Investigação do potencial terapêutico da Lepidium meyenii (maca) e macamidas sintéticas: avaliação das atividades citotóxica e neuroprotetora

Abstract

Introduction: Lepidium meyenii (maca) is a plant with diverse biological activities, including antioxidant, cytotoxic, and anti-inflammatory properties. Among its metabolites, macamides stand out as potential antitumor’ and neuroprotective compounds. Glioblastoma (GBM) and Parkinson's disease (PD), two central nervous system (CNS) pathologies, have unfavorable prognoses and limited therapeutic options, representing relevant targets for new compounds. Objective: This study aimed to evaluate the antitumor potential of fractions of the crude extract of maca root and identify its bioactive compounds, as well as to investigate the antitumor and neuroprotective potential of synthetic macamides. Methodology: The crude extract of maca root underwent bioguided fractionation to assess the cytotoxicity of the fractions, which was tested on rat glioma cells (C6). The metabolomic profile of the fractions was characterized by UHPLC-Q-TOF-MS/MS and correlated with biological activity by chemometric analysis. In parallel, macamides were synthesized and their antitumor activity was evaluated in multiple glioma and GBM cell lines (C6, U87, U343, GL15) and in primary astrocyte cultures using the MTT assay. Cell migration (scratch assay), cell cycle (flow cytometry), and PI3K/AKT and STAT3 signaling pathways (Western blotting) were investigated in U87 cells. The cytotoxic effect of macamides on U87 and U343 spheroids was assessed by analyzing cell viability (MTT assay) and morphological changes. Neuroprotective activity was evaluated in cellular models of PD using SH-SY5Y and PC12 cells treated with the neurotoxins salsolinol and dopamine, respectively. Results and discussion: Maca extract fractions reduced the viability of C6 cells (200 μg/mL), and from the metabolomic analysis, the main bioactive compounds correlated with this cytotoxicity were the polyunsaturated fatty acids 9-oxo-10E,12E-octadecadienoic and linolenic acids, in addition to macamide B. Macamides (5-100 μM) demonstrated potent cytotoxicity against all GBM cell lines tested, with high selectivity, since they did not affect astrocyte viability. Furthermore, macamides inhibited the migration of U87 cells, induced cell cycle arrest in the G0/G1 phase, and inhibited the PI3K/AKT and STAT3 signaling pathways. The cytotoxic effect was also confirmed in spheroid models by reducing cell viability and altering morphological integrity. In the context of PD, macamides protected SH-SY5Y cells from salsolinol-induced neurotoxicity, but showed no protective effect on dopamine-treated PC12 cells. Conclusion: Taken together, the results demonstrate that macamides are key bioactive metabolites of maca, exhibiting dual therapeutic potential. Their ability to selectively induce GBM cell death by inhibiting crucial signaling pathways and exhibiting neuroprotective effects positions them as promising compounds for the development of new therapies for CNS diseases.