Novel transdermal curcumin attenuates cisplatin induced neuropathy in a mouse model of breast cancer

Cisplatin-induced neuropathy remains a major challenge to treat. Cisplatin disrupts mitochondrial homeostasis and increases reactive oxygen species (ROS) contributing to neuronal injury. We examined the ability of curcumin to prevent CIPN because it has antioxidant and neuroprotective properties. However, a major challenge is the reduced absorption and bioavailability of oral and systemically administered curcumin. To address this challenge, we used a novel transdermal curcumin (TDC) preparation which is bioavailable in the blood and central nervous system after topical application to the abdomen of mice. We used a transgenic mouse model of breast cancer (C3TAg) which shows the evolutionary spectrum of human breast cancer and its isotype control FVB/N mice. At ~4 months of age female C3TAg mice develop palpable tumors and demonstrate mechanical, thermal and musculoskeletal hyperalgesia (P<0.0001 vs FVB/N). Mice were treated with vehicle or cisplatin (2.3 mg/kg/day i.p.) for two cycles of 5-days and 5 days of rest in the presence or absence of TDC/VAS-101 (0.1 mL) applied daily by rubbing on the abdomen of mice through the endpoint. Similar to cisplatin, TDC alone significantly reduced tumor weight (P<0.05 vs vehicle), and didn't decrease the anti-tumor efficacy of cisplatin. By day 5, cisplatin induced significant mechanical and cold hyperalgesia in both strains (p<0.001 vs vehicle and BL), and musculoskeletal hyperalgesia at day 16 in C3TAg mice (P<0.001 vs BL; P<0.0001 vs vehicle). TDC co-treatment significantly attenuated cisplatin induced hyperalgesia (mechanical and cold, P<0.0001 vs cisplatin) and prevented musculoskeletal hyperalgesia (P<0.001 vs cisplatin). Notably, in C3TAg mice, TDC alone significantly decreased constitutive mechanical (P<0.001 vs vehicle; P<0.01 vs BL) and cold hyperalgesia (P<0.01 vs vehicle). These changes in hyperalgesia were accompanied by a significant reduction in phospho-p38 mitogen-activated protein kinase (MAPK) in dorsal root ganglion (DRG) neurons in C3TAg mice co-treated with TDC and cisplatin compared to cisplatin treatment (P<0.001) suggesting the activation of pain signaling. Furthermore, in primary DRG neurons and HT22 hippocampal neuronal cell line in culture, cisplatin elevated ROS and caused mitochondrial depolarization (P<0.0001; P<0.001 vs vehicle), which was prevented by TDC (P<0.0001). In HT22 neurons, cisplatin increased calcium release and lowered subsequent metabolic activity and viability (P<0.001 vs. vehicle), which were significantly inhibited by TDC (P<0.001), indicating that TDC targets the pain generating Ca²⁺ release from neuronal cells. In conclusion, TDC alleviates cancer- and chemotherapy-related hyperalgesia via inhibition of p38 MAPK and oxidative stress, while restoring mitochondrial function and limiting tumor growth. Thus, the novel TDC has a translational potential for preventing CIPN.