AC105 Increases Extracellular Magnesium Delivery and Reduces Excitotoxic Glutamate Exposure within Injured Spinal Cords in Rats

Magnesium (Mg ) homeostasis is impaired following spinal cord injury (SCI) and the loss of extracellular Mg contributes to secondary injury by various mechanisms, including glutamate neurotoxicity. The neuroprotective effects of high dose Mg supplementation have been reported in many animal models. Recent studies found that lower Mg doses also improved neurologic outcomes when Mg was formulated with polyethylene glycol (PEG), suggesting that a PEG/ Mg formulation might increase Mg delivery to the injured spinal cord, compared with that of MgSO alone. Here, we assessed spinal extracellular Mg and glutamate levels following SCI in rats using microdialysis. Basal levels of extracellular Mg (∼0.5 mM) were significantly reduced to 0.15 mM in the core and 0.12 mM in the rostral peri-lesion area after SCI. A single intravenous infusion of saline or of MgSO at 192 μmoL/kg did not significantly change extracellular Mg concentrations. However, a single infusion of AC105 (a MgCl in PEG) at an equimolar Mg dose significantly increased the Mg concentration to 0.3 mM (core area) and 0.25 mM (rostral peri-lesion area). Moreover, multiple AC105 treatments completely restored the depleted extracellular Mg concentrations after SCI to levels in the uninjured spinal cord. Repeated MgSO infusions slightly increased the Mg concentrations while saline infusion had no effect. In addition, AC105 treatment significantly reduced extracellular glutamate levels in the lesion center after SCI. These results indicate that intravenous infusion of PEG-formulated Mg normalized the Mg homeostasis following SCI and reduced potentially neurotoxic glutamate levels, consistent with a neuroprotective mechanism of blocking excitotoxicity.