Combined Magnesium/Polyethylene Glycol Facilitates the Neuroprotective Effects of Magnesium in Traumatic Brain Injury at a Reduced Magnesium Dose

Abstract

Aims: While a number of studies have shown that free magnesium (Mg) decline is a feature of traumatic brain injury (TBI), poor central penetration of Mg has potentially limited clinical translation. This study examines whether polyethylene glycol (PEG) facilitates central penetration of Mg after TBI, increasing neuroprotection while simultaneously reducing the dose requirements for Mg.

Methods: Rats were exposed to diffuse TBI and administered intravenous MgCl2 either alone (254 μmol/kg or 25.4 μmol/kg) or in combination with PEG (1 g/kg PEG) at 30-min postinjury. Vehicle-treated (saline or PEG) and sham animals served as controls. All animals were subsequently assessed for blood-brain barrier permeability and edema at 5 h, and functional outcome for 1 week postinjury.

Results: Optimal dose (254 μmol/kg) MgCl2 or Mg PEG significantly improved all outcome parameters compared to vehicle or PEG controls. Intravenous administration of 10% MgCl2 alone (25.4 μmol/kg) had no beneficial effect on any of the outcome parameters, whereas 10% Mg in PEG had the same beneficial effects as optimal dose Mg administration.

Conclusion: Polyethylene glycol facilitates central penetration of Mg following TBI, reducing the concentration of Mg required to confer neuroprotection while simultaneously reducing the risks associated with high peripheral Mg concentration.

Keywords: Blood-brain barrier; Edema; Magnesium; Neurotrauma; Treatment.

Conflict of interest statement

The authors declare no conflict of interest.

© 2016 John Wiley & Sons Ltd.

Figures

Figure 1

BBB permeability in rats at 5 h following moderate diffuse TBI. Animals were treated at 30 min after TBI with 254 μmol/kg MgCl2 (optimal dose), Mg PEG (254 μmol/kg MgCl2 in 1 g/kg PEG), PEG alone, an equal volume of vehicle (saline), 10% MgCl2 (25 μmol/kg), or 10% Mg PEG. ****P < 0.0001 versus shams.

Figure 2

Edema at 5 h after moderate diffuse TBI in rats. Animals were treated at 30 min after TBI with 254 μmol/kg MgCl2, Mg PEG (254 μmol/kg MgCl2 in 1 g/kg PEG), PEG alone, an equal volume of vehicle (saline), 10% MgCl2 (25 μmol/kg), or 10% Mg PEG. ***P < 0.001 versus shams; †P < 0.05 versus vehicle.

Figure 3

Motor function over 7 days following TBI as assessed using the rotarod. Animals treated with 254 μmol/kg MgCl2, Mg PEG (254 μmol/kg MgCl2 in 1 g/kg PEG), or 10% MgCl2 (25 μmol/kg) in PEG performed significantly better (P < 0.0001) than vehicle‐, PEG‐ or 10% MgCl2 (25 μmol/kg)‐treated controls. For clarity, significance symbols have been omitted.

Figure 4

Object recognition test outcomes after diffuse TBI in rats. Animals were treated with 254 μmol/kg MgCl2, Mg PEG (254 μmol/kg MgCl2 in 1 g/kg PEG), PEG alone, an equal volume of vehicle (saline), 10% MgCl2 (25 μmol/kg), or 10% Mg PEG at 30‐min postinjury. ****P < 0.0001 compared to original object.

Figure 5

H&E‐stained hippocampal (CA3) sections at 7 days following diffuse TBI in rats. A: sham; B saline vehicle; C: 254 μmol/kg MgCl2; D: 10% MgCl2 (25 μmol/kg); E: PEG alone; F: 10% Mg PEG. Arrows indicate the CA3 field with extensive dark cell change visible. Scale bar = 200 μm.