Avaliação do potencial neuroprotetor de substâncias isoladas de produtos naturais e derivados sintéticos: uma integração de respostas celulares e metabolômica

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the development of motor symptoms. Available therapies primarily target symptoms, highlighting the need for new strategies capable of halting or slowing disease progression. In this context, natural products represent a significant source of bioactive molecules with neuroprotective potential. Ayahuasca, a beverage prepared from Banisteriopsis caapi and Psychotria viridis, contains alkaloids with antioxidant and neuroactive properties. Thus, this study evaluated the neuroprotective potential of Ayahuasca, its main alkaloids, harmine (HRE), harmaline (HRL), dimethyltryptamine (DMT) and three synthetic tetrahydro-β-carboline (THβ-carboline) derivatives, KCT1, KCT2, KCT3 using an in vitro model of PD with SH-SY5Y cells subjected to 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. The effects of treatment with these substances were assessed regarding cell viability, neuroprotection, oxidative stress, and senescence. Additionally, metabolomic analyses of intracellular and extracellular contents were optimized for the in vitro model and performed to investigate metabolic alterations associated with the neuroprotection induced by the various treatments. At low concentrations, the treatments increased cell viability and demonstrated a neuroprotective effect against 6-OHDA. At a concentration of 1.25 µg/mL, the treatments reduced mitochondrial oxidative stress with the exception of HRA and KCT1 while HRA, HRL, DMT, KCT3, Ayahuasca, and L-DOPA reduced cellular senescence. Metabolomic analysis indicated that the treatments with the substances induced alterations in phenylalanine and sphingolipid metabolism. As well as alterations in the biosynthesis of phenylalanine, tyrosine, and tryptophan, with distinct profiles between intracellular and extracellular material. Taken together, the results demonstrate the neuroprotective potential of Ayahuasca, its alkaloids, and the synthetic derivatives evaluated, associated with the modulation of oxidative stress, senescence, and metabolic pathways related to amino acid and lipid metabolism.