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Neuronal p38 MAPK Signaling Contributes to Cisplatin-Induced Peripheral Neuropathy.

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Inhibiting p38 mitogen-activated protein kinase (MAPK) activation in dorsal root ganglion neurons with neflamapimod effectively reduced chemotherapy-induced peripheral neuropathy (CIPN) and its associated pain.

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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.