A novel compound RS-0466 reverses beta-amyloid-induced cytotoxicity through the Akt signaling pathway in vitro.
beta-Amyloid peptide is the principal protein in the senile plaques of Alzheimer's disease and is considered to be responsible for the pathology of Alzheimer's disease. Several studies have shown that beta-amyloid is cytotoxic, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an indicator of viability in cells. Utilizing the MTT assay, we screened an in-house library to find compounds that suppress beta-amyloid-induced inhibition of MTT reduction. From among the screening hits, we focused on 6-ethyl-N,N'-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine (named RS-0466), which had been newly synthesized in our laboratory. This compound was found to be capable of significantly inhibiting beta-amyloid-induced cytotoxicity in HeLa cells and of reversing the decrease of phosphorylated Akt induced by beta-amyloid. Furthermore, RS-0466 reversed the beta-amyloid-induced impairment of long-term potentiation in rat hippocampal slices. These results raise the possibility that RS-0466 or its derivatives have potential as a therapeutic agent for Alzheimer's disease patients, and its effect is at least in part mediated by activation of Akt.
Nakagami
Yasuhiro
Y
Neuroscience and Immunology Research Laboratories, Sankyo Co, Ltd, 1-2-58 Hiromachi, Tokyo Shinagawa 140-8710, Japan. yasuhiro@shina.sankyo.co.jp
Nishimura
Satoko
S
Murasugi
Takako
T
Kubo
Takekazu
T
Kaneko
Isao
I
Meguro
Masaki
M
Marumoto
Shinji
S
Kogen
Hiroshi
H
Koyama
Kazuo
K
Oda
Tomiichiro
T
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D004396:Coloring Agents; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
C475699:6-ethyl-N,N'-bis(3-hydroxyphenyl)(1,3,5)triazine-2,4-diamine; D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D014227:Triazines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C022616:thiazolyl blue