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The positive effect of adult undifferentiated mesenchymal stem cells (MSCs) on neuronal survival has already been reported, although the mechanisms by which MSCs exert their effect are still a matter of debate. Here we have demonstrated that MSCs are able to prolong the survival of dorsal root ganglion (DRG) neurons mainly by inhibiting some proteolytic enzymes, and in particular the pathway of metalloproteinases (MMPs), a family of proteins that are involved in many neuronal processes, including survival. The inhibition of MMPs was both direct, by acting on MT-MMP1, and indirect, by acting on those proteins that regulate MMPs' activation, such as Timp-1 and Sparc. The importance of the MMPs' down-regulation for neuronal survival was also demonstrated by using N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycyl hydroxamic acid (NNGH), a wide range inhibitor of metalloproteinases, which was able to increase the survival of DRG neurons in a significant manner. The down-regulation of MMPs, obtained both by MSC contact and by chemical inhibition, led to the inactivation of caspase 3, the executor of apoptotic death in DRG neurons cultured alone, while caspase 7 was found to be irrelevant for the apoptotic process. The capacity of MSCs to prevent apoptosis mainly by inactivating the metalloproteinase pathway is an important finding that sheds light on MSCs' mechanism of action, making undifferentiated MSCs a promising tool for the treatment of many different neurodegenerative pathologies., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

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.