Abstract
Magnesium plays important roles in the nervous system. An increase in the Mg2+ concentration in cerebrospinal fluid enhances neural functions, while Mg2+ deficiency is implicated in neuronal diseases in the central nervous system. We have previously demonstrated that high concentrations of glutamate induce excitotoxicity and elicit a transient increase in the intracellular concentration of Mg2+ due to the release of Mg2+ from mitochondria, followed by a decrease to below steady-state levels. Since Mg2+ deficiency is involved in neuronal diseases, this decrease presumably affects neuronal survival under excitotoxic conditions. However, the mechanism of the Mg2+ decrease and its effect on the excitotoxicity process have not been elucidated. In this study, we demonstrated that inhibitors of Mg2+ extrusion, quinidine and amiloride, attenuated glutamate excitotoxicity in cultured rat hippocampal neurons. A toxic concentration of glutamate induced both Mg2+ release from mitochondria and Mg2+ extrusion from cytosol, and both quinidine and amiloride suppressed only the extrusion. This resulted in the maintenance of a higher Mg2+ concentration in the cytosol than under steady-state conditions during the ten-minute exposure to glutamate. These inhibitors also attenuated the glutamate-induced depression of cellular energy metabolism. Our data indicate the importance of Mg2+ regulation in neuronal survival under excitotoxicity.
Highlights
Magnesium plays important roles in the nervous system [1,2]
We examined whether changes in [Mg2+ ]i are involved in neuronal cell death via excitotoxicity in rat hippocampal neurons
We demonstrated that inhibitors of Mg2+ extrusion attenuate glutamate excitotoxicity in cultured rat hippocampal neurons (Figure 1)
Summary
Magnesium plays important roles in the nervous system [1,2]. Elevation of the Mg2+ concentration in cerebrospinal fluid (CSF) increases synapse formation, enhances recognition and learning abilities in rats [3], and causes neural stem cell proliferation in mice [4]. A deficiency of Mg2+ in the brain is implicated in neuronal diseases, and some researchers have reported lower Mg2+ concentrations than normal in the brain of patients with neurodegenerative diseases [5,6]. Significant loss of dopaminergic neurons in the substantia nigra, similar to the loss seen in Parkinson’s disease, was elicited merely by feeding them a low-magnesium diet for two generations [7]. Supplementation or overexpression of the Mg2+ channel have neuro-protective effects on cellular and animal models of Parkinson’s [8,9,10] and Alzheimer’s diseases [11].
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