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The Journal of Neuroscience, July 2, 2003, 23(13):5816-5826

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Novel Role of Vitamin K in Preventing Oxidative Injury to Developing Oligodendrocytes and Neurons

Jianrong Li,¹ Judith C. Lin,² Hong Wang,¹ James W. Peterson,³ Barbara C. Furie,² Bruce Furie,² Sara L. Booth,³ Joseph J. Volpe,¹ and Paul A. Rosenberg¹

¹Department of Neurology, Division of Neuroscience, Children's Hospital, and ²Center for Hemostasis and Thrombosis Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, and ³Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111

Oxidative stress is believed to be the cause of cell death in multiple disorders of the brain, including perinatal hypoxia/ischemia. Glutamate, cystine deprivation, homocysteic acid, and the glutathione synthesis inhibitor buthionine sulfoximine all cause oxidative injury to immature neurons and oligodendrocytes by depleting intracellular glutathione. Although vitamin K is not a classical antioxidant, we report here the novel finding that vitamin K₁ and K₂ (menaquinone-4) potently inhibit glutathione depletion-mediated oxidative cell death in primary cultures of oligodendrocyte precursors and immature fetal cortical neurons with EC₅₀ values of 30 nM and 2 nM, respectively. The mechanism by which vitamin K blocks oxidative injury is independent of its only known biological function as a cofactor for -glutamylcarboxylase, an enzyme responsible for posttranslational modification of specific proteins. Neither oligodendrocytes nor neurons possess significant vitamin K-dependent carboxylase or epoxidase activity. Furthermore, the vitamin K antagonists warfarin and dicoumarol and the direct carboxylase inhibitor 2-chloro-vitamin K₁ have no effect on the protective function of vitamin K against oxidative injury. Vitamin K does not prevent the depletion of intracellular glutathione caused by cystine deprivation but completely blocks free radical accumulation and cell death. The protective and potent efficacy of this naturally occurring vitamin, with no established clinical side effects, suggests a potential therapeutic application in preventing oxidative damage to undifferentiated oligodendrocytes in perinatal hypoxic/ischemic brain injury.

Key words: glutathione depletion; oxidative stress; cell death; vitamin K; neuron; oligodendrocyte; white matter; cystine deprivation; menaquinone-4; cerebral palsy

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Received Oct. 31, 2002; revised Apr. 11, 2003; accepted May. 7, 2003.

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