Magnesium polyethylene glycol: a novel therapeutic agent for traumatic brain injury.

Abstract

A number of experimental studies have shown that decline in intracellular free magnesium is a ubiquitous feature of traumatic brain injury (TBI), and that restoration of magnesium homeostasis improves both cognitive and motor outcome. However, a recent large, randomized clinical trial of magnesium in TBI failed, in part because of poor central penetration of the magnesium salt. Subsequent experimental studies in spinal cord injury have shown that magnesium penetration into the CNS can be facilitated if the magnesium salt is administered in a solution containing polyethylene glycol (PEG), a polymer that facilitates transport across the blood brain barrier and throughout the extracellular space. Accordingly, the current study characterised the therapeutic potential of high and low dose magnesium chloride, either alone or in combination with PEG, on oedema, blood brain barrier permeability, brain histology and functional outcome following moderate diffuse TBI in rats. Adult male Sprague Dawley rats (350-380 g) exposed to moderate diffuse TBI induced using the impact acceleration injury model, were administered intravenous magnesium polyethylene glycol (Mg PEG) (254 μmoles/kg MgCl₂ in 1g/kg PEG), the same concentration (optimal dose) of MgCl₂ or PEG alone, or equal volume vehicle at 30 min postinjury. A separate group of surgically prepared animals were neither injured or treated and served as shams. All animals were subsequently assessed for oedema, blood barrier permeability, brain histology and functional outcome for up to 1 week after trauma. Administration of either Mg PEG or optimal dose MgCl₂ alone significantly improved all outcome parameters compared to vehicle treated or PEG treated controls with no significant difference between the magnesium treatment groups. Indeed, magnesium treatment restored all parameters to sham levels. However, intravenous administration of one-tenth the magnesium concentration (25.4 μmoles/kg; low dose) had no beneficial effect on any of the outcome parameters whereas one-tenth the magnesium concentration in PEG (25.4 μmoles/kg MgCl₂ in 1g/kg PEG) had the same beneficial effects as optimal dose MgCl₂. We conclude that PEG facilitates movement of the magnesium salt across the blood brain barrier following TBI and that the combination of low dose magnesium in PEG significantly attenuates oedema, blood brain barrier permeability and improves motor and cognitive outcome following TBI.