Dose effects of oxaliplatin on persistent and transient Na+ conductances and the development of neurotoxicity

Abstract

Background: Oxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity--acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na(+) channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na(+) channel dysfunction.

Methodology/principal findings: Specifically the function of transient and persistent Na(+) currents were followed during treatment and were investigated in relation to oxaliplatin dose level. Eighteen patients were assessed before and after a single oxaliplatin infusion with motor and sensory axonal excitability studies performed on the median nerve at the wrist. While refractoriness (associated with Na(+) channel inactivation) was significantly altered post-oxaliplatin infusion in both motor (Pre: 31.7±6.4%; Post: 68.8±14.5%; P≤.001) and sensory axons (Pre: 31.4±5.4%; Post: 21.4±5.5%; P<.05), strength-duration time constant (marker of persistent Na(+) conductances) was not significantly altered post-infusion (Motor Pre: 0.395±0.01 ms; Post: 0.394±0.02 ms; NS; Sensory Pre:0.544±0.03 ms; Post: 0.535±0.05 ms; NS). However, changes in strength-duration time constant were significantly correlated with changes in refractoriness in motor and sensory axons (Motor correlation coefficient = -.65; P<.05; Sensory correlation coefficient = .67; P<.05).

Conclusions/significance: It is concluded that the predominant effect of acute oxaliplatin exposure in human motor and sensory axons is mediated through changes in transient rather than persistent Na(+) conductances. These findings are likely to have implications for the design and trial of neuroprotective strategies.

Figure 1. Changes in Na⁺ channel associated parameters post-oxaliplatin in motor axons.

A) Refractoriness pre (black bars) and post (white bars) single oxaliplatin infusion demonstrating significant change post-oxaliplatin in motor axons (Refractoriness Pre: 31.7±6.4%; Post 68.8±14.5%; P≤.001). B) Strength-duration time constant pre (black bars) and post (white bars) oxaliplatin infusion, demonstrating unchanged results following oxaliplatin treatment (Pre: 0.395±0.01 ms; Post: 0.394±0.02 ms; NS). C) Inset diagram of the changes in the recovery cycle of excitability pre- (black circles) and post-oxaliplatin infusion (white circles) for all patients, with error bars representing standard error of the mean and refractoriness outlined by a box and an arrow demonstrating direction of change.

Figure 2. Changes in Na⁺ channel associated parameters post-oxaliplatin in sensory axons.

A) Refractoriness pre (black bars) and post (white bars) oxaliplatin treatment (Pre: 31.4±5.4%; Post: 21.4±5.5%; P<.05), demonstrating significant reduction post-oxaliplatin in sensory axons. B) Strength-duration time constant pre (black bars) and post (white bars) treatment (Pre: 0.544±.03 ms; Post: 0.535±.05 ms; NS), with no significant effect post oxaliplatin treatment. C) Changes in the recovery cycle of excitability pre- (black circles) and post-oxaliplatin infusion (white circles) for all patients, with error bars representing standard error of the mean and refractoriness outlined by a box and an arrow demonstrating direction of change.

Figure 3. Relationship of Na⁺ channel-associated parameters with oxaliplatin dose level in motor axons.

A) Relationship of Na⁺ channel-associated parameters with single oxaliplatin dose level in motor axons. Patients were divided into three single dose levels with means of 66, 85 and 105 mg/m². Change in refractoriness was significantly correlated with increasing single dose (correlation coefficient = .80; P≤.001). B) Correlation of cumulative oxaliplatin dose with the change in strength-duration time constant post-oxaliplatin in motor axons, illustrating the association of higher cumulative doses with an increase in strength-duration time constant (Correlation coefficient = .75; P≤.001). C) Relationship of changes in refractoriness compared to changes in SDTC in motor axons. Change in refractoriness post-oxaliplatin was significantly associated with change in SDTC post-oxaliplatin (correlation coefficient = −.65; P<.05).

Figure 4. Relationship of Na⁺ channel-associated parameters with oxaliplatin dose level in sensory axons.

A) Correlation of cumulative oxaliplatin dose with refractoriness pre-oxaliplatin infusion in sensory axons, demonstrating the development of chronic changes in sensory excitability with increasing dose (Correlation coefficient = −.72; P<.01). B) Relationship of refractoriness post-infusion and SDTC post-infusion in sensory axons (Correlation coefficient = .67; P<.05).