| Autor: |
Nakagami, Yasuhiro, Nishimura, Satoko, Murasugi, Takako, Kaneko, Isao, Meguro, Masaki, Marumoto, Shinji, Kogen, Hiroshi, Koyama, Kazuo, Oda, Tomiichiro |
| Předmět: |
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| Zdroj: |
British Journal of Pharmacology; Nov2002, Vol. 137 Issue 5, p676, 7p |
| Abstrakt: |
1 Fibril formation of amyloid β peptide (Aβ) is considered to be responsible for the pathology of Alzheimer's disease (AD). The Aβ fibril is formed by a protein misfolding process in which intermolecular β-sheet interactions become stabilized abnormally. Thus, to develop potential antiAD drugs, we screened an in-house library to find compounds which have a profile as a β-sheet breaker. 2 We searched for a β-sheet breaker profile in an in-house library of approximately 113,000 compounds. From among the screening hits, we focused on N,N'-bis(3-hydroxyphenyl)pyridazine3,6-diamine (named RS-0406), which had been newly synthesized in our laboratory. This compound (10-100 µg ml[sup -1]) was found to be capable of significantly inhibiting 25 µM Aβ[sub 1-42] fibrillogenesis and, furthermore, disassembling preformed Aβ[sub l-42] fibrils in vitro. 3 We then investigated the effect of RS-0406 on 111 nm Aβ[sub 1-42]-induced cytotoxicity in primary hippocampal neurons, and found that 0.3-3 µg ml[sup -1] RS-0406 ameliorates the cytotoxicity. Moreover, 3 µg ml[sup -1] RS-0406 reversed 1 µM Aβ[sub 1-42]-induced impairment of long-term potentiation in hippocampal slices. 4 In this study, we have succeeded in identifying RS-0406 which has potential to inhibit Aβ[sub 1-42] fibrillogenesis, and to protect neurons against Aβ[sub 1-42]-induced biological toxicity in vitro. These results suggest that RS-0406 or one of the derivatives could become a therapeutic agent for AD patients. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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