• Min-Young Noh, Kwangwoo Chun, Byung Yong Kang, Heejaung Kim, Ji-Seon Park, Han-Chang Lee, Young-Ha Kim, Saekwang Ku, and Seung Hyun Kim.
• Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea.
• Biochem. Biophys. Res. Commun. 2013 May 31; 435 (2): 274-81.

AbstractGlycogen synthase kinase-3 (GSK-3) is emerging as a prominent therapeutic target of Alzheimer's disease (AD). A number of studies have been undertaken to develop GSK-3 inhibitors for clinical use. We report two novel GSK-3 inhibitors (C-7a and C-7b) showing good activity and pharmacokinetic (PK) profiles. IC50 of new GSK-3 inhibitors were in the range of 120-130 nM, and they effectively reduced the Aβ-oligomers induced neuronal toxicity. Also, new GSK-3 inhibitors decreased the phosphorylated tau at pThr231, pSer396, pThr181, and pSer202, and inhibited the GSK-3 activity against Aβ-oligomers induced neuronal cell toxicity. In B6;129-Psen1(tm1Mpm) Tg(APPSwe, tauP301L)1Lfa/Mmjax model of AD, oral administration of C-7a (20 mg/kg, 50 mg/kg) showed increased total arm entries and spontaneous alteration of Y-maze which was regarded as short-term memory. In particular, 50 mg/kg C-7a treated mice significantly decreased the level of phosphorylated tau (Ser396) in brain hippocampus. We suggest that new GSK-3 inhibitor (C-7a) is potential candidates for the treatment of AD.Copyright © 2013 The Author. Published by Elsevier Inc. All rights reserved.

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