Journal of Pharmacological Sciences (Jan 2014)

N-Stearoyltyrosine Protects Against Glutamate-Induced Oxidative Toxicity by an Apoptosis-Inducing Factor (AIF)-Mediated Caspase-Independent Cell Death Pathway

  • Rui Yang,
  • Heng-Jing Cui,
  • Hua Wang,
  • Yan Wang,
  • Jian-Hua Liu,
  • Yong Li,
  • Yang Lu

DOI
https://doi.org/10.1254/jphs.13184fp
Journal volume & issue
Vol. 124, no. 2
pp. 169 – 179

Abstract

Read online

N-Stearoyltyrosine (NsTyr), a synthesized anandamide (AEA) analogue, could exert potent neuroprotective effects on cerebral ischemia models both in vivo and in vitro via intervening in multiple injuries. Glutamate, a major excitatory neurotransmitter, plays a critical role during stroke/cerebral ischemia. In this study, we explored the protective effects of NsTyr on glutamate neurotoxicity in PC12 cells and investigated its underlying mechanisms. NsTyr treatment attenuated glutamate-induced oxidative toxicity in a dose-dependent manner and the best performance was observed at 10 μΜ. NsTyr treatment suppressed glutamate-induced upregulation of lipoxygenase 12/15 (LOX 12/15) activity and reactive oxygen species (ROS) elevation, attenuated the increase of BH3-interacting domain death agonist (Bid) in the mitochondria, prevented the loss of mitochondria membrane potential and consequently inhibited apoptosis-inducing factor (AIF) translocation into the nucleus. The results demonstrated that NsTyr could protect cells against AIF-mediated caspase-independent cell death induced by glutamate, which may be due to the blockage of Bid-mediated mitochondrial damage via reducing LOX 12/15 activity and ROS accumulation. Keywords:: N-stearoyltyrosine, glutamate, oxidative toxicity, apoptosis-inducing factor (AIF), caspase-independent