Neuronal p38 MAPK Signaling Contributes to Cisplatin-Induced Peripheral Neuropathy

Yugal Goel; Donovan A Argueta; Kristen Peterson; Naomi Lomeli; Daniela A Bota; Kalpna Gupta

doi:10.3390/antiox14040445

Neuronal p38 MAPK Signaling Contributes to Cisplatin-Induced Peripheral Neuropathy

Antioxidants (Basel). 2025 Apr 8;14(4):445. doi: 10.3390/antiox14040445.

Authors

Yugal Goel¹, Donovan A Argueta¹, Kristen Peterson¹, Naomi Lomeli², Daniela A Bota^{2

3}, Kalpna Gupta^{1

4}

Affiliations

¹ Hematology/Oncology, Department of Medicine, University of California, Irvine, CA 92697, USA.
² Department of Neurology, Department of Medicine, University of California, Irvine, CA 92697, USA.
³ Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA.
⁴ Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.

Abstract

This study investigates the role of p38 mitogen-activated protein kinase (MAPK) activation in dorsal root ganglion (DRG) neurons in the development and progression of chemotherapy-induced peripheral neuropathy (CIPN). This research evaluates whether inhibiting activation of p38 MAPK could reduce neuropathic outcomes in a transgenic breast cancer mouse model (C3TAg) and wild-type mice (FVB/N) treated with cisplatin. Cisplatin treatment stimulated p38 MAPK phosphorylation and nuclear translocation in DRG neurons. Neflamapimod, a specific inhibitor of p38 MAPK alpha (p38α), proven to be safe in clinical trials, inhibited neuronal cisplatin-induced p38 MAPK phosphorylation in vitro and in vivo. Neflamapimod also reduced cisplatin-induced oxidative stress, mitochondrial dysfunction, and cleaved caspase-3 expression in DRG neurons in vitro, protecting neuronal integrity and preventing axonal damage. Functionally, neflamapimod improved mechanical and musculoskeletal hyperalgesia, and cold sensitivity in cisplatin-treated mice, reversing neuropathic pain and neurotoxicity. This study identifies p38 MAPK activation as a critical driver of CIPN and highlights its potential as a therapeutic target for CIPN. Targeting p38 MAPK activation with neflamapimod offers a promising strategy to mitigate neurotoxicity and hyperalgesia without exacerbating cancer progression, positioning it as a novel intervention for CIPN.

Keywords: CIPN; cancer; cisplatin; dorsal root ganglion; neuron; p38 MAPK; pain.