Vitamin K2 protects PC12 cells against Aβ _(1-42) and H₂O₂-induced apoptosis via p38 MAP kinase pathway

Abstract

Alzheimer's is an age-related disease with a hallmark of progressive loss of memory formation followed by a damage in the brain function due to the neural degeneration and extracellular beta-amyloid (Aβ) plaques accumulation. This study examines the protective effects of vitamin K2 on toxicity induced by (Aβ) and HO in PC12 cells as an appropriate model of Alzheimer's cell damage. PC12 cells pretreated with vitamin K2 (5-200 μM) for 4, 24 and 48 h, and exposed to either Aβ (25 µM) for 48 h or HO (150 µM) for 24 h. Then the protective, antioxidant and anti-apoptotic effects of vitamin K2 in PC12 cells were investigated. Vitamin K2 pretreatment (5-200 μM) significantly decreased the Aβ and HO cytotoxicity. In addition, vitamin K2 could attenuate reactive oxygen species (ROS) level after exposure of cells to HO for 24 h and Aβ for 48 h. Cell apoptosis significantly increased following application of Aβ (25 μM) and HO (150 µM) compared to control. However, flow cytometry histograms of PI-stained cells after pretreatment with vitamin K2 (20 and 50 μM) showed significantly reduced apoptosis. Vitamin K2 increased the amount of glutathione after exposure of cells to HO for 24 h and Aβ for 48 h. Western blot analysis of PC12 cells showed that 25 μM Aβ and 150 µM HO treatment could increase Bax, PARP cleavage, Phospho-p38 MAPK. Moreover, the activated form of caspase 3 proteins led to the reduction in the Bcl-2. Real-time PCR of PC12 cells showed that 150 µM HO treatment increased the ratio of Bax/Bcl-2 while vitamin K2 (20 and 50 μM) reduced the rate. According to these findings, it seems that vitamin K2 possess anti-apoptotic and antioxidant effects and suggests that vitamin K2 may be a valuable protective candidate against the progression of Alzheimer's disease via inactivating p38 MAP kinase pathway.

Vitamin K2 protects against Aβ42-induced neurotoxicity by activating autophagy and improving mitochondrial function in Drosophila

“…Vitamin K 2 generates from the activity of intestinal bacteria or the conversion of dietary vitamin K 1 [ 7 ]. It has been reported that vitamin K 2 has a variety of biological functions, including anti-inflammation [ 8 ], antioxidant stress, antiapoptosis [ 9 ], stimulating autophagy [ 10 ] and serves as a mitochondrial electron carrier during oxidative respiration [ 11 ].…”

Vitamin K2 Modulates Organelle Damage and Tauopathy Induced by Streptozotocin and Menadione in SH-SY5Y Cells

“…Moreover, the LDH assay showed that vitamin K2 significantly improved the cell membrane integrity which was found to be compromised by the treatment of streptozotocin and menadione. Such a neuroprotective role of vitamin K2 was also observed when differentiated rat pheochromocytoma PC12 cells were pre-treated with vitamin K2 and exposed to Aβ peptide and H 2 O 2 [28]. A similar cytoprotective effect of vitamin K2 was observed in astroglioma C6 cells, where it has been found to protect the C6 cells from Aβ-induced toxicity in a dose-dependent manner [29].…”

“…While post-treatment of vitamin K2 significantly reduced the ROS levels as indicated by the decreased fluorescence intensity of DCFH-DA, suggesting that vitamin K2 protected against streptozotocin-and menadione-induced toxicity by suppressing ROS accumulation. Similarly, vitamin K2 was found to be effective against Aβ [29] and H 2 O 2 [28] induced ROS generation. Increasing evidence reveals that increased ROS production is associated with damage to mitochondrial DNA and a decrease in mitochondrial membrane potential.…”

“…In addition, it was found that lower intake of vitamin K diet was directly associated with cognitive deficits in the aged population [27]. Current studies also showed the antioxidative effect of vitamin K2 on various in vitro models such as differentiated rat pheochromocytoma PC 12 cells [28] and rat astroglia C6 cells by inhibiting the toxicity and oxidative damage induced by Aβ involving various regulatory pathways [29]. Moreover, vitamin K2 was also observed to significantly inhibit the rotenone-induced ROS production, p38 activation and caspase activation in microglial cells [30].…”

Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease

“…MK-4 improved energy production and rescued PINK1 mutation found in Parkinson’s disease [51]. More recently, research identified vitamin K2 protection of neurons via a novel mechanism involving P38 MAP kinase pathway [108]. Further to this, various K2 analogs have been found to be decisive in neuronal differentiation [109].…”