Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage‐gated sodium channels

Webster, Richard; Brain, Keith L.; Wilson, Richard H.; Grem, Jean L.; Vincent, Angela

doi:10.1038/sj.bjp.0706407

Cited by 127 publications

(87 citation statements)

References 38 publications

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“…Patch-clamp technique studies performed on neurons isolated from the central nervous system of the cockroach showed that OXA was able to alter VGNaCs through a pathway involving calcium ions [13]. Taken together, these data are consistent with a channelopathy involving VGNaCs [11,12,13].…”

Section: Introductionsupporting

confidence: 76%

“…The first is probably related to an axonopathy due to the accumulation of platinum compounds within the dorsal root ganglia, the second to a transient impairment of ion channel function, but there is still no agreement about which channel is involved [6][7][8][11][12][13], neither about the possible correlation between acute and chronic neurotoxocity.…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, -pompilidotoxin, which slows Na + channel inactivation, induces changes resembling those observed in OXA neurotoxicity, whereas VGKC blockers such as apamin were not able to reproduce OXA-induced hyperexcitability [12]. Patch-clamp technique studies performed on neurons isolated from the central nervous system of the cockroach showed that OXA was able to alter VGNaCs through a pathway involving calcium ions [13].…”

Section: Introductionmentioning

confidence: 99%

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Polymorphism of CAG motif of SK3 gene is associated with acute oxaliplatin neurotoxicity

Basso

Modoni

Spada

et al. 2010

Cancer Chemother Pharmacol

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Purpose. There is no agreement on which channel is involved in oxaliplatin neurotoxicity, most investigators favouring voltage-gated sodium channels. However, the small conductance Ca ++ activated K + channels, encoded by the SK 1-3 genes, are also involved in membrane excitability, playing a role in after-hyperpolarisation at the motor nerve terminal. As the SK3 gene is characterised in Caucasians by a highly polymorphic CAG motif within the exon 1, we hypothesise that SK3 gene polymorphism may influence the development of acute nerve hyperexcitability in oxaliplatin-treated patients. Methods.Patients eligible for an oxaliplatin-containing regimen were enrolled. Detailed neurological examination, nerve conduction studies and needle electromyography were performed before and after oxaliplatin administration. DNA was extracted by polymerase chain reaction and each allele was isolated and sequenced.Results. We evaluated 40 patients. After oxaliplatin administration, 28 patients developed symptoms of neurotoxicity, which were severe in eleven. Patients were divided into 3 groups according to neurophysiologic data : G0 (normal peripheral nerve excitability [PNE]), 16 patients; G1 (mild PNE), 15 patients; G2 (severe PNE), 9 patients. Genetic analysis showed different alleles ranging from 13 to 23 CAG repeats. Patients carrying alleles containing 13-15 CAG repeats experienced a significantly higher incidence of severe nerve hyperexcitability (chi-square 48.6; df 16; p = .0001). Conclusion.The results suggest that OXA-neurotoxicity may be related to distribution of the polymorphic CAG motif of the SK3 gene, which might modulate nerve after-hyperpolarisation. The 13-14 CAG repeat allele could mark patients susceptible to acute OXA neurotoxicity.3

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Section: Introductionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Polymorphism of CAG motif of SK3 gene is associated with acute oxaliplatin neurotoxicity

Basso

Modoni

Spada

et al. 2010

Cancer Chemother Pharmacol

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“…Oxaliplatin modifications of Na ϩ current include a slowing of inactivation kinetics (Adelsberger et al 2000;Wu et al 2009), reduction in current amplitude (Benoit et al 2006;Grolleau et al 2001;Wu et al 2009), and hyperpolarized shift in the voltage dependence of inactivation (Benoit et al 2006). Effects on Na ϩ channels have been suggested to alter axon excitability in patients treated with oxaliplatin (Kiernan and Krishnan 2006;Webster et al 2005). We considered the possibility that these direct effects of oxaliplatin might have produced results presented here because oxaliplatin can take many weeks to clear the blood (Levi et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Oxaliplatin neurotoxicity of sensory transduction in rat proprioceptors

Bullinger

Nardelli

Wang

et al. 2011

Journal of Neurophysiology

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Bullinger KL, Nardelli P, Wang Q, Rich MM, Cope TC. Oxaliplatin neurotoxicity of sensory transduction in rat proprioceptors. J Neurophysiol 106: 704 -709, 2011. First published May 18, 2011 doi:10.1152/jn.00083.2011.-Neurotoxic effects of oxaliplatin chemotherapy, including proprioceptive impairments, are debilitating and dose limiting. Here, we sought to determine whether oxaliplatin interrupts normal proprioceptive feedback by impairing sensory transduction of muscle length and force by neurons that are not damaged by dying-back neuropathy. Oxaliplatin was administered over 4 wk to rats in doses that produced systemic changes, e.g., decreased platelets and stunted weight gain, but no significant abnormality in the terminal ends of primary muscle spindle sensory neurons. The absence of neuropathy enabled the determination of whether oxaliplatin caused functional deficits in sensory encoding without the confounding issue of axon death. Rats were anesthetized, and action potentials encoding muscle stretch and contraction were recorded intra-axonally from dorsal roots. In striking contrast with normal proprioceptors, those from oxaliplatin-treated rats typically failed to sustain firing during static muscle stretch. The ability of spindle afferents to sustain and centrally conduct trains of action potentials in response to rapidly repeated transient stimuli, i.e., vibration, demonstrated functional competence of the parent axons. These data provide the first evidence that oxaliplatin causes persistent and selective deficits in sensory transduction that are not due to axon degeneration. Our findings raise the possibility that even those axons that do not degenerate after oxaliplatin treatment may have functional deficits that worsen outcome. chemotherapy; neuropathy; muscle spindle; electrophysiology; afferent PERIPHERAL NEUROPATHY is the most common dose-limiting factor of oxaliplatin chemotherapy (for reviews, see Argyriou et al. 2008;Krishnan et al. 2005;Pasetto et al. 2006). Acute neurotoxicity, predominantly sensory in nature, is seen in nearly all patients and is characterized by cold intolerance, dysthesias, and, less commonly, laryngeal spasms (Wilson et al. 2002). With continued treatment, a cumulative sensory neuropathy can develop similar to that seen in patients treated with other platinum compounds. The onset of the neuropathy is gradual, and the severity worsens with an increase in cumulative dose. Chronic neuropathy is thought to primarily affect large-diameter sensory fibers (for evidence and earlier citations, see Jamieson et al. 2005), which include muscle afferents that provide the central nervous system with proprioceptive information. Consistent with this notion, patients often lose deep tendon reflexes, mediated by muscle spindle afferents, and develop proprioceptive loss seen as problems with coordinating movement, e.g., loss of dexterity and sensory ataxia.Sensory contributions to behavior and experience depend on conduction and central transmission of signals that are encoded by specialize...

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“…Further, oxaliplatin administration has been described to slow sodium channel inactivation kinetics [1,34]. A change in sodium channel properties may predispose to ectopic activity, leading to paresthesia and fasciculations [36]. Cold exposure affects sodium channel kinetics [37] and, accordingly, sodium channel dysfunction is aggravated by cold temperatures [38].…”

Section: Introductionmentioning

confidence: 99%

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

Nassini¹,

Benemei²,

Fusi³

et al. 2013

TOPAINJ

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Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common dose-limiting side effect of many chemotherapeutic drugs, including platinum-based compounds (e.g., cisplatin and oxaliplatin), taxanes (e.g., paclitaxel), vinca alkaloids (e.g., vincristine), and the first-in-class proteasome inhibitor, bortezomib. Among the various sensory symptoms of CIPN, paresthesia, dysesthesia, spontaneous pain, and mechanical and thermal hypersensitivity are prominent. Inflammation, oxidative stress, loss of intraepidermal nerve fibers, modifications of mitochondria, and various ion channels alterations are part of the several mechanisms contributing to CIPN. Because attempts to mitigate chemotherapeutic-induced acute neuronal hyperexcitability and the subsequent peripheral neuropathy have yielded unsatisfactory results, a more in-depth understanding of the mechanism(s) responsible for the neurotoxic action of anticancer drugs is required.Some members of the transient receptor potential (TRP) family of channels, as the TRPV1 and TRPV4 (vanilloid), TRPA1 (ankyrin) and TRPM8 (melastatin) are expressed on the plasma membrane of primary sensory neurons (nociceptors), where they are activated by an unprecedented series of physical and chemical stimuli. There is evidence that TRPV1, TRPV4, TRPA1 and TRPM8 are prominent contributors of mechanical and thermal hypersensitivity in models of CIPN. In particular, in vitro and in vivo studies have pointed out the unique role of TRPA1 and oxidative stress in the mechanism responsible for cold and mechanical hyperalgesia in rodent models of CIPN.

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Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage‐gated sodium channels

Cited by 127 publications

References 38 publications

Polymorphism of CAG motif of SK3 gene is associated with acute oxaliplatin neurotoxicity

Polymorphism of CAG motif of SK3 gene is associated with acute oxaliplatin neurotoxicity

Oxaliplatin neurotoxicity of sensory transduction in rat proprioceptors

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

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