiltration along degenerated axons in nerve intoxicated with paclitaxel. Longitudinal frozen sectioned nerve segment stained for CD68 and MBP. a MBP staining of nerve segment intoxicated with paclitaxel. The vast majority of fibers appear normal with the exception of a single fiber that show degenerated myelin (arrow). b CD68 staining. Macrophages (CD68-positive cells) infiltrate along a degenerating fiber, while not associating with other normal fibers (arrow). c Merged image of a and b. Scale bar 50 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4940970&req=5

Fig4: Macrophages infiltration along degenerated axons in nerve intoxicated with paclitaxel. Longitudinal frozen sectioned nerve segment stained for CD68 and MBP. a MBP staining of nerve segment intoxicated with paclitaxel. The vast majority of fibers appear normal with the exception of a single fiber that show degenerated myelin (arrow). b CD68 staining. Macrophages (CD68-positive cells) infiltrate along a degenerating fiber, while not associating with other normal fibers (arrow). c Merged image of a and b. Scale bar 50 μm
Mentions: Macrophages infiltrate sciatic nerves in animals intoxicated with paclitaxel [11, 12]. In peripheral neuropathies, macrophages generally associate with degenerated fibers by invading basal lamina and ingesting axonal and myelin debris [13, 16]. We asked whether paclitaxel induced a similar pattern of macrophage invasion in intoxicated nerves. In longitudinal sections, we stained for myelin basic protein (MBP) to identify both healthy and degenerated, fragmented myelinated axons in conjunction with CD68, a lysosomal protein present in activated and phagocytic macrophages [17]. We found macrophages infiltrating degenerating fibers in the midst of normal-looking fibers (Fig. 4).Fig. 4

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