Sorafenib-induced palmar-plantar erythrodysesthesia: neuroinflammation and neuronal damage as potential mechanisms

Sorafenib is a chemotherapeutic that modulates cellular pathways involved in tumor growth and angiogenesis, improving cancer control and patient survival. However, treatment is often interrupted due to palmar-plantar erythrodysesthesia (PPE), a sensory hypersensitivity syndrome characterized by burning, pain, and hyperkeratosis in peripheral areas that substantially impairs patients’ quality of life. PPE’s mechanisms remain poorly understood, and current therapies remain limited (Neurotoxicology (2015) 50:101). This study (CEUA-CCS-UFRJ nº A29-23-051-20 and 127/25) aimed to characterize sorafenib-induced neurotoxicity and investigate its underlying mechanisms. Swiss mice (6–8 weeks old) received vehicle (0.5% carboxymethylcellulose) or sorafenib (320 mg/kg, p.o., 5 times/week for 30 days). Mechanical and thermal sensitivity to cold and heat were assessed, and spinal cord (SC), dorsal root ganglia (DRG), and plantar skin were collected for molecular and immunohistochemical analyses. Sorafenib-treated mice showed significantly increased mechanical and thermal sensitivity after three weeks, indicating altered sensory responses. To investigate potential mechanisms underlying these changes, neuronal damage and neuroinflammation were assessed by evaluating ATF3, TNF-α, and TLR4 gene expression by RT-qPCR. All three markers were significantly increased in the DRG, but not in the SC, suggesting activation of inflammatory pathways at the peripheral sensory level. EGFR expression, due to its role in pain processing, was also increased in the SC. Intraepidermal nerve fiber density was assessed in plantar skin by PGP9.5 immunostaining and was reduced in treated animals. Together, these findings indicate that sorafenib-induced PPE involves neuronal damage and neuroinflammatory changes and shares relevant features with chemotherapy-induced peripheral neuropathy. This model may help elucidate the mechanisms underlying PPE and support the development of new therapeutic strategies.