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

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.

Effects of polyethylene glycol and magnesium sulfate administration on clinically relevant neurological outcomes after spinal cord injury in the rat.

The purpose of this study was to determine the long-term effects of polyethylene glycol (PEG) and magnesium sulfate (MgSO(4)) on clinically relevant motor, sensory, and autonomic outcomes after spinal cord injury (SCI). Rats were injured by clip compression (50 g; T4) and treated 15 min and 6 hr postinjury intravenously (tail vein) with PEG (1 g/kg, 30% w/w in saline; n = 11), MgSO(4) (300 mg/kg; n = 5), PEG + MgSO(4) (n = 6), or saline (n = 10). Behavioral testing lasted for 6 weeks, followed by histological analysis of the spinal cord. Both PEG and MgSO(4) resulted in enhanced locomotor recovery and lower susceptibility to neuropathic pain (mechanical allodynia) compared with saline. At 6 weeks, BBB scores were 7.3 +/- 0.2, 7.7 +/- 0.4, and 6.4 +/- 0.6 in PEG-treated, MgSO(4)-treated, and saline-treated control groups, respectively. Likewise, at 6 weeks PEG-, MgSO(4)-, and saline-treated control animals showed 3.5 +/- 0.4, 2.8 +/- 0.9, and 5.0 +/- 0.5 avoidance responses to at-level touch, respectively. PEG + MgSO(4) improved locomotor recovery and reduced pain but did not provide additional benefit compared with either treatment alone. Neither treatment, nor their combination, attenuated mean arterial pressure (MAP) increases during autonomic dysreflexia. However, saline-treated controls had significantly lower resting MAP than PEG-treated rats and tended to have lower resting MAP than MgSO(4)-treated rats 6 weeks postinjury. MgSO(4) treatment and PEG + MgSO(4) treatment resulted in significant increases in dorsal myelin sparing, and the latter resulted in significant reductions in lesion volume, compared with saline-treated controls. Furthermore, mean lesion volumes correlated negatively with the corresponding mean BBB scores and positively with the corresponding mean pain scores. In conclusion, both PEG and MgSO(4) enhanced long-term clinical outcomes after SCI.

Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone.

Treatment with isolated allogeneic mesenchymal cells has the potential to enhance the therapeutic effects of conventional bone marrow transplantation in patients with genetic disorders affecting mesenchymal tissues, including bone, cartilage, and muscle. To demonstrate the feasibility of mesenchymal cell therapy and to gain insight into the transplant biology of these cells, we used gene-marked, donor marrow-derived mesenchymal cells to treat six children who had undergone standard bone marrow transplantation for severe osteogenesis imperfecta. Each child received two infusions of the allogeneic cells. Five of six patients showed engraftment in one or more sites, including bone, skin, and marrow stroma, and had an acceleration of growth velocity during the first 6 mo postinfusion. This improvement ranged from 60% to 94% (median, 70%) of the predicted median values for age- and sex-matched unaffected children, compared with 0% to 40% (median, 20%) over the 6 mo immediately preceding the infusions. There was no clinically significant toxicity except for an urticarial rash in one patient just after the second infusion. Failure to detect engraftment of cells expressing the neomycin phosphotransferase marker gene suggested the potential for immune attack against therapeutic cells expressing a foreign protein. Thus, allogeneic mesenchymal cells offer feasible posttransplantation therapy for osteogenesis imperfecta and likely other disorders originating in mesenchymal precursors.