Magnesium chloride in a polyethylene glycol formulation as a neuroprotective therapy for acute spinal cord injury: preclinical refinement and optimization.

ABSTRACT

Intravenously administered magnesium has been extensively investigated as a neuroprotective agent traumatic brain injuries and stroke. Numerous investigators have reported the neuroprotective benefits of magnesium in animal models of spinal cord injury (SCI) as well, but typically with doses that far exceed human tolerability. To develop magnesium into a clinically relevant therapy for SCI, further refinement and improvement of the magnesium formulation is necessary. In this series of experiments, we evaluated the neuroprotective efficacy of magnesium in a polyethylene glycol (PEG) formulation using an acute model of thoracic SCI. Following thoracic contusion (Infinite Horizon) rat SCI model, we independently confirmed the neuroprotective efficacy of the magnesium and PEG combination which had been previously reported in a thoracic clip compression model of SCI (Ditor et al., 2007). We established that the 254 micromol/kg dose of MgCl(2) was superior to 127 micromol/kg MgCl(2) with respect to tissue sparing and locomotor recovery. Additionally, the number of infusions (2, 4, or 6), time between infusions (6 vs 8 hours), and different magnesium salts (MgCl(2) vs MgSO(4)) were evaluated to determine an "optimal" treatment regimen. We observed that an "optimized" regimen of MgCl(2) within PEG conferred greater tissue neuroprotection and improved locomotor recovery compared to methylprednisolone. Further a 4 hour time window of histologic and behavioral efficacy was established. The goal of these experiments was to help guide the treatment parameters for a clinical trial of magnesium within a polyethylene glycol formulation in acute human spinal cord injury.