Newly developed glycogen synthase kinase-3 (GSK-3) inhibitors protect neuronal cells death in amyloid-beta induced cell model and in a transgenic mouse model of Alzheimer's disease

Min Young Noh, Kwangwoo Chun, Byung Yong Kang, Heejaung Kim, Ji Seon Park, Han Chang Lee, Young Ha Kim, Saekwang Ku, Seung Hyun Kim

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Glycogen 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 120-130nM, 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-Psen1tm1Mpm Tg(APPSwe, tauP301L)1Lfa/Mmjax model of AD, oral administration of C-7a (20mg/kg, 50mg/kg) showed increased total arm entries and spontaneous alteration of Y-maze which was regarded as short-term memory. In particular, 50mg/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.

Original languageEnglish
Pages (from-to)274-281
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume435
Issue number2
DOIs
StatePublished - 2013 May 31

Fingerprint

Glycogen Synthase Kinase 3
Cell death
Amyloid
Transgenic Mice
Alzheimer Disease
Cell Death
Oligomers
Toxicity
Pharmacokinetics
Short-Term Memory
Inhibitory Concentration 50
Oral Administration
Hippocampus
Brain
Data storage equipment
Therapeutics

Keywords

  • Alzheimer's disease
  • Amyloid-beta
  • GSK-3 inhibitor
  • TAU

Cite this

Noh, Min Young ; Chun, Kwangwoo ; Kang, Byung Yong ; Kim, Heejaung ; Park, Ji Seon ; Lee, Han Chang ; Kim, Young Ha ; Ku, Saekwang ; Kim, Seung Hyun. / Newly developed glycogen synthase kinase-3 (GSK-3) inhibitors protect neuronal cells death in amyloid-beta induced cell model and in a transgenic mouse model of Alzheimer's disease. In: Biochemical and Biophysical Research Communications. 2013 ; Vol. 435, No. 2. pp. 274-281.
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Newly developed glycogen synthase kinase-3 (GSK-3) inhibitors protect neuronal cells death in amyloid-beta induced cell model and in a transgenic mouse model of Alzheimer's disease. / Noh, Min Young; Chun, Kwangwoo; Kang, Byung Yong; Kim, Heejaung; Park, Ji Seon; Lee, Han Chang; Kim, Young Ha; Ku, Saekwang; Kim, Seung Hyun.

In: Biochemical and Biophysical Research Communications, Vol. 435, No. 2, 31.05.2013, p. 274-281.

Research output: Contribution to journalArticle

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