Cisplatin-induced neuropathic pain is mediated by upregulation of N-type voltage-gated calcium channels in dorsal root ganglion neurons.
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 ICa(V)in a concentration-dependent manner (0.01-50μM; 13.8-77.3%; IC505.07μM). Subtype-specific measurements of VGCCs showed differential effects on ICa(V). While the ICa(V)of P/Q-, L- and T-type VGCCs were reduced, ICa(V)of N-type VGCCs were increased by 30.3% during depolarization to 0mV. Exposure of DRG neurons to cisplatin (0.5 or 5μM) for 24-48h in vitro significantly increased a CaMK II-mediated ICa(V)current density. Immunostaining and western blot analysis revealed an increase of N-type VGCC protein level in DRG neurons 24h after cisplatin exposure. Cisplatin-mediated activation of caspase-3 was prevented by inhibition of N-type VGCCs using Ɯ-conotoxin MVIIA. Behavioral experiments showed that Ɯ-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.
Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany.
Markus
M
Leo
Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany.
Linda-Isabell
LI
Schmitt
Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany.
Martin
M
Erkel
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany.
Margarita
M
Melnikova
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany.
Jürgen
J
Thomale
Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. Electronic address: tim.hagenacker@uk-essen.de.
Tim
T
Hagenacker
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000139:chemically induced* / Q000503:physiopathology; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*; D000096926:Benzenesulfonamides
D000970:Antineoplastic Agents; D001596:Benzylamines; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D002945:Cisplatin; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides
Cisplatin; Conotoxin; Dorsal root ganglion; Neuropathic pain; Polyneuropathy; Voltage-gated calcium channels