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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
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Role of MAPKs in platinum-induced neuronal apoptosis

Arianna Scuteri1, Alessia Galimberti, Daniele Maggioni

  • 1Dipartimento di Neuroscienze e Tecnologie Biomediche, Università degli Studi di Milano-Bicocca, Monza, Italy. arianna.scuteri@unimib.it

Neurotoxicology
|May 12, 2009
PubMed

Insights

Platinum chemotherapy drugs cause nerve damage by inducing apoptosis in sensory neurons. Specific mitogen-activated protein kinases (MAPKs) like p38 and ERK1/2 mediate this damage, while JNK/Sapk plays a protective role.

Area of Science:

  • Neuroscience
  • Oncology
  • Pharmacology

Background:

  • Platinum derivatives (oxaliplatin, cisplatin) are vital in solid cancer therapy.
  • Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting side effect.
  • The precise mechanisms of platinum-induced neuronal apoptosis remain incompletely understood.

Purpose of the Study:

  • To investigate the role of mitogen-activated protein kinases (MAPKs) in platinum-induced apoptosis of dorsal root ganglion (DRG) neurons.
  • To elucidate the specific signaling pathways involved in chemotherapy-induced peripheral neuropathy.

Main Methods:

  • DRG neurons from E15 rat embryos were exposed to toxic doses of oxaliplatin or cisplatin.
  • Western blotting and specific MAPK inhibitors were used to analyze MAPK activation and function.
  • Bcl-2 family protein modulation was assessed in relation to apoptosis.

Main Results:

  • Both oxaliplatin and cisplatin induced dose-dependent neuronal apoptosis, modulated by Bcl-2 family proteins.
  • Platinum agents activated p38 and early ERK1/2, while reducing JNK/Sapk.
  • Inhibition studies revealed p38 and ERK1/2 activation mediate apoptosis, whereas JNK/Sapk exhibits neuroprotection.

Conclusions:

  • MAPK signaling pathways differentially regulate platinum-induced DRG neuron apoptosis.
  • Early p38 and ERK1/2 activation are key mediators of CIPN.
  • JNK/Sapk signaling may represent a potential therapeutic target for mitigating platinum neurotoxicity.

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