Vitamin K prevents oxidative cell death by inhibiting activation of 12-lipoxygenase in developing oligodendrocytes.
Oxidative mechanisms of injury are important in many neurological disorders. Developing oligodendrocytes (pre-OLs) are particularly sensitive to oxidative stress-mediated injury. We previously demonstrated a novel function of phylloquinone (vitamin K(1)) and menaquinone 4 (MK-4; a major form of vitamin K2) in protecting pre-OLs and immature neurons against glutathione depletion-induced oxidative damage (Li et al. [ 2003] J. Neurosci. 23:5816-5826). Here we report that vitamin K at nanomolar concentrations prevents arachidonic acid-induced oxidative injury to pre-OLs through blocking the activation of 12-lipoxygenase (12-LOX). Arachidonic acid metabolism is a potential source for reactive oxygen species (ROS) generation during ischemia and reperfusion. Exposure of pre-OLs to arachidonic acid resulted in oxidative cell death in a concentration-dependent manner. Administration of vitamin K (K(1) and MK-4) completely prevented the toxicity. Consistent with our previous findings, inhibitors of 12-LOX abolished ROS production and cell death, indicating that activation of 12-LOX is a key event in arachidonic acid-induced pre-OL death. Vitamin K(1) and MK-4 significantly blocked 12-LOX activation and prevented ROS accumulation in pre-OLs challenged with arachidonic acid. However, vitamin K itself did not directly inhibit 12-LOX enzymatic activity when assayed with purified 12-LOX in vitro. These results suggest that vitamin K, or likely its metabolites, acts upstream of activation of 12-LOX in pre-OLs. In summary, our data indicate that vitamin K prevents oxidative cell death by blocking activation of 12-LOX and ROS generation.
Li
Jianrong
J
The F.M. Kirby Neurobiology Center, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Wang
Hong
H
Rosenberg
Paul A
PA
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000187:drug effects* / Q000378:metabolism; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D009836:Oligodendroglia / Q000187:drug effects* / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000201:enzymology; D014812:Vitamin K / Q000378:metabolism / Q000494:pharmacology*; D024482:Vitamin K 2 / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
D017382:Reactive Oxygen Species; D024482:Vitamin K 2; D014812:Vitamin K; C030814:menatetrenone; D016718:Arachidonic Acid; D001092:Arachidonate 12-Lipoxygenase