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

Biochem Biophys Res Commun. 2013 May 31;435(2):274-81. doi: 10.1016/j.bbrc.2013.04.065. Epub 2013 Apr 28.

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 120-130 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology*
  • Amyloid beta-Peptides*
  • Animals
  • Apoptosis / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / enzymology*
  • Neuroprotective Agents / administration & dosage
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / chemistry*
  • Rats
  • Rats, Sprague-Dawley
  • Treatment Outcome

Substances

  • Amyloid beta-Peptides
  • Neuroprotective Agents
  • Protein Kinase Inhibitors
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3