New findings for old players: Imidazolium salts as protective drugs in C. elegans models of stress and neurodegeneration

Abstract

Imidazolium salts are attractive pharmacological agents that have been linked to a wide range of biological effects, including antitumoral, antimicrobial, anthelmintic and anti-inflammatory. In this study, we aim to evaluate the role of these compounds as antioxidant and anti- aging agents. We synthesized imidazolium salts and analyzed their ability to improve oxidative stress (OS) resistance. We used an established model in biomedical research, the free-living nematode C. elegans, and exposed them to the oxidizing agent FeSO4. We identified a derivate, 1-Mesithyl-3-(3-sulfonatopropyl) imidazolium (MSI), that enhances animal resistance to OS. To delineate MSI roles, we split this work into two goals: i) to describe MSI action mechanisms and, ii) to evaluate MSI role in neurodegenerative models. To gain insight into its mechanism of action, we evaluated MSI ability to activate DAF-16 (FOXO in vertebrates), a transcription factor relevant for cytoprotective defense mechanisms. Unexpectedly, our experiments revealed that MSI stress protection was not dependent on DAF-16. These results support the idea that other transcription factors (such as SKN-1 (Nrf-2 in vertebrates), HSF-1), could be involved in MSI protection. We are currently performing experiments to identify the role of these molecular players, in MSI-induced stress resistance. The second goal is held by the theory that links OS to aging and neurodegeneration. We are currently evaluating if MSI increases lifespan, healthspan, and improves biological markers of neurodegeneration in a C. elegans model of Alzheimer disease. This strain expresses Aß1-42 in muscle and shows age- dependent protein aggregation and paralysis. Our preliminary results show that MSI delays paralysis in this strain. Additional research is needed to underpin the protective role of MSI and to determine if these effects can be extrapolated in other neurodegenerative scenarios.