Neuronal p38 MAPK Signaling Contributes to Cisplatin-Induced Peripheral Neuropathy

Area of Science:

• Neuroscience
• Pharmacology
• Oncology

Background:

• Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of cancer treatment.
• The precise mechanisms underlying CIPN development and progression remain incompletely understood.
• Dorsal root ganglion (DRG) neurons are primary targets for neurotoxic chemotherapeutic agents.

Purpose of the Study:

• To investigate the role of p38 mitogen-activated protein kinase (MAPK) activation in DRG neurons in CIPN.
• To evaluate the therapeutic potential of inhibiting p38 MAPK activation for mitigating CIPN.

Main Methods:

• Utilized a cisplatin-treated breast cancer mouse model (C3TAg) and wild-type mice (FVB/N).
• Assessed p38 MAPK phosphorylation and nuclear translocation in DRG neurons.
• Administered neflamapimod, a specific p38 MAPK alpha (p38α) inhibitor.
• Evaluated neuronal integrity, oxidative stress, mitochondrial function, and apoptosis markers (cleaved caspase-3) in vitro.
• Assessed functional outcomes including mechanical hyperalgesia, allodynia, and cold sensitivity in vivo.

Main Results:

• Cisplatin treatment increased p38 MAPK phosphorylation and nuclear translocation in DRG neurons.
• Neflamapimod inhibited cisplatin-induced p38 MAPK activation in vitro and in vivo.
• Neflamapimod treatment reduced oxidative stress, mitochondrial dysfunction, and cleaved caspase-3 expression in DRG neurons.
• Neflamapimod administration reversed cisplatin-induced mechanical and cold hypersensitivity in mice.
• Neflamapimod treatment protected against axonal damage and neurotoxicity.

Conclusions:

• p38 MAPK activation in DRG neurons is a critical mediator of CIPN.
• Inhibition of p38 MAPK activation using neflamapimod represents a promising therapeutic strategy for preventing and treating CIPN.
• Neflamapimod mitigates CIPN-associated neurotoxicity and pain without interfering with cancer progression.