N-stearoyltyrosine protects against glutamate-induced oxidative toxicity by an apoptosis-inducing factor (AIF)-mediated caspase-independent cell death pathway.
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.
Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, China.
Rui
R
Yang
Heng-Jing
HJ
Cui
Hua
H
Wang
Yan
Y
Wang
Jian-Hua
JH
Liu
Yong
Y
Li
Yang
Y
Lu
D021581:Active Transport, Cell Nucleus; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000502:physiology / Q000633:toxicity*; D008084:Lipoxygenase / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics; D058632:Neuroprostanes / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000502:physiology* / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics*; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D051033:Apoptosis Inducing Factor; D051023:BH3 Interacting Domain Death Agonist Protein; C494816:Bid protein, rat; D058632:Neuroprostanes; D018377:Neurotransmitter Agents; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D014443:Tyrosine; C087584:N-stearoyltyrosine; D008084:Lipoxygenase