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

TLDR

Oxidative stress, driven by glutamate, cystine deprivation, homocysteic acid, and buthionine sulfoximine, is implicated in cell death of immature neurons and oligodendrocytes in brain disorders such as perinatal hypoxia/ischemia. Vitamin K protects these cells by inhibiting free‑radical accumulation independently of its γ‑glutamylcarboxylase cofactor role, as oligodendrocytes and neurons lack vitamin K‑dependent carboxylase activity and vitamin K antagonists do not abrogate protection. Vitamin K1 and K2 potently prevent glutathione‑depletion–mediated oxidative death in oligodendrocyte precursors and fetal cortical neurons, with EC₅₀ values of 30 nM and 2 nM, indicating therapeutic potential for perinatal hypoxic/ischemic brain injury.

Abstract

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 K 1 and K 2 (menaquinone-4) potently inhibit glutathione depletion-mediated oxidative cell death in primary cultures of oligodendrocyte precursors and immature fetal cortical neurons with EC 50 values of 30 n m and 2 n m , respectively. The mechanism by which vitamin K blocks oxidative injury is independent of its only known biological function as a cofactor for γ-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 K 1 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.