title: Tideglusib protects neural stem cells against NMDA receptor overactivation.
abstract: BACKGROUND
  N-methyl-d-aspartate (NMDA) receptors are major pharmacological targets to prevent or reduce the progression of neurodegenerative diseases. Successful therapy with NMDA receptor antagonists in humans has been limited by the severe side effects of complete receptor blockade. The aim of the present study was to investigate the possible protective effects of tideglusib against NMDA receptor overactivation in neural stem cells.
  
  
  METHODS
  We measured the alteration in membrane integrity, free radical generation, intracellular Ca(2+) accumulation, mitochondrial membrane potential (MMP)/mitochondrial morphology and glycogen synthase kinase-3 (α/β isoforms and phospho-GSK-3α/β) protein expression levels following treatments.
  
  
  RESULTS
  NMDA treatment, with or without d-serine, significantly increased LDH leakage and triggered cell death in neural stem cells. Reactive oxygen species (ROS) formation and intracellular Ca(2+) levels were increased following NMDA receptor overactivation. The significant reduction in MMP was found in NMDA/d-serine-treated cells. Tideglusib significantly decreased ROS production and membrane degradation, but did not change intracellular Ca(2+) levels following NMDA receptor activation. Both in the presence or in the absence of NMDA/d-serine, tideglusib increased MMP and the levels of phospho-GSK-3β in NSCs. Moreover, GW9662 (a peroxisome-proliferator-activated receptor gamma (PPARγ) antagonist) treatment significantly inhibited the protective effect of tideglusib in NMDA/d-serine-treated cells.
  
  
  CONCLUSIONS
  Our study provides the evidence that GSK-3β and PPARγ may be directly involved in pathways leading to NMDA receptor-induced cell death and that the inhibitors including tideglusib may exert neuroprotective effect against these receptor overactivation.
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Ege University, Bornova, Turkey. Electronic address: guliz.armagan@ege.edu.tr.
authors.forename: Güliz
authors.initials: G
authors.lastname: Armagan
authors.affiliation: Department of Physiology, School of Medicine, Ege University, Bornova, Turkey; Center for Brain Research, Ege University, Bornova, Turkey.
authors.forename: Ayşegül
authors.initials: A
authors.lastname: Keser
authors.affiliation: Department of Restorative Dentistry, Faculty of Dentistry, Ege University, Bornova, Turkey.
authors.forename: Çiğdem
authors.initials: Ç
authors.lastname: Atalayın
authors.affiliation: Department of Physiology, School of Medicine, Ege University, Bornova, Turkey; Center for Brain Research, Ege University, Bornova, Turkey.
authors.forename: Taner
authors.initials: T
authors.lastname: Dagcı
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects; D020782:Matrix Metalloproteinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D058953:Neural Stem Cells / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D005609:Free Radicals; D018696:Neuroprotective Agents; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D013830:Thiadiazoles; D038362:Glycogen Synthase Kinase 3; D020782:Matrix Metalloproteinases; C520571:tideglusib; D002118:Calcium
keywords: Excitotoxicity; Neural stem cell; Neuroprotection; Tideglusib