Journal
EXPERIMENTAL NEUROLOGY
Volume 288, Issue -, Pages 62-74Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2016.11.003
Keywords
Neuropathic pain; Polyneuropathy; Cisplatin; Voltage-gated calcium channels; Dorsal root ganglion; Conotoxin
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [HA6202/4-1]
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Cisplatin is important in the treatment of various types of cancer. Although it is highly effective, it also has severe side effects, with neurotoxicity in dorsal root ganglion (DRG) neurons being one of the most common. The key mechanisms of neurotoxicity are still controversially discussed; however, disturbances of the calcium homeostasis in DRG neurons have been suggested to mediate cisplatin neurotoxicity. By using the whole-cell patch-clamp technique, immunostaining and behavioral experiments with Sprague-Dawley rats, we examined the influence of short- and long-term exposure to cisplatin on voltage-gated calcium channel (VGCC) currents (Ica(v)) in small DRG neurons. In vitro exposure to cisplatin reduced I-Ca(V) in a concentration-dependent manner (0.01-50 mu M; 13.8-77.3%; IC50 5.07 mu M). Subtype-specific measurements of VGCCs showed differential effects on I-Ca(V). While the I-Ca(V) of P/Q-, L- and T-type VGCCs were reduced, I-Ca(V) of N-type VGCCs were increased by 30.3% during depolarization to 0 mV. Exposure of DRG neurons to cisplatin (0.5 or 5 mu M) for 24-48 h in vitro significantly increased a CaMK H-mediated I-Ca(V) current density. Immunostaining and western blot analysis revealed an increase of N-type VGCC protein level in DRG neurons 24 h after cisplatin exposure. Cisplatin-mediated activation of caspase-3 was prevented by inhibition of N-type VGCCs using-conotoxin MVIIA. Behavioral experiments showed that-conotoxin MVIIA treatment prevented neuropathic syndromes in vivo by inhibiting upregulation of the N-type protein level. Here we show evidence for the first time for a crucial role of N-type VGCC in the genesis of cisplatin-induced polyneuropathy. (C) 2016 Elsevier Inc. All rights reserved.
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