Cisplatin modulates voltage gated channel currents of dorsal root ganglion neurons of rats

The anticancer drug cis-diammindichloroplatin (CDDP, cisplatin) causes severe side effects like peripheral sensitive neuropathy. The toxicity of CDDP has been linked to changes in intracellular calcium homeostasis ([Ca2+](i)). Voltage activated calcium channel currents (I-Ca(V)) are important for the regulation of [Ca2+](i); therefore, this study was designed to examine the effect of CDDP on I-Ca(V) in comparison to voltage activated potassium (I-K(V)) and sodium (I-Na(V)) channel currents using the whole cell patch clamp method on dorsal root ganglion neurons of rats. In small neurons (<= diameter 20 mu m) CDDP reduced peak and sustained I-Ca(V) concentration dependently (1-100 mu M). The IC50 was 23.9 +/- 4.5 mu M (+/- S.D.) for the peak current with a Hill-coefficient of 0.6 +/- 0.1 and 38.8 +/- 6.1 mu M for the sustained current (Hill-coefficient: 0.7 +/- 0.1). I-K(V) were reduced by 20.9 +/- 4.8% (10 mu M) and I-Na(V) were only reduced by 9.2% +/- 7.2% (10 mu M). I-Ca(V) of large neurons (> diameter 25 mu m) were less sensitive to CDDP. The peak I-Ca(V) was reduced by 14.1 +/- 2.3% and I-K(V) by 12.8 +/- 3.4% (100 mu M). The sensitivity of I-Na(V) in large neurons to CDDP was not different compared to small neurons. We conclude that the reduction of I-Ca(V) in small cells may be responsible for the neurotoxic side effects CDDP causes in sensory neurons. (c) 2006 Elsevier Inc. All rights reserved.