Novel Nrf2 inducers endowed with anti-inflammatory effect for the treatment of neurodegenerative diseases
Patrycja Michalska1,2, Izaskun Buendia1,2, Enrique Luengo1, Pablo Duarte1,2, Cristina Fernández Mendívil1, Manuela García-López1, Rafael León1,2*,
1Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029, Madrid, España; 2 Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006, Madrid, España
*Corresponding author: Rafael León
Neurodegenerative diseases (NDDs) share several physiopathological mechanisms such as the presence of aberrant protein aggregates, oxidative stress and neuroinflammation. Given the role of these factors in the development of NDDs, compounds able to regulate them simultaneously are of great interest.
At physiological conditions, the main route to combat oxidative stress and neuroinflammation is the Nrf2/EpRE pathway. Besides, it has been observed, that the Nrf2 pathway is deregulated in neurodegenerative disorders1. Based on this hypothesis we carried out the design, synthesis and pharmacological evaluation of a new family of Nrf2 inducers with complementary activities for the treatment of NDDs2.
Newly developed compounds were able to induce the Nrf2-EpRE pathway, and also demonstrated a complementary anti-inflammatory effect that was not dependent on the Nrf2 inducing properties . Besides the compounds showed an interesting neuroprotective effect against in vitro and ex vivo model models of oxidative stress and toxicity induced by protein aggregation. Altogether, these results indicate these compounds are of interest to be further evaluated in in vivo models of NDDs.
(1) Ramsey, et al. J. Neuropathol. Exp. Neurol. 2007, 66: 75-85.
(2) Buendia, et al. Future Med. Chem. 2015, 15: 1961-9.