Attenuation of Magnesium Sulfate on CoCl_2-Induced Cell Death by Activating ERK1/2/MAPK and Inhibiting HIF-1α via Mitochondrial Apoptotic Signaling Suppression in a Neuronal Cell Line

Abstract

Magnesium sulfate (MgSO₄) ameliorates hypoxia/ischemia-induced neuronal apoptosis in a rat model. This study aimed to investigate the mechanisms governing the anti-apoptotic effect of MgSO₄ on cobalt chloride (CoCl₂)-exposed NB41A3 mouse neuroblastoma cells. MgSO₄ increased the viability of NB41A3 cells treated with CoCl₂ in a dose-dependent manner. MgSO₄ treatment was shown to lead to an increase in the anti-apoptotic Bcl-2 family proteins, with a concomitant decrease in the pro-apoptotic proteins. MgSO₄ also attenuated the CoCl₂-induced disruption of mitochondrial membrane potential (ΔΨ(m)) and reduced the release of cytochrome c form the mitochondria to the cytosol. Furthermore, exposure to CoCl₂ caused activation of the hypoxia-inducible factor 1α (HIF-1α). On the other hand, MgSO₄ markedly reduced CoCl₂-induced HIF-1α activation and suppressed HIF-1α downstream protein BNIP3. MgSO₄ treatment induced ERK1/2 activation and attenuated CoCl₂-induced activation of p38 and JNK. Addition of the ERK1/2 inhibitor U0126 significantly reduced the ability of MgSO₄ to protect neurons from CoCl₂-induced mitochondrial apoptotic events. However, incubation of cultures with the p38 and JNK inhibitors did not significantly affect MgSO₄-mediated neuroprotection. MgSO₄ appears to suppress CoCl₂-induced NB41A3 cell death by activating ERK1/2/ MAPK pathways, which further modulates the role of Bcl-2 family proteins and mitochondria in NB41A3 cells. Our data suggest that MgSO₄ may act as a survival factor that preserves mitochondrial integrity and inhibits apoptotic pathways.

A Biodegradable Mg-Based Alloy Inhibited the Inflammatory Response of THP-1 Cell-Derived Macrophages Through the TRPM7–PI3K–AKT1 Signaling Axis

“…Recently, Yan et al reported that magnesium could inhibit the immune response by downregulation of all members of the MAPK pathways (51). However, other studies found that magnesium could attenuate CoCl 2 -induced neuronal cell death by activating the ERK1/2 pathway and could inhibit the calcification of extracellular matrix, thereby protecting articular cartilage through ERK/autophagy pathway (52, 53). Interestingly, our results confirmed that magnesium could effectively decrease the activity of the p38 and JNK pathways induced by LPS but not the ERK1/2 pathway.…”

An overview of biological research on hypoxia-inducible factors (HIFs)

“…Raf activates downstream MAPK/ERK kinase (MEK), which phosphorylates ERK and increases the expression level of HIF-1a [64]. Salceda confirmed by reporter gene analysis and EMSA experiments that in hypoxic Hep3B cells the ERK pathway inhibitor PD98059 can block the transcriptional activity of HIF-1 without affecting its DNA binding activity [65]. Richard showed that the HIF-1a subunit can be phosphorylated by activated ERK1 or ERK2, but the activity of ERK1 or ERK2 could not be detected.…”

Description of Hemoproteins and Elemental Homeostasis in Brain Tumors

“…Inositol-3-phosphate signaling system is dominant for maintaining the proliferative activity of embryonic cells, so the increase of calcium concentration, which is a secondary messenger, leads to the activation of this system [12]. In malignant brain tumors magnesium level was reduced, but increased magnesium level has been shown to stabilize and activate hypoxia-inducible factor 1α (HIF-1α), which, in turn, reduces hypoxia-induced effects in the cell [13] [14]. HIF-1α has been shown as a master regulator of hypoxic response [13].…”

“…In malignant brain tumors magnesium level was reduced, but increased magnesium level has been shown to stabilize and activate hypoxia-inducible factor 1α (HIF-1α), which, in turn, reduces hypoxia-induced effects in the cell [13] [14]. HIF-1α has been shown as a master regulator of hypoxic response [13]. that HIF-1a is a mediator of hypoxic cell damage, particularly in the brain [19].…”