ihydropyrimidinone-derived selenoesters efficacy and safety in an in vivo model of A beta aggregatio

Author(s)

de Oliveira Pereira, Flavia Suelen ^[1] ; Rocha Barbosa, Flavio Augusto ^[2] ; Santos Canto, Romulo Farias ^[3] ; Lucchese, Cristiane ^[4] ; Pinton, Simone ^[1] ; Braga, Antonio Luiz ^[2] ; de Azeredo, Juliano Braun ^[5] ; Quines, Caroline Brandao ^[1] ; Avila, Daiana Silva ^[1]

Affiliation

^[1] Fed Univ Pampa, Lab Biochem & Toxicol Caenorhabditis Elegans, Grad Program Biochem, Uruguaiana, RS - Brazil

^[2] Fed Univ Santa Catarina UFSC, Chem Dept, Lab Synth Bioact Selenium Cpds LabSelen, Florianopolis, SC - Brazil

^[3] Fed Univ Hlth Sci Porto Alegre, Dept Pharmacosci, Porto Alegre, RS - Brazil

^[4] Univ Fed Pelotas, Pelotas, RS - Brazil

^[5] Fed Univ Pampa, Pharm Course, Grad Program Pharmaceut Sci, Uruguaiana, RS - Brazil

• Document type: Journal article
• Source: NeuroToxicology; v. 88, p. 14-24, JAN 2022.
• Web of Science Citations: 0

Abstract

In a previous in vitro study, dihydropyrimidinone-derived selenoesteres demonstrated antioxidant properties, metal chelators and inhibitory acetylcholinesterase (AChE) activity, making these compounds promising candidates for Alzheimer's Disease (AD) treatment. However, these effects have yet to be demonstrated in an in vivo animal model; therefore, this study aimed to evaluate the safety and efficacy of eight selenoester compounds in a Caenorhabditis elegans model using transgenic strains for amyloid-beta peptide (A beta) aggregation. The L1 stage worms were acutely exposed (30 min) to the compounds at concentrations ranging from 5 to 200 mu M and after 48 h the maintenance temperature was increased to 25 degrees C for A beta expression and aggregation. After 48 h, several parameters related to phenotypic manifestations of A beta toxicity and mechanistic elucidation were analyzed. At the concentrations tested no significant toxicity of the compounds was found. The selenoester compound FA90 significantly reduced the rate of paralyzed worms and increased the number of swimming movements compared to the untreated worms. In addition, FA90 and FA130 improved egg-laying induced by levamisole and positively modulated HSP-6 and HSP-4 expression, thereby increasing reticular and mitochondrial protein folding response in C. elegans, which could attenuate A beta aggregation in early exposure. Therefore, our initial screening using an alternative model demonstrated that FA90, among the eight selenoesters evaluated, was the most promising compound for AD evaluation screening in more complex animals. (AU)

• FAPESP's process: 14/50249-8 - Green chemistry: sustainable synthetic methods employing benign solvents, safer reagents, and bio-renewable feedstock
• Grantee: Arlene Gonçalves Corrêa
• Support Opportunities: Research Grants - Research Centers in Engineering Program