Therapeutic agents for the treatment of neurodegenerative diseases: Nrf2 as central player

Abstract

The continuous aging of population has led to an ever-increasing number of people afflicted by neurodegenerative diseases (NDDs). NDDs share many pathophysiological pathways, such as mitochondrial dysfunction, aberrant protein aggregation, oxidative stress and neuroinflammation. Although the multifactorial nature of NDDs hinders the development of efficient treatments, there is a great interest in the development of compounds directed to reduce oxidative stress and neuroinflammation as these alterations play a crucial role in the evolution of those pathologies. The Nrf2 pathway plays a central role in the defense against both, oxidative stress and neuroinflammation. Besides, this pathway is deregulated in NDDs. Herein, we propose the design, synthesis, and pharmacological evaluation of new compounds, hybrids of melatonin (potent antioxidant) and cinnamic acid (moderate Nrf2 inducer), as potential treatments for NDDs. The pharmacological screening of newly developed compounds showed the compounds are Nrf2 inducers, potent scavengers and anti-inflammatory agents. Besides, these compounds have demonstrated an interesting neuroprotective profile against different in vitro models, and a broad security profile. Furthermore, compound 11 has demonstrated a potent neurogenic effect via melatonin receptors and Nrf2 induction. Altogether, these results indicate these compounds should be further evaluated in in vivo models of NDDs.