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.

The Evaluation of Magnesium Chloride within a Polyethylene Glycol Formulation in a Porcine Model of Acute Spinal Cord Injury

“…Magnesium has a long history of investigation as a neuroprotective agent in stroke and brain injury, and the formulation of MgCl 2 in PEG had been shown by independent laboratories and in different rodent injury models (thoracic and cervical SCI) to be beneficial post-SCI. [9][10][11][12][13]19 With these promising data from rodent injury models, we conducted this study to evaluate the robustness of this therapeutic effect in a large animal model. The pig spinal cord is much more similar in caliber and length to the human spinal cord than the rodent cord, and it has a more comparable CSF-filled intrathecal space.…”

“…Dosages of AC105 used in this study were similar to those evaluated in previous rodent SCI studies. 18,19 In addition to the three experimental treatment groups, a fourth group of ''sham'' animals (n = 4), which received exactly the same surgical procedure as the SCI group but sustained no contusion injury or treatment, was included to serve as a baseline ''uninjured'' condition for the MRI and histological analysis (Table 1).…”

“…It was developed as a therapeutic intervention for acute spinal cord injury (SCI) and was subsequently reported to be neuroprotective in compressive and contusive models of thoracic and cervical SCI in the rat. 11,18,19 Treating animals with AC105 decreased lesion volumes by 67%, and open field locomotion (Basso, Beattie, Bresnahan) scores were significantly improved compared to a saline-treated group (10.0 -0.2 vs. 7.8 -0.4). 19 Importantly, the doses of magnesium in the AC105 formulation (5 infusions of 190 lmol/kg) used in the rodent thoracic and cervical SCI model by Kwon and colleagues 19 and Lee and colleagues, 18 respectively, were within the range of human tolerability and comparable to doses that previously have appeared to be safe in clinical trials of stroke and cardiac arrest (4 g of bolus within 12 h post-injury, followed by 16 g over 24 h).…”

“…11,18,19 Treating animals with AC105 decreased lesion volumes by 67%, and open field locomotion (Basso, Beattie, Bresnahan) scores were significantly improved compared to a saline-treated group (10.0 -0.2 vs. 7.8 -0.4). 19 Importantly, the doses of magnesium in the AC105 formulation (5 infusions of 190 lmol/kg) used in the rodent thoracic and cervical SCI model by Kwon and colleagues 19 and Lee and colleagues, 18 respectively, were within the range of human tolerability and comparable to doses that previously have appeared to be safe in clinical trials of stroke and cardiac arrest (4 g of bolus within 12 h post-injury, followed by 16 g over 24 h). [20][21][22][23][24][25] A comparison between MgSO 4 -PEG and MgCl 2 -PEG showed no statistical difference between the two salts, but the investigators noted that the AC105-treated group appeared to have slightly better locomotor recovery early post-SCI.…”

“…[20][21][22][23][24][25] A comparison between MgSO 4 -PEG and MgCl 2 -PEG showed no statistical difference between the two salts, but the investigators noted that the AC105-treated group appeared to have slightly better locomotor recovery early post-SCI. 19 The aim of the present study was to test AC105 within a large animal model of SCI, using a recently described porcine model. 26 Both AC105 and an equivalent dose of magnesium within a clinically available MgSO 4 formulation without PEG were evaluated in this experiment.…”