Magnesium attenuates persistent functional deficits following diffuse traumatic brain injury in rats Robert Vink a, * , Christine A. O’Connor a , Alan J. Nimmo b , Deanne L. Heath b a Department of Pathology, The University of Adelaide, Adelaide, South Australia 5005, Australia b School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Queensland 4811, Australia Received 18 August 2002; received in revised form 4 October 2002; accepted 21 October 2002 Abstract Although a number of studies have demonstrated that magnesium improves acute motor and cognitive outcome after traumatic brain injury, others have failed to show positive effects on cognitive outcome and none have examined persistent functional deficits. The present study shows that severe impact-acceleration induced, diffuse traumatic brain injury in rats produced profound motor and cognitive deficits that persisted for at least 4 weeks after trauma. Intravenous administration of magnesium sulfate (250 mmoles/kg) at 30 min after injury significantly improved rotarod (sensorimotor) and open field (stress/anxiety) performance, and led to a faster rate of recovery in the Barnes maze (learning). We conclude that posttraumatic magnesium administration attenuates long-term motor and cognitive defi- cits after traumatic brain injury, and that this improvement may include some reduction of post-traumatic stress and anxiety. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Diffuse axonal injury; Magnesium; Neurotrauma; Deficits Several mechanisms are associated with the development of functional deficits following traumatic brain injury (TBI). At the time of the traumatic event, mechanical disruption of tissue in the form of lacerations, axonal stretching and shearing make up what is known as primary injury [10]. After the primary injury, a cascade of biochemical and physiological changes take place that cause significantly more neuronal injury than the primary event [10,18]. This autodestructive cascade is known as secondary injury, and the fact that this secondary injury develops over time following the traumatic event provides a window of oppor- tunity to pharmacologically inhibit aspects of the secondary injury cascade and potentially improve outcome. Magne- sium has been proposed to be a particularly effective phar- macological intervention in TBI given that it inhibits a number of the secondary injury factors, including, amongst others, glutamate release, the activity of the N-methyl-D- aspartate channel, calcium channels, lipid peroxidation, free radical production, edema formation and opening of the mitochondrial permeability transition pore (for review, see Ref. [24]). Consistent with its beneficial effects on multiple secondary injury factors, magnesium has now been success- fully used to improve both motor and cognitive outcome following experimental TBI [2,7,14,20,22]. Unfortunately, most studies examining the effects of magnesium have been limited to the immediate 1–2 week period after trauma making it unclear whether the functional improvement observed is relevant to long-term functional outcome or simply related to the transient nature of second- ary injury. Moreover, some of the findings in this short time period have been contradictory. Specifically, some studies have reported that magnesium improves spatial learning after TBI [22] whereas others have reported no significant improvement in spatial learning with magnesium adminis- tration following TBI [2]. We have therefore chosen to examine the effects of magnesium sulfate on 4 week motor and cognitive outcome following severe diffuse TBI in rats. This 4 week time point is likely to reflect persistent functional deficits rather than transient changes related to secondary injury. Furthermore, we have for the first time incorporated the open field test in our trauma studies [16,23], introducing a measure of stress/anxiety that has not previously been addressed in studies of experimental diffuse TBI. Neuroscience Letters 336 (2003) 41–44 0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(02)01244-2 www.elsevier.com/locate/neulet * Corresponding author. Tel.: 161-8-8222-3092; fax: 161-8- 8222-3093. E-mail address: robert.vink@adelaide.edu.au (R. Vink).