High Dose Magnesium Sulfate Exposure Induces Apoptotic Cell Death in the Developing Neonatal Mouse Brain

Abstract

Background: Magnesium sulfate (MgSO₄) is often used as a treatment for pre-eclampsia/eclampsia and preterm labor, resulting in the exposure of a significant number of neonates to this drug despite a lack of evidence suggesting that it is safe, or effective as a tocolytic. While there is evidence that MgSO₄ may be neuroprotective in perinatal brain injury, recent reviews have suggested that the effects are dependent upon dose, and that higher doses may actually increase neonatal morbidity and mortality. There is a lack of evidence investigating the neurotoxic effects of neonatal magnesium (Mg) exposure on the developing brain, specifically in terms of neurodevelopmental apoptosis, a cell-killing phenomenon known to be potentiated by other drugs with mechanisms of action at Mg-binding sites (i.e. NMDA receptor antagonists such as MK-801, ketamine, and PCP). Objective: To investigate the effects of Mg exposure on the neonatal mouse brain at different postnatal ages to determine whether MgSO₄ treatment causes significant cell death in the developing mouse brain. Methods: C57Bl/6 mice were treated with four doses of MgSO₄ (250 mg/kg) on postnatal days 3 (P3), 7 (P7) or 14 (P14). Caspase-3 immunohistochemistry, cupric silver staining, and electron microscopy techniques were used to examine Mg-treated brains for neurotoxic effects. Results: Qualitative evaluation using cupric silver staining revealed widespread damage throughout the brain in P7 animals. Results of electron microscopy confirmed that the cell death process was apoptotic in nature. Quantitative evaluation of damage to the cortex, caudate-putamen, hippocampus, thalamus, and cerebellum showed that Mg treatment caused significant brain damage in animals treated on P3 and P7, but not P14. Conclusions: Administration of high doses of Mg may be detrimental to the fetal brain, particularly if exposure occurs during critical periods of neurodevelopment.

Possible Neuroprotective Effects of Magnesium Sulfate and Melatonin as Both Pre- and Post-Treatment in a Neonatal Hypoxic-Ischemic Rat Model

“…The studies that investigated the potential neuroprotective effect of magnesium have revealed conflicting data [3,[6][7][8][9][10][11][12][13][14][15][16][17] . MgSO 4 given 1, 12 and 24 h after HI insult did not decrease the severity of delayed cerebral energy failure [12] .…”

“…Results: Percent infarcted brain volume was significantly reduced in pups receiving the drugs (either magnesium sulfate, melatonin or their combi-Magnesium sulfate (MgSO 4 ) is an NMDA receptor antagonist which prevents excitotoxic calcium-induced injury through the noncompetitive voltage-dependent inhibition of NMDA receptor, which reduces calcium entry into the cell [5] . Although conflicting data exist on the beneficial effects of magnesium in experimental and clinical neonatal HI models [6][7][8][9][10][11][12][13][14][15][16][17] , magnesium bears major advantages as a neuroprotective agent in that it can be safely administered to newborn infants with severe perinatal asphyxia [8,9] .…”

What Is Their Fate after Magnesium Sulfate?

“…We read with interest the recent article by Dribben et al [1] , which we believe is important and has several implications. Firstly, this article demonstrates that the effects of magnesium sulfate are age-and model-dependent.…”

“…Taken together, the studies of Dribben et al [1] , Krueger et al [4] and Mikati et al [5] argue that further investigations to understand the effects of MgSO 4 on the newborn, as well as the adult (eclamptic mother), should be a priority. They also argue that large scale controlled prospective clinical studies examining these effects are still very much needed.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Ketamine-induced apoptosis is enhanced by cotreatment with diazepam or midazolam in a rodent model (Fredriksson et al, 2004;Young et al, 2005), but diazepam has still been long used to alleviate psychotomimetic adverse effects of ketamine in humans. In addition, magnesium loading that has been used in (pre)eclampsia, may be neurotoxic for the developing nervous system (Dribben et al, 2009), and at least one clinical trial with MgSO 4 supplementation to pregnant women with preterm labor had to be preliminarily stopped due to increased pediatric mortality (Mittendorf et al, 1997), especially to neonatal intraventricular hemorrhage (Mittendorf et al, 2002). These last cases are just two examples of problems recently encountered in the treatment affecting negatively the developing fetal or neonatal brain.…”