Erythropoietin overrides the triggering effect of DNA platination products in a mouse model of cisplatin-induced neuropathy.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Yoon
Min-Suk
MS
Department of Neurology, University of Duisburg-Essen, Essen, Germany. Min-Suk.Yoon@uni-due.de
Katsarava
Zaza
Z
Obermann
Mark
M
Schäfers
Maria
M
Liedert
Bernd
B
Dzagnidze
Anna
A
Kribben
Andreas
A
Egensperger
Rupert
R
Limmroth
Volker
V
Diener
Hans-Christoph
HC
Thomale
Juergen
J
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D004249:DNA Damage; D004921:Erythropoietin / Q000627:therapeutic use*; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology; D009431:Neural Conduction / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010147:Pain Measurement; D011115:Polyneuropathies / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D011994:Recombinant Proteins; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology
D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D004921:Erythropoietin; D002945:Cisplatin