Anticancer Agents Med Chem. 2013 Feb;13(2):373-9.

Oxaliplatin-induced hyperexcitation of rat sciatic nerve fibers: an intra-axonal study.

Alexia Kagiava1,2, Efstratios K. Kosmidis3 and George Theophilidis1

1 Laboratory of Animal Physiology, Department of Zoology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, 54 124, Greece;

2 Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus;

3 Laboratory of Physiology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, 54 124, Greece

 

ABSTRACT:

Oxaliplatin is an agent that is used extensively in gastrointestinal cancer chemotherapy. The agent’s major dose-limiting toxicity is peripheral neuropathy that can manifest as a chronic or as an acute syndrome. Oxaliplatin-induced acute neuropathy is purportedly caused by an alteration of the biophysical properties of voltage-gated sodium channels. However, sodium channel blockers have not been successful at preventing acute neuropathy in the clinical setting. We performed intra-axonal recordings from the isolated rat sciatic nerve preparation under the effect of oxaliplatin. The depolarization phase of single action potentials remains intact after 1-5 h of exposure to 150 μm oxaliplatin whereas there is a statistically significant broadening of the repolarization phase. Apart from changes in spike shape, oxaliplatin also had drastic concentration- and time-dependent effects on the firing responses of fibers to short stimuli. In the intra-axonal recordings, three groups of firing patterns were identified. The first group shows high frequency bursting (90 – 130 Hz), the second shows a characteristic plateau with durations ranging from 45 – 140 ms depending on the exposure time, and the third combines a plateau and a bursting period. Our results implicate the voltage-gated potassium channels as additional oxaliplatin targets, opening up new perspectives for the pharmacological prevention of peripheral neuropathy.

Keywords: Action potential, colorectal cancer, hyperexcitability, intra-axonal recordings, peripheral neuropathy, oxaliplatin, sciatic nerve fiber

PMID: 22721389

 

SUPPLEMENT:

Oxaliplatin is a third generation platinum-based chemotherapeutic currently indicated for use in combination with infusional 5-fluorouracil/leucovorin for the treatment of adjuvant (stage III) and advanced colorectal cancer. The successful completion of treatment cycles is highly important for the optimal clinical outcome of the patient. However, manifestation of oxaliplatin induced peripheral neuropathy is the major dose-limiting toxicity of the drug, often resulting in treatment discontinuation. Confronting peripheral neuropathy is therefore of major importance but as of today this need has not been met. Elucidating the exact physiological mechanisms of oxaliplatin associated peripheral neuropathy will hopefully provide the means towards its effective treatment. There is evidence in the literature to support that oxaliplatin causes peripheral nerve hyperexcitation by delaying the inactivation of voltage gated sodium channels (VGNaCs). However, the use of the sodium channel blocker carbamazepine in the clinical setting has failed to become the golden standard and Ca2+/Mg2+ infusion is currently the most widely-accepted practice for reducing the incidence and intensity of acute oxaliplatin-induced symptoms.

The findings of our study suggest that the oxaliplatin-induced hyperexcitability of peripheral nerves may also implicate voltage gated potassium channel (VGKC) malfunction. Comparing oxaliplatin treated nerve fibers with controls, there was no significant change in the duration of the action potential depolarizing phase, even after 4 h of continuous exposure to 150 μM oxaliplatin, and no increase in the amplitude of the maximum nerve compound action potential. On the contrary, oxaliplatin drastically elongated the duration of the repolarization phase. Oxaliplatin also had drastic concentration- and time-dependent effects on the firing responses of fibers to short stimuli. In the intra-axonal recordings, three groups of firing patterns were identified (Fig.1 A,B and C). The first group (A) shows high frequency bursting (90 – 130 Hz), the second group (B) shows a characteristic plateau with durations ranging from 45 – 140 ms depending on the exposure time, and the third group (C) combines a plateau and a bursting period. Similar patterns of response to the ones we describe here have been reported for 4-AP, a classical blocker of VGKCs, in sciatic nerve fibers from young rats. Early myelinated axons bathed in 4-AP gave rise to action potential bursts following a single stimulus. The bursts often arose from a depolarizing potential that followed the first spike and was followed by a hyperpolarizing afterpotential. The firing patterns recorded in response to a brief pulse (0.01 ms) in the presence of oxaliplatin show exceptionally slow dynamics. Some of the late responses last for more than a hundred ms, opening up the possibility of the involvement of channels with much slower dynamics than the reported VGNaC inactivation slowdown. A possible candidate is the KCNQ channels located in the rat nodal surface, which mediate a slow potassium current that regulates cell excitability.

Our results, along with those published from other groups, point to the voltage-gated potassium channels as additional targets of oxaliplatin. Pharmacological protection of potassium channels should be investigated to prevent acute neuropathy, one of the main dose-limiting toxicities of oxaliplatin.

CONCLUSION

We report intra-axonal recordings from the isolated rat sciatic nerve preparation under the effect of oxaliplatin. Our results, along with those published from other groups, point to the voltage gated potassium channels as additional targets of oxaliplatin. Pharmacological protection of potassium channels should be investigated for the prevention of acute neuropathy, one of the main dose limiting toxicities of oxaliplatin.

Acknowledgements:

This work was part of Dr. A. Kagiava’s Ph.D. thesis. The authors would like to thank Dr. M. Watkins and VITA Limited, United Kingdom (Europe) for supporting part of this research (Grant No. 85240, Research Committee, Aristotle University, Thessaloniki, Greece). Dr. E.K. Kosmidis received financial support from the Research Committee of the Aristotle University of Thessaloniki (Young Investigator Grant No. 87986).
Figure_1Figure 1: Oxaliplatin-induced firing patterns to individual peripheral nerve fibers during intra-axonal recordings. A bursting, B depolarized plateau, and C (a combination of A and B) . The nerve fibers were incubated in 150.0 µM oxaliplatin solution. t: is the time of the recording after the application of oxaliplatin. Dotted lines indicate the 0 V membrane potential level.

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