Vitamin K prevents oxidative cell death by inhibiting activation of 12‐lipoxygenase in developing oligodendrocytes

Abstract

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 K₁) 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 (K₁ 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 K₁ 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.