Nrf2 a key stone for the development of drugs of the future
Rafael León and Manuela G. López
Department of Pharmacology, Medical College, Autonomous University of Madrid
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Neurodegenerative diseases (NDDs) are currently considered a worldwide pandemia with a prevalence of about 47 million people. It is estimated that, in 2050, two billion people will be over 60 years old, thus the number of people affected is expected to triple. However, neurodegeneration is not only a hallmark of known NDDs like Alzheimer´s, Parkinson´s or ALS, but also contributes to other prevalent pathologies like stroke, major depression, schizophrenia or neuropathic pain. Therefore, the search for effective drugs capable of controlling neuronal cell death is one of the great challenges of this century. Of interest is the fact that NDDs share common pathomechanisms such as high damage mediated by oxidative stress, chronic neuroinflammation, failure of autophagy and activation of deleterious pathways for neuronal survival. Another common characteristic is the interconnection between these pathways that causes feedback pathological loops that accelerates the advance of the disease. Therefore, their therapeutic approach must be directed to several pathological nodes, as the design of multitarget drugs capable of stopping different pathological pathways at the same time. In this sense, the intrinsic cellular defense pathway, the Nrf2-ARE pathway, has been proposed as a therapeutic alternative for the development of effective drugs. Therefore, we are developing new multitarget compounds that combine the Nrf2 induction activity with other specific targets capable of reducing oxidative stress, neuroinflammation and the formation of protein aggregates, besides activating neuronal survival pathways that could be of potential therapeutic relevance to afford neuroprotection in a broad variety of neurological diseases.