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Giannini Foundation Fellowship","award":["R01s HL147562"],"award-info":[{"award-number":["R01s HL147562"]}]},{"name":"A.P. Giannini Foundation Fellowship","award":["CA263806"],"award-info":[{"award-number":["CA263806"]}]},{"name":"A.P. Giannini Foundation Fellowship","award":["K99 AT012494"],"award-info":[{"award-number":["K99 AT012494"]}]},{"name":"NCATS\/NIH TL-1 [5 TL1 TR 1415-8] training grant","award":["R01s HL147562"],"award-info":[{"award-number":["R01s HL147562"]}]},{"name":"NCATS\/NIH TL-1 [5 TL1 TR 1415-8] training grant","award":["CA263806"],"award-info":[{"award-number":["CA263806"]}]},{"name":"NCATS\/NIH TL-1 [5 TL1 TR 1415-8] training grant","award":["K99 AT012494"],"award-info":[{"award-number":["K99 AT012494"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>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 (p38\u03b1), 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.<\/jats:p>","DOI":"10.3390\/antiox14040445","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T05:03:07Z","timestamp":1744174987000},"page":"445","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Neuronal p38 MAPK Signaling Contributes to Cisplatin-Induced Peripheral Neuropathy"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1224-9271","authenticated-orcid":false,"given":"Yugal","family":"Goel","sequence":"first","affiliation":[{"name":"Hematology\/Oncology, Department of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8234-141X","authenticated-orcid":false,"given":"Donovan A.","family":"Argueta","sequence":"additional","affiliation":[{"name":"Hematology\/Oncology, Department of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8991-0155","authenticated-orcid":false,"given":"Kristen","family":"Peterson","sequence":"additional","affiliation":[{"name":"Hematology\/Oncology, Department of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Lomeli","sequence":"additional","affiliation":[{"name":"Department of Neurology, Department of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9680-9060","authenticated-orcid":false,"given":"Daniela A.","family":"Bota","sequence":"additional","affiliation":[{"name":"Department of Neurology, Department of Medicine, University of California, Irvine, CA 92697, USA"},{"name":"Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalpna","family":"Gupta","sequence":"additional","affiliation":[{"name":"Hematology\/Oncology, Department of Medicine, University of California, Irvine, CA 92697, USA"},{"name":"Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"iv45","DOI":"10.1093\/neuonc\/nos203","article-title":"Peripheral Neuropathies from Chemotherapeutics and Targeted Agents: Diagnosis, Treatment, and Prevention","volume":"14","author":"Grisold","year":"2012","journal-title":"Neuro-Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1056\/NEJM199001113220210","article-title":"Cisplatin Neurotoxicity","volume":"322","author":"Mollman","year":"1990","journal-title":"N. 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