BUSCADOR RECOLECTA

Digital.CSIC. Repositorio Institucional del CSIC

oai:digital.csic.es:10261/222261

Neuroinflammation is increasingly associated to the onset and progression of neurodegenerative diseases. Furthermore, several lines of evidence have demonstrated the capacity of aberrant protein aggregates to activate the immune response, accelerating the advance of the disease. Compound ITH12674 is a melatonin-sulforaphane hybrid designed to exert a dual drug-prodrug mechanism of action that combines potent NRF2 induction and free radical scavenger activity. ITH12674 also showed neuroprotective properties in oxidative stress related models, that were dependant on its NRF2 inducing properties. Given the high impact of neuroinflammation in the pathogenesis of neurodegeneration, we foresaw to study the anti-inflammatory properties of ITH12674. ITH12674 reduced inflammatory markers in glial cell cultures and hippocampal tissue after LPS administration. The anti-inflammatory effect was related to inhibition of TLR4 receptors due to a direct interaction with the TLR4/MD2 complex at the hydrophobic cavity of MD2. ITH12674 is endowed with anti-inflammatory properties, that are complementary to the NRF2 inducing activity and neuroprotective properties. Thus, ITH12674 could be of potential interest for the treatment of diseases with chronic neuroinflammation., This work was supported by grants from IS Carlos III co-financed by the European Regional Development’s funds (FEDER), Programa Miguel Servet II (CP16/00014) and research project (grant PI17/01700) to RL; Fundación La Caixa, CaixaImpulse program (grant CI17-00048) to RL; Comunidad Autónoma de Madrid (grant B2017/BMD-3827) and Spanish Ministry of Science, Innovation and Education (grant RTI2018-095793-B-I00) to MGL. P.M., P.D. and C.F.-M thanks MECD for FPU fellowships (13/0373716/03977 and 15/03269 respectively). I.B thanks MECD for Juan de la Cierva fellowship (FJCI-2016/28282). We would also like to thank “Fundación Teófilo Hernando” for its continued support., Peer reviewed