Erythropoietin overrides the triggering effect of DNA platination products in a mouse model of Cisplatin-induced neuropathy
1 Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany
2 Department of Nephrology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany
3 Institute of Pathology and Neuropathology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany
4 Institute for Cell Biology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany
BMC Neuroscience 2009, 10:77 doi:10.1186/1471-2202-10-77Published: 15 July 2009
Cisplatin mediates its antineoplastic activity by formation of distinct DNA intrastrand cross links. The clinical efficacy and desirable dose escalations of cisplatin are restricted by the accumulation of DNA lesions in dorsal root ganglion (DRG) cells leading to sensory polyneuropathy (PNP). We investigated in a mouse model by which mechanism recombinant erythropoietin (rhEPO) protects the peripheral nervous system from structural and functional damage caused by cisplatin treatment with special emphasis on DNA damage burden.
A cumulative dose of 16 mg cisplatin/kg resulted in clear electrophysiological signs of neuropathy, which were significantly attenuated by concomitant erythropoietin (cisplatin 32,48 m/s ± 1,68 m/s; cisplatin + rhEPO 49,66 m/s ± 1,26 m/s; control 55,01 m/s ± 1,88 m/s; p < 0,001). The co-application of rhEPO, however, did not alter the level of unrepaired cisplatin-DNA lesions accumulating in DRG target cells. Micro-morphological analyses of the sciatic nerve from cisplatin-exposed mice showed damaged myelin sheaths and mitochondria. Co-administered rhEPO inhibited myelin sheaths from structural injuries and resulted in an increased number of intact mitochondria.
The protective effect of recombinant erythropoietin is not mediated by reducing the burden of DNA platination in the target cells, but it is likely to be due to a higher resistance of the target cells to the adverse effect of DNA damage. The increased frequency of intact mitochondria might also contribute to this protective role.