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

ANDERSEN, N.; VEUTHEY, T.; SILBESTRI, G.F; RAYES, D.H.; DE ROSA, M.J.

Congreso; Reunión Anual de Sociedades Biocientíficas 2019; 2019

Sociedad Argentina de Investigación Clínica (SAIC), la Sociedad de Farmacología Experimental (SAFE), la Sociedad Argentina de Biología (SAB), la Sociedad Argentina de Protozoología (SAP), la Asociación Argentina de Nanomedicinas (NANOMED-ar), La Asociació

Imidazoliumsalts are attractive pharmacological agents that have been linked to a widerange of biological effects, including antitumoral,antimicrobial, anthelmintic and anti-inflammatory. Inthis study, we aim to evaluate the role of these compounds as antioxidant andanti-aging agents. We synthesized imidazoliumsalts and analyzed their ability to improve oxidative stress (OS) resistance.We used an established model in biomedical research, the free-living nematodeC. elegans, andexposed 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 splitthis work into two goals: i) to describe MSI action mechanismsand, ii) to evaluate MSI role in neurodegenerative models. Togain insight into its mechanism of action, we evaluated MSI ability to activateDAF-16 (FOXO in vertebrates), a transcription factor relevant for cytoprotectivedefense mechanisms. Unexpectedly, our experiments revealed that MSI stressprotection was not dependent on DAF-16. These results support the idea thatother transcription factors (such as SKN-1 (Nrf-2 in vertebrates), HSF-1),could be involved in MSI protection. We are currently performing experiments toidentify the role of these molecular players, in MSI-induced stress resistance.Thesecond goal is held by the theory that links OS to aging and neurodegeneration.We are currently evaluating if MSI increases lifespan, healthspan, andimproves biological markers of neurodegeneration in a C. elegansmodel of Alzheimer disease. This strain expresses Aβ1-42 in muscle and showsage-dependent protein aggregation and paralysis. Our preliminary results showthat MSI delays paralysis in this strain. Additional research is needed tounderpin the protective role of MSI and to determine if these effects can beextrapolated in other neurodegenerative scenarios.