RS-4252 inhibits amyloid beta-induced cytotoxicity in HeLa cells.
Progressive deposition of amyloid beta peptide in the senile plaques is a principal event in the neurodegenerative process of Alzheimer's disease. Several reports have demonstrated that amyloid beta is cytotoxic using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an indicator of viability in cells. With the MTT assay, we screened an in-house library to find compounds which suppress amyloid beta-induced inhibition of MTT reduction. We have previously reported that 6-ethyl-N,N'-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine (named RS-0466), found in an in-house library, was capable of significantly inhibiting amyloid beta-induced cytotoxicity in HeLa cells. From further screening hits, we newly focused on 4-(7-hydroxy-2,2,4-trimethyl-chroman-4-yl)benzene-1,3-diol (named RS-4252), which show comparable potency to RS-0466 to ameliorate amyloid beta-induced cytotoxicity. Furthermore, RS-4252 reversed the decrease in phosphorylated Akt by amyloid beta. These results imply that RS-4252 or one of its derivatives has the potential to be a therapeutic for Alzheimer's disease patients, and that activation of Akt is at least in part involved in the effect.
Nishimura
Satoko
S
Neuroscience and Immunology Research Laboratories, Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Murasugi
Takako
T
Kubo
Takekazu
T
Kaneko
Isao
I
Meguro
Masaki
M
Marumoto
Shinji
S
Kogen
Hiroshi
H
Koyama
Kazuo
K
Oda
Tomiichiro
T
Nakagami
Yasuhiro
Y
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D002839:Chromans / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000633:toxicity; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013778:Tetrazolium Salts / Q000032:analysis; D013844:Thiazoles / Q000032:analysis; D014227:Triazines / Q000494:pharmacology
C479963:4-(7-hydroxy-2,2,4-trimethyl-chroman-4-yl)benzene-1,3-diol; C475699:6-ethyl-N,N'-bis(3-hydroxyphenyl)(1,3,5)triazine-2,4-diamine; D016229:Amyloid beta-Peptides; D002839:Chromans; D010446:Peptide Fragments; D010636:Phenols; D011518:Proto-Oncogene Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D014227:Triazines; C078592:amyloid beta-protein (1-40); C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C022616:thiazolyl blue