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Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current.

Infusion of the chemotherapeutic agent oxaliplatin leads to an acute and a chronic form of peripheral neuropathy. Acute oxaliplatin neuropathy is characterized by sensory paresthesias and muscle cramps that are notably exacerbated by cooling. Painful dysesthesias are rarely reported for acute oxalip... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America April 24, 2012, Vol.109(17), pp.6704-6709
Main Author: Sittl, Ruth
Other Authors: Lampert, Angelika , Huth, Tobias , Schuy, E Theresa , Link, Andrea S , Fleckenstein, Johannes , Alzheimer, Christian , Grafe, Peter , Carr, Richard W
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 1091-6490 ; DOI: 10.1073/pnas.1118058109
Link: http://search.proquest.com/docview/1009802295/?pq-origsite=primo
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title: Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current.
format: Article
creator:
  • Sittl, Ruth
  • Lampert, Angelika
  • Huth, Tobias
  • Schuy, E Theresa
  • Link, Andrea S
  • Fleckenstein, Johannes
  • Alzheimer, Christian
  • Grafe, Peter
  • Carr, Richard W
subjects:
  • Animals–Pharmacology
  • Antineoplastic Agents–Cytology
  • Axons–Physiology
  • Ganglia, Spinal–Drug Effects
  • Humans–Physiology
  • Mice–Physiology
  • Nav1.6 Voltage-Gated Sodium Channel–Pharmacology
  • Nerve Tissue Proteins–Chemically Induced
  • Neurons–Drug Effects
  • Organoplatinum Compounds–Physiology
  • Peripheral Nervous System Diseases–Physiology
  • Sodium Channels–Physiology
  • Antineoplastic Agents
  • Nav1.6 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • Organoplatinum Compounds
  • Scn8a Protein, Human
  • Sodium Channels
  • Oxaliplatin
ispartof: Proceedings of the National Academy of Sciences of the United States of America, April 24, 2012, Vol.109(17), pp.6704-6709
description: Infusion of the chemotherapeutic agent oxaliplatin leads to an acute and a chronic form of peripheral neuropathy. Acute oxaliplatin neuropathy is characterized by sensory paresthesias and muscle cramps that are notably exacerbated by cooling. Painful dysesthesias are rarely reported for acute oxaliplatin neuropathy, whereas a common symptom of chronic oxaliplatin neuropathy is pain. Here we examine the role of the sodium channel isoform [Na.sub.v]1.6 in mediating the symptoms of acute oxaliplatin neuropathy. Compound and single-action potential recordings from human and mouse peripheral axons showed that cooling in the presence of oxaliplatin (30-100 [micro]M; 90 min) induced bursts of action potentials in myelinated A, but not unmyelinated C-fibers. Whole-cell patch-clamp recordings from dissociated dorsal root ganglion (DRG) neurons revealed enhanced tetrodotoxin-sensitive resurgent and persistent current amplitudes in large, but not small, diameter DRG neurons when cooled (22[degrees]C) in the presence of oxaliplatin. In DRG neurons and peripheral myelinated axons from [Scn8a.sup.med/med] mice, which lack functional [Na.sub.v]1.6, no effect of oxaliplatin and cooling was observed. Oxaliplatin significantly slows the rate of fast inactivation at negative potentials in heterologously expressed [mNa.sub.v]1.6r in ND7 cells, an effect consistent with prolonged Nav open times and increased resurgent and persistent current in native DRG neurons. This finding suggests that [Na.sub.v]1.6 plays a central role in mediating acute cooling-exacerbated symptoms following oxaliplatin, and that enhanced resurgent and persistent sodium currents may provide a general mechanistic basis for cold-aggravated symptoms of neuropathy. chemotherapy | peripheral nerve | abnormal axonal excitability | repetitive action potential discharge doi/10.1073/pnas.1118058109
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 1091-6490 ; DOI: 10.1073/pnas.1118058109
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleAnticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current.
creatorSittl, Ruth ; Lampert, Angelika ; Huth, Tobias ; Schuy, E Theresa ; Link, Andrea S ; Fleckenstein, Johannes ; Alzheimer, Christian ; Grafe, Peter ; Carr, Richard W
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subjectAnimals–Pharmacology ; Antineoplastic Agents–Cytology ; Axons–Physiology ; Ganglia, Spinal–Drug Effects ; Humans–Physiology ; Mice–Physiology ; Nav1.6 Voltage-Gated Sodium Channel–Pharmacology ; Nerve Tissue Proteins–Chemically Induced ; Neurons–Drug Effects ; Organoplatinum Compounds–Physiology ; Peripheral Nervous System Diseases–Physiology ; Sodium Channels–Physiology ; Antineoplastic Agents ; Nav1.6 Voltage-Gated Sodium Channel ; Nerve Tissue Proteins ; Organoplatinum Compounds ; Scn8a Protein, Human ; Sodium Channels ; Oxaliplatin
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descriptionInfusion of the chemotherapeutic agent oxaliplatin leads to an acute and a chronic form of peripheral neuropathy. Acute oxaliplatin neuropathy is characterized by sensory paresthesias and muscle cramps that are notably exacerbated by cooling. Painful dysesthesias are rarely reported for acute oxaliplatin neuropathy, whereas a common symptom of chronic oxaliplatin neuropathy is pain. Here we examine the role of the sodium channel isoform [Na.sub.v]1.6 in mediating the symptoms of acute oxaliplatin neuropathy. Compound and single-action potential recordings from human and mouse peripheral axons showed that cooling in the presence of oxaliplatin (30-100 [micro]M; 90 min) induced bursts of action potentials in myelinated A, but not unmyelinated C-fibers. Whole-cell patch-clamp recordings from dissociated dorsal root ganglion (DRG) neurons revealed enhanced tetrodotoxin-sensitive resurgent and persistent current amplitudes in large, but not small, diameter DRG neurons when cooled (22[degrees]C) in the presence of oxaliplatin. In DRG neurons and peripheral myelinated axons from [Scn8a.sup.med/med] mice, which lack functional [Na.sub.v]1.6, no effect of oxaliplatin and cooling was observed. Oxaliplatin significantly slows the rate of fast inactivation at negative potentials in heterologously expressed [mNa.sub.v]1.6r in ND7 cells, an effect consistent with prolonged Nav open times and increased resurgent and persistent current in native DRG neurons. This finding suggests that [Na.sub.v]1.6 plays a central role in mediating acute cooling-exacerbated symptoms following oxaliplatin, and that enhanced resurgent and persistent sodium currents may provide a general mechanistic basis for cold-aggravated symptoms of neuropathy. chemotherapy | peripheral nerve | abnormal axonal excitability | repetitive action potential discharge doi/10.1073/pnas.1118058109
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titleAnticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current.
authorSittl, Ruth ; Lampert, Angelika ; Huth, Tobias ; Schuy, E Theresa ; Link, Andrea S ; Fleckenstein, Johannes ; Alzheimer, Christian ; Grafe, Peter ; Carr, Richard W
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