BUSCADOR RECOLECTA

Digital.CSIC. Repositorio Institucional del CSIC

oai:digital.csic.es:10261/281171

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 derivatives, which additionally induce the NRF2 transcription factor, master regulator of oxidative stress. NF1086 is a melatonin derivative which duplicates NRF2 expression at a concentration below 1 ¿M, has antioxidant properties and is predicted to cross the BBB through the PAMPA test. Further on, in vivo target validation was assessed by measuring NRF2 and some of its target genes in brain samples after peripheral administration. To test the potential effects of NF1086 in tauopathy, primary cortical neuronal cultures were treated with adeno-associated particles which express the human tau protein with P301L mutation (AAV-hTauP301L). In this in vitro model, phosphorylated tau was signi¿¿cantly reduced in cultures treated with NF1086. We next evaluated if the compound could provide neuroprotective effects in vivo. Tauopathy in adult (3-4 months) C57BL/6J mice was generated by injecting stereotaxically AAV-hTauP301L in both hippocampi; mice were treated with 20 or 50 mg/Kg/day orally for 35 days, starting after the tauopathy induction. NF1086 treatment prevented cognitive decline promoted by tauopathy. Moreover, it reduced tau hyperphosphorylated protein in different brain regions and reduced neuroin¿¿ammation. Interestingly, similar results were achieved in aged 20 months old mice. In conclusion, NF1086 is a melatonin derivative that induces NRF2 with neuroprotective properties with potential therapeutic interest in tauopathy and related NDDs; however, future studies need to be conducted to elucidate its mechanism of action. Acknowledgments. The Comunidad Autónoma de Madrid (grant B2017/BMD-3827), the Universidad Autónoma de Madrid, the Ministerio de Economía y Competencia (RTI2018- 095793-B-I00) and the Ministerio de Ciencia, Innovación y Universidades (FPU18/00630) for supporting this work.