Improved outcome after spinal cord compression injury in mice treated with docosahexaenoic acid Siew-Na Lim a, b , Wenlong Huang a, c , Jodie C.E. Hall a, d , Adina T. Michael-Titus a , John V. Priestley a, ⁎ a Centre for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK b Department of Neurology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taipei, Taiwan c Pain Research Group, Department of Surgery and Cancer, Imperial College London, SW10 9NH, UK d Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH 43210, USA abstract article info Article history: Received 17 May 2012 Revised 20 September 2012 Accepted 24 September 2012 Available online 28 September 2012 Keywords: Trauma Spinal cord injury Polyunsaturated fatty acid Docosahexaenoic acid Neuroprotection In this study we have characterised the locomotor recovery, and temporal profile of cell loss, in a novel thoracic com- pression spinal cord injury (SCI) in the mouse. We have also shown that treatment with docosahexaenoic acid (DHA) is neuroprotective in this model of SCI, strengthening the growing literature demonstrating that omega-3 polyunsaturated fatty acids are neuroprotective after SCI. Compression SCI in C57BL/6 mice was produced by placing a 10 g weight for 5 min onto a 2 mm×1.5 mm platform applied to the dura at vertebral level T12. Mice partly recovered from complete hindlimb paralysis and by 28 days post-surgery had plateaued at an average BMS locomotor score of 4.2, equivalent to weight support with plantar stepping. During the same period, neuronal loss at the epicentre increased from 26% of ventral horn neurons by day 1, to 68% by day 28. Delayed loss of oligodendrocytes was also seen (e.g. 84% by day 28 in the dorsal columns) and microglia/macrophage activation was maximal at 7 days. In contrast, axonal damage, judged by a decrease in the non-phosphorylated form of 200 kD neurofilament, was an early event, as the loss was seen by day 1 and did not change markedly over time. Mice that received an intravenous (i.v.) injection of 500 nmol/kg DHA 30 min after SCI, showed improved locomotor recovery and, at 28 day survival, reduced neuronal, oligodendrocyte and neurofilament loss, and reduced microglia/macrophage activation. For some of these indices of SCI, enrichment of the diet with 400 mg/kg/day DHA led to further improvement. However, dietary DHA supplementation, without the initial i.v. injection, was ineffective. © 2012 Elsevier Inc. All rights reserved. Introduction Traumatic spinal cord injury (SCI) has devastating consequences for patients, and current treatments, such as acute decompression (Fehlings and Perrin, 2006) or administration of methylprednisolone (Hurlbert and Hamilton, 2008), are controversial or of limited efficacy. In preclinical studies, major progress has been made in both the fields of neuroprotection and neuroregeneration (Kwon et al., 2010), but translation into the clinic has been disappointing. Neuroprotective strategies are particularly appealing because they aim to stop the spread of injury, and the complex cascade of events that follow the primary insult means there are many possible targets for neuroprotective agents. However, although there are promising new agents under development (Kwon et al., 2011a), many clinical trials have failed, either because of limited efficacy or unexpected toxicity (Tator and Fehlings, 1999). There is, therefore, still a need for the development of new neuroprotective agents, which are safe and effective when delivered after spinal cord injury. Recently, a number of preclinical studies have demonstrated that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are neuroprotective when administered after SCI. n -3 PUFAs are essential fatty acids that have crucial roles in the development and mature functioning of the nervous system. Particularly important is docosahexaenoic acid (DHA), a long chain (22 carbon) n -3 PUFA that accounts for approximately 50% of the PUFAs in central nervous system (CNS) membranes. We have shown in rat hemisection and compression models of SCI that DHA administered as an intravenous bolus 30 min after injury leads to increased neuronal, oligodendrocyte and axonal survival at the lesion epicentre, and improved locomotor function (Huang et al., 2007b; King et al., 2006; Ward et al., 2010). When the acute bolus is combined with dietary DHA supplementation for several weeks following injury, addi- tional cell and axonal survival is seen, and further improvement of func- tional outcome (Huang et al., 2007b; Ward et al., 2010). Most recently we have shown that a multi-nutrient dietary formulation containing n -3 PUFAs is also neuroprotective (Zbarski-Barquero et al., 2012). Neuroprotection has also been reported in studies involving treatment with DHA prior to SCI (Figueroa et al., 2012) or treatment after SCI with Experimental Neurology 239 (2013) 13–27 ⁎ Corresponding author at: Centre for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, UK. Fax: +44 20 78822218. E-mail address: j.v.priestley@qmul.ac.uk (J.V. Priestley). 0014-4886/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.expneurol.2012.09.015 Contents lists available at SciVerse ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr