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Chemotherapy induced Peripheral Neuropathy (CIPN) is a a well known complication limiting Cisplatin (CDDP) and Docetaxel (DOCE) chemotherapy in patients with cancer. Erythropoietin (EPO) is an heamatopoietic growth factor that has been reported to display neurothrophic properties, in particular it has proved to be neuroprotective in several rodent models of nervous system damage, including CDDP induced peripheral neuropathy. In this study we evaluated the neuroprotective ability of EPO against CDDP and DOCE induced neurotoxicity in primary cultures of sensitive neurons dissociated from Dorsal Root Ganglia (DRG) obtained from 15-day-old rat embryos, aiming to investigate the mechanism underlying EPO neuroprotective action. Briefly, primary cultures of sensitive neurons have been exposed to CDDP (25M), DOCE (100nM) or to the same doses of the chemotherapics but in the presence of EPO (10nM). In this in vitro model EPO turned out to be protective against both CDDP and DOCE induced neurotoxicity, in fact an increased neuronal survival was evident in cultures exposed to the combination treatment with CDDP plus EPO and DOCE plus EPO. Several evidences suggest that AKT pathway may play an important role in EPO neuroprotective action. Therefore we analyzed by western blot the levels of expression and activation (phosphorylation) of AKT in neurons exposed to the CDDP, DOCE or to the cotreatment with EPO. Results obtained indicated that modulation of the levels of phosphorylated AKT (pAKT) occurs following 14 hours treatment with CDDP, when a sharp decrease in the levels of activated AKT was highlighted, on the contrary DOCE induced only a sligth increase in the level of pAKT. Cotreatment with EPO was able to partially prevent CDDP induced decrease in the level of pAKT. Using a specific inhibitor of AKT activation (Wortmannin) we therefore investigate the role of AKT in EPO neuroprotection. The presence of Wortmannin (100nM) did prevent EPO neuroprotective action against CDD

An unsolved question is how platinum derivatives used for solid cancer therapy cause peripheral neuropathy in patients and apoptosis in "in vitro" models of chemotherapy-induced peripheral neuropathy. DRG neurons from E15 rat embryos were treated with toxic doses of oxaliplatin or cisplatin. Here, the role of MAPKs in neuronal apoptosis was studied. Both oxaliplatin and cisplatin induced a dose-dependent neuronal apoptosis, modulated by the proteins of Bcl-2 family. Regarding MAPKs, platinum derivatives activated p38 while they reduced the active form and the total amount of JNK/Sapk. Both oxaliplatin and cisplatin activated ERKs at early stages, although they behaved differently at later stages. By using specific inhibitors of the various MAPKs it was demonstrated that the platinum-induced neuronal apoptosis is mediated by early p38 and ERK1/2 activation, while JNK/Sapk has a neuroprotective role. These results suggest a role for the different MAPKs in peripheral neuropathies characterized by apoptosis of DRG neurons.

Mesenchymal stem cells (MSCs) have been found to be useful in the management of different models of neurological diseases. In the present study, we tested the possible protective effect of MSCs on sensory dorsal root ganglia (DRG) explants exposed to the toxic effect of CDDP, a widely used anticancer drug. DRG explants cultured on a collagen layer and exposed to NGF for 2 h (differentiating neurons) or for 5 days (fully differentiated neurons) were treated with CDDP and subsequently co-cultured with MSCs. MSCs were able to support the survival of both differentiating and fully differentiated DRG neurons up to 2 months after the drug treatment, reducing the CDDP-induced death of DRG neurons. MSCs were, however, unable to restore the correct length of DRG neurites compromised by CDDP treatment. The positive effect on neuronal survival was exerted through the contact between DRG and MSCs, and not mediated by neurotrophic factors released by the MSCs. Our observations could represent a starting point for designing a neuroprotective strategy to limit CDDP induced neuropathy without interfering with its anticancer properties.