The chemotherapeutic oxaliplatin alters voltage-gated Na+ channel kinetics on rat sensory neurons

Adelsberger, Helmuth; Quasthoff, Stefan; Großkreutz, Julian; Lepier, Alexandra; Eckel, Florian; Lersch, C.

doi:10.1016/s0014-2999(00)00667-1

Cited by 257 publications

(224 citation statements)

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“…The best-known acute cellular effects of oxaliplatin on neurons are its actions on voltage-gated Na ϩ channels. 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).…”

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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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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“…31 There is some experimental evidence from various animal models that the acute neurosensory symptoms that occur during oxaliplatin administration may be linked to an increased neuronal excitability induced by a specific action of oxaliplatin on some isoforms of voltage-gated sodium channels located on the cellular membrane of sensory neurons. 31,32,33 It is unclear at present whether the acute and chronic neurotoxicity observed with oxaliplatin is due to a common cellular mechanism. The cumulative sensory neuropathy that develops after chronic treatment has been well characterized by decreased nerve conduction in patients and in animals.…”

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confidence: 99%

Lhermitte sign and urinary retention

Taieb

Trillet‐Lenoir

Rambaud

et al. 2002

Cancer

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BACKGROUNDRegimens combining oxaliplatin with fluorouracil and folinic acid are standard therapeutic options for patients with metastatic colorectal carcinoma. Oxaliplatin has a good safety profile, although it is responsible for dose‐limiting neurotoxicity typically consisting of two distinct clusters of symptoms. Cold‐induced distal paresthesiae occur during or shortly after infusion in most patients and are usually transient and mild. A persistent sensory peripheral neuropathy may develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia and functional impairment.METHODSThe authors report four cases of atypical neurotoxicity induced by oxaliplatin in patients treated for metastatic colorectal carcinoma. Two patients were male and two were female, with an age range of 52–59 years.RESULTSThree patients experienced Lhermitte sign and two experienced urinary retention. In all cases, the cumulative dose of oxaliplatin was higher than 1000 mg (range, 1248–2040 mg). Brain and spinal magnetic resonance imaging was performed in two patients and was normal. Somatosensory evoked potentials were recorded in two patients and suggested cervical dorsal column dysfunction. Symptoms resolved a few weeks after discontinuation of oxaliplatin.CONCLUSIONSLhermitte sign may be induced via a neurotoxic effect on the ascending axons of these T‐shaped neurons. An atonic bladder may be the result of damage to the sensory portion of the sacral reflex arc, either in the dorsal roots, as for example in diabetic neuropathy, or in the posterior columns, as in tabes dorsalis. Alternatively, it may result from a paralysis of the parasympathetic fibers that control the bladder musculature. It is unclear at present whether the micturition difficulties observed in patients in the current series are due to sensory neuropathy or to autonomic neuropathy, event if the former hypothesis seems more likely, as autonomic neuropathy has not been previously observed with oxaliplatin, and its association with cisplatin is exceedingly rare and controversial. Cancer 2002;94:2434–40. © 2002 American Cancer Society.DOI 10.1002/cncr.10500

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“…32 Recently, the acute neurotoxicity of oxaliplatin was associated with its interference with neuron voltage-gated sodium channels through one of its metabolites, oxalate, a calcium chelator. [33][34][35] Microtubule-targeting agents (e.g., paclitaxel, vincristine) display axonal toxicity, with the longest axons being the first affected. 36 For paclitaxel, studies in animal models using high doses initially supported the hypothesis that the drug's neurotoxicity arises from disruption of microtubules and impairment of axonal transport, but numerous reports now refute this idea.…”

Section: Chemotherapy-induced Peripheral Neuropathymentioning

confidence: 99%

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

Bordet

Pruss

2009

Neurotherapeutics

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Summary:Neuropathic pain syndromes arise from dysfunction of the nerve itself, through traumatic or nontraumatic injury. Unlike acute pain syndromes, the pain is long-lasting and does not respond to common analgesic therapies. Drugs that disrupt nerve conduction and transmission or central sensitization, currently the only effective treatments, are only modestly effective for a portion of the patients suffering from neuropathic pain and come with the cost of serious adverse effects. Neurodegeneration, as a reaction to nerve trauma or chronic metabolic or chemical intoxication, appears to be an underlying cause of neuropathic pain. Identifying mechanisms of neurodegeneration and designing neuroprotective therapies is an ambitious goal toward treating or even preventing the development of these disabling disorders.

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The chemotherapeutic oxaliplatin alters voltage-gated Na+ channel kinetics on rat sensory neurons

Cited by 257 publications

References 16 publications

Oxaliplatin neurotoxicity of sensory transduction in rat proprioceptors

Oxaliplatin neurotoxicity of sensory transduction in rat proprioceptors

Lhermitte sign and urinary retention

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

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