Neuroprotective Potential of Acmella oleracea Aerial Parts and Root Extracts: The Role of Phenols and Alkylamides Against Neuropathic Pain

<b><i>Background</i></b>: Chemotherapy-induced neuropathic pain is a major side effect of antineoplastic treatment. This study investigated the neuroprotective potential of <i>Acmella oleracea</i> L. extracts containing the N-alkylamide spilanthol, phenolic acids, and glycosylated flavonoids. <b><i>Methods</i></b>: Hydroalcoholic extracts of aerial parts (AP) and roots (R) of in vitro seedlings were quali-quantitatively characterized by HPLC-DAD-MS and by ¹H-NMR. Different concentrations (15-150 µg/mL) of AP and R were tested in SH-SY5Y cells differentiated into neurons exposed to oxaliplatin (10 µM), assessing cell viability (MTT), cytotoxicity (LDH), SOD activity, and expression of ATF-3, Ire1α, and Nf-H genes. To evaluate the impact on neuropathic pain, CD-1 mice were treated intraperitoneally with oxaliplatin (2.4 mg/kg), the effect of AP and R extracts (200-1200 mg/kg) were measured by the cold plate test. <b><i>Results</i></b>: AP extract was rich in phenols and alkylamides, whereas R extract showed higher phenolic levels but lower alkylamides content. Both extracts significantly reduced mortality and cytotoxicity and counteracted oxidative imbalance by enhancing SOD activity. Gene expression analysis confirmed their neuroprotective effects. In vivo, oxaliplatin induced a 50% reduction in pain threshold, while acute treatment with AP and R extracts dose-dependently alleviated neuropathic pain. Despite the lower spilanthol content in R extract, its efficacy was comparable to AP, suggesting an important role of phenolic compounds. <b><i>Conclusions</i></b>: Extracts from both aerial parts and roots of <i>A. oleracea</i> show promise in alleviating chemotherapy-induced neuropathy through mechanisms not solely related to spilanthol. Further studies to elucidate the contribution of phenolic components are desirable.