期刊
NEUROTOXICOLOGY
卷 88, 期 -, 页码 14-24出版社
ELSEVIER
DOI: 10.1016/j.neuro.2021.10.012
关键词
Acetylcholinesterase; Amyloid-beta; Chaperones; Alternative model; Dihydropyrimidinones; Selenoesters
资金
- Universidade Federal do Pampa (UNI-PAMPA)
- Programa de Pos-Graduacao em Bioquimica
- FAPERGS
- CNPq
- CNPq (Universal Grants) [453963/2014-5]
- FAPERGS/PqG [18/2551-0000434-0]
- CNPq/FAPERGS/DECIT/SCTIE-MS/PRONEM [16/2551-0000248-7]
- PROPPI/UNIPAMPA
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-Brasil (CAPES) [001]
- CERSusChem GSK/FAPESP [2014/50249-8]
- CNPq researcher scholarship
The study evaluated the safety and efficacy of eight selenoester compounds in a Caenorhabditis elegans model for Alzheimer's Disease treatment. Among them, FA90 showed promising results in reducing worm paralysis rate and increasing swimming movements, indicating its potential for further evaluation in more complex animals.
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.
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