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

Abstract

Magnesium (Mg²⁺) homeostasis is impaired following spinal cord injury (SCI) and the loss of extracellular Mg²⁺ contributes to secondary injury by various mechanisms, including glutamate neurotoxicity. The neuroprotective effects of high dose Mg²⁺ supplementation have been reported in many animal models. Recent studies found that lower Mg²⁺ doses also improved neurologic outcomes when Mg²⁺ was formulated with polyethylene glycol (PEG), suggesting that a PEG/ Mg²⁺ formulation might increase Mg²⁺ delivery to the injured spinal cord, compared with that of MgSO₄ alone. Here, we assessed spinal extracellular Mg²⁺ and glutamate levels following SCI in rats using microdialysis. Basal levels of extracellular Mg²⁺ (∼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 MgSO₄ at 192 μmoL/kg did not significantly change extracellular Mg²⁺ concentrations. However, a single infusion of AC105 (a MgCl₂ in PEG) at an equimolar Mg²⁺ dose significantly increased the Mg²⁺ concentration to 0.3 mM (core area) and 0.25 mM (rostral peri-lesion area). Moreover, multiple AC105 treatments completely restored the depleted extracellular Mg²⁺ concentrations after SCI to levels in the uninjured spinal cord. Repeated MgSO₄ infusions slightly increased the Mg²⁺ 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 Mg²⁺ normalized the Mg²⁺ homeostasis following SCI and reduced potentially neurotoxic glutamate levels, consistent with a neuroprotective mechanism of blocking excitotoxicity.

Keywords: magnesium; microdialysis; polyethylene glycol; rat; spinal cord injury.