NGF protects dorsal root ganglion neurons from oxaliplatin by modulating JNK/Sapk and ERK1/2.
The involvement of the Mitogen-Activated Protein Kinases (MAPKs) family in platinum derivative-induced peripheral neuropathy has already been demonstrated. In particular, it has been evidenced that in Dorsal Root Ganglion (DRG) neurons prolonged exposure to oxaliplatin (OHP) induces early activation of p38 and ERK1/2, which mediate neuronal apoptosis, while the neuroprotective action of JNK/Sapk is downregulated by the drug treatment. In this study, the exposure of OHP-treated neurons to a neuroprotective stimulus, represented by a high dose of NGF, counteracts OHP-induced neuronal mortality. This effect was achieved by restoring the MAPK activation existing in untreated control cells. Increased viability occurred also after the administration of retinoic acid (RA), a pro-differentiative agent able to activate both JNK/Sapk and ERK1/2. The use of specific chemical inhibitors of MAPKs confirms the importance of this class of proteins for the neuroprotective pathway, since they reverse the protective effect. In summary, our findings assess the validity of MAPKs as the target of neuroprotective therapies during chemotherapeutic treatment. Moreover they also describe a double role for ERK1/2, depending on cellular stimulation, since it mediates neuronal apoptosis after OHP exposure. However, it is also important, as is JNK/Sapk, in preserving the correct cellular differentiation that is pivotal for neuronal survival.
Scuteri
Arianna
A
Dipartimento di Neuroscienze e Tecnologie Biomediche, Università degli Studi di Milano-Bicocca, via Cadore 48, 20052 Monza, Italy. arianna.scuteri@unimib.it
Galimberti
Alessia
A
Ravasi
Maddalena
M
Pasini
Silvia
S
Donzelli
Elisabetta
E
Cavaletti
Guido
G
Tredici
Giovanni
G
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000633:toxicity; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000201:enzymology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009944:Organoplatinum Compounds / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D020932:Nerve Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8