Molecular Neuroprotective Responses to Achyrocline satureioides Extract in Caenorhabditis elegans: Modulation of Conserved FOXO/NRF2 Pathways and Resistance to Neurotoxic Insults.

Achyrocline satureioides is widely consumed as an herbal infusion in South America; however, the toxicological profile of its aqueous extract (ASAE), particularly under conditions of neurotoxic stress, remains incompletely characterized. In the present study, we investigated the safety profile of ASAE and its capacity to modulate chemically induced neurotoxicity by integrating in silico toxicological predictions with in vivo assays in Caenorhabditis elegans. Wild-type and mutant strains deficient in key stress-response regulators (daf-2, daf-16, and skn-1) were exposed to ASAE (10-50 mg/mL). Toxicological and neurofunctional endpoints included survival under methylmercury (MeHg) exposure, PTZ-induced paralysis, locomotor performance, lipofuscin accumulation as a biomarker of oxidative damage, and activation of stress-responsive signaling pathways. Chronic ASAE exposure did not induce developmental toxicity or reduce lifespan at the tested concentrations. Notably, ASAE pre-exposure was associated with reduced behavioral deficits induced by MeHg and delayed PTZ-induced paralysis, indicating reduced susceptibility to chemically induced neurotoxic insults. Mechanistic analyses suggested that these findings are consistent with the involvement of conserved stress-response pathways involving daf-16 and skn-1, regulators functionally analogous to mammalian FOXO and NRF2 signaling. Consistent with these findings, computational toxicology predicted low systemic toxicity for major ASAE constituents and limited interaction with toxicity-related biomarkers. Collectively, these results indicate that ASAE exhibits a favorable toxicological profile and modulates conserved molecular pathways that enhance resilience to neurotoxic stress in C. elegans.