[P05.141] Recombinant Erythropoietin Ameliorates Cisplatin-Induced Neuropathy in Mice without Affecting the Level of Pt-DNA Adducts

Min-Suk Yoon, Zaza Katsarava, Anna Dzagnidze, Essen, NRW, Germany, Maria Schäfers, Bernd Liedert, Rupert Egensperger, Andreas Kribben, Volker Limmroth, Hans-Christopher Diener, Jürgen Thomale, Essen, Germany

OBJECTIVE: Cisplatin is the most potent drug in the treatment of solid tumor mediating its antineoplastic effect by formation of specific platinum DNA-adducts leading to cell apoptosis. The treatment however is limited by severe neurotoxic side-effects. BACKGROUND: We aimed to investigate the neuroprotective effect of recombinant erythropoietin (rhEPO) in a mouse model of Cisplatin-induced neuropathy. DESIGN/METHODS: Male C57Bl/6 mice were randomly divided into three groups (A-C, n=10 in each group). All groups were treated eight weeks. Mice of group A and B were injected with cisplatin (2mg/ kg i.p) once per week and mice of group B were additionally treated with rhEPO (40g/ kg s.c.) thrice per week. Controls (group C) were injected with saline (500l, i.p.) once per week. Nerve conduction velocity study was performed in all mice. Structurally defined platinum DNA-adducts in the nuclei of individual cells were detected and quantified by using a monoclonal antibody specific for Pt-(G-G) intrastrand cross-links in DNA and quantitative image analysis. RESULTS: After a cumulative dose of 16 mg/ kg Cisplatin mice of group A displayed clear signs of polyneuropathy as measured by electroneurography (p<0.001). Renal failure as a competing mechanism for peripheral neuropathy was excluded as serum creatinine and creatinine clearance in group A and C were quite similar. Moreover, cisplatin led to a significant reduction in withdrawal thresholds (p<0.001) in terms of mechanical sensitivity, representing a clinical feature of polyneuropathy including sensory loss and hypersensitivity. Concomitant application of rhEPO ameliorated the neurotoxic side-effects with respect to sensory nerve conduction velocity (p<0.001) as well as withdrawal thresholds in mechanical sensitivity, which failed statistical significance (p=0.313). Quantification of DNA-adducts in DRG reveals that rhEPO apparently did not affect the adduct formation. CONCLUSIONS/RELEVANCE: We concluded that rhEPO ameliorates cisplatin-induced neurotoxicity. However, its neuroprotective effect is apparently not mediated via attenuation of DNA-adduct formation.
Category - Peripheral Nerve
SubCategory - Basic Science

Wednesday, May 2, 2007 4:00 PM

Poster Sessions: Peripheral Nerve: Genetics and Cell Biology (4:00 PM-7:00 PM)

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