Caracterización farmacológica de derivados de melatonina y resveratrol para el potencial tratamiento de la enfermedad de Alzheimer

This study has been developed within a multidisciplinary project designed to search for multitarget compounds with NRF2 inducing capacity, by inhibiting the Keap1-NRF2 interaction, for the treatment of Alzheimer¿s disease. We have focused on melatonin and resveratrol derivatives, which additionally induce NRF2 transcription factor, master regulator of oxidative stress. For this study, two melatonin (CH213 and CH507) and one resveratrol (PL119) derivatives, which were the ones that duplicated NRF2 expression at concentrations below 10 ¿M, were selected. We found that these compounds were not neurotoxic in the human neuroblastoma cell line SH-SY5Y at the concentration of 100 ¿M. Thereafter, neuroprotection in a tau hyperphosphorylation in vitro model induced by okadaic acid (OA) was studied; compounds CH507 and PLC119 presented significant neuroprotection, while CH213 did not. Nevertheless, neuroprotection of compound CH213 against OA was studied in primary neuronal cultures achieving significant results. Additionally, their potential anti neuroinflammatory effects were studied in primary rat glial cultures exposed to LPS; in this model, only compound CH213 reduced nitric oxide production and IL-1b. CH123 was further studied in an acute model of hippocampal slices, where toxicity was induced by incubation with OA for 6 h and in organotypic hippocampal cultures of 14 months old APPTau mice; in these models, CH213 was able to provide neuroprotection and reduce oxidative stress. Finally, since QR2, also known as MT3, is overexpressed in AD patients, we sought of interest to perform a molecular docking study to evaluate how the compounds could interact with this receptor. In conclusion, CH213 is a melatonin derivative that induces NRF2 with antineuroinflammatory, antioxidant and neuroprotective properties; however, future studies in in vivo AD models need to be conducted to validate the in vitro results here obtained