Vitamin K has the potential to protect neurons from methylmercury‐induced cell death In Vitro

Abstract

Vitamin K (VK) has a protective effect on neural cells. Methylmercury is a neurotoxicant that directly induces neuronal death in vivo and in vitro. Therefore, in the present study, we hypothesized that VK inhibits the neurotoxicity of methylmercury. To prove our hypothesis in vitro, we investigated the protective effects of VKs (phylloquinone, vitamin K(1); menaquinone-4, vitamin K(2) ) on methylmercury-induced death in primary cultured neurons from the cerebella of rat pups. As expected, VKs inhibited the death of the primary cultured neurons. It has been reported that the mechanisms underlying methylmercury toxicity involve a decrement of intracellular glutathione (GSH). Actually, treatment with GSH and a GSH inducer, N-acetyl cysteine, inhibited methylmercury-induced neuronal death in the present study. Thus, we investigated whether VKs also have protective effects against GSH-depletion-induced cell death by employing two GSH reducers, L-buthionine sulfoximine (BSO) and diethyl maleate (DEM), in primary cultured neurons and human neuroblastoma IMR-32 cells. Treatment with VKs affected BSO- and DEM-induced cell death in both cultures. On the other hand, the intracellular GSH assay showed that VK(2), menaquinone-4, did not restore the reduced GSH amount induced by methylmercury or BSO treatments. These results indicate that VKs have the potential to protect neurons against the cytotoxicity of methylmercury and agents that deplete GSH, without increasing intracellular GSH levels. The protective effect of VKs may lead to the development of treatments for neural diseases involving GSH depletion.

Protective effect of VK2 on glucocorticoid-treated MC3T3-E1 cells

“…In this study, we observed significant apoptosis of the DEX-treated MC3T3-E1 cells and an anti-apoptotic effect of VK 2 . Studies have demonstrated that VK 2 has some biological effects as a co-factor, including anti-apoptotic effects in erythroid progenitors (36), maintaining endothelial cell survival (37) and protecting neurons from methylmercury-induced cell death (38). The anti-apoptotic effects of VK 2 are believed to be related to its role as an electron carrier in the regulation of mitochondrial function (39).…”

Structure–Activity Relationship Study of Vitamin K Derivatives Yields Highly Potent Neuroprotective Agents

“…This protection has been established in multiple models involving the depletion of glutathione, including exposure to methylmercury, L-buthionine sulfoximine (BSO), elevated levels of extracellular glutamate, and cystine depletion. 22, 23 …”

Potentiation of Methylmercury-Induced Death in Rat Cerebellar Granular Neurons Occurs by Further Decrease of Total Intracellular GSH with BDNF <i>via</i> TrkB <i>in Vitro</i>

“…24) The intracellular GSH level in neuron culture is decreased by exposure to methylmercury. 14,15,19) This lowering of the intracellular GSH level is one of the most important factors for methylmercury-induced cell death in neuron cultures, as methylmercury induces production of reactive oxygen species, and the methylmercury-induced cell death is inhibited by treatment with antioxidative enzymes and antioxidants such as GSH, Trolox and vitamin E. 12,13,16,28,29) The present results show that BDNF alone induced a slight lowering of the intracellular GSH level and further increased the methylmercury-induced lowering of the intracellular GSH level. Actually, BDNF treatment additionally lowered the intracellular GSH level and promoted cell death in CGN and B35 TrkB -cell cultures treated with GSH reducers, BSO or DEM, but not in B35 Mock .…”

“…9,10) During the process of methylmercury-and glutamate-induced cell deaths, a decrease of the intracellular GSH level and increase of ROS production are generally observed, and these changes are known to play a key role in the toxicological process. [11][12][13][14][15][16][17][18] Therefore, we hypothesized that BDNF potentiates the methylmercury-induced death of neuronal cells by decreasing the intracellular GSH level via TrkB. To elucidate our hypothesis, we investigated the intracellular GSH levels in cultures of cerebellar granular cells from rat pups after treatment by methylmercury and/or BDNF.…”