Tideglusib protects neural stem cells against NMDA receptor overactivation

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 Ca2+ accumulation, mitochondrial membrane potential (MMP)/mitochondrial morphology and glycogen synthase kinase-3 (alpha/beta isoforms and phospho-GSK-3 alpha/beta) 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 Ca2+ 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-3 beta in NSCs. Moreover, GW9662 (a peroxisome-proliferator-activated receptor gamma (PPAR gamma) antagonist) treatment significantly inhibited the protective effect of tideglusib in NMDA/D-serine-treated cells. Conclusion: Our study provides the evidence that GSK-3 beta and PPAR gamma 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. (C) 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z.o.o. All rights reserved.