Brain Advance Access published online on September 27, 2007
Brain, doi:10.1093/brain/awm223
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A combination of intravenous and dietary docosahexaenoic acid significantly improves outcome after spinal cord injury
Neuroscience Centre, Institute of Cell & Molecular Science, Queen Mary University of London, UK
Correspondence to:
Dr. W. L. Huang, Neuroscience Centre, Institute of Cell and Molecular Science, Queen Mary University of London, 4 Newark Street, E1 2AT, London, UK E-mail: w.huang{at}qmul.ac.uk
Previous studies have shown that omega-3 polyunsaturated fatty acids such as 
-linolenic acid and docosahexaenoic acid (DHA) are neuroprotective in models of spinal cord injury (SCI) in rodents. However, the mechanism of action underlying these effects has not been elucidated, and the optimum treatment regime remains to be defined. We have therefore carried out a detailed analysis of the effects of DHA in adult rats subject to thoracic compression SCI. Saline or DHA (250 nmol/kg) was administered intravenously (i.v.) 30 min after compression. After injury, the saline group received a standard control diet for 1 or 6 weeks, whereas DHA-injected animals received either a control or a DHA-enriched diet (400 mg/kg/day) for 1 or 6 weeks. Other groups received a DHA-enriched diet only for 1 week following injury, or received acute DHA (250 nmol/kg; i.v.) treatment delayed up to 3 h after injury. We also assessed oxidative stress and the inflammatory reaction at the injury site, neuronal and oligodendrocyte survival and axonal damage and the locomotor recovery.
At 24 h, lipid peroxidation, protein oxidation, RNA/DNA oxidation and the induction of cyclooxygenase-2 were all significantly reduced by i.v. DHA administration. At 1 week and 6 weeks, macrophage recruitment was reduced and neuronal and oligodendrocyte survival was substantially increased. Axonal injury was reduced at 6 weeks. Locomotor recovery was improved from day 4, and sustained up to 6 weeks. Rats treated with a DHA-enriched diet in addition to the acute DHA injection were not significantly different from the acute DHA-treated animals at 1 week, but at 6 weeks showed additional improvements in both functional and histological outcomes. DHA treatment was ineffective if the acute injection was delayed until 3 h post-injury, or if the DHA was administered for 1 week solely by diet. Our results in a clinically relevant model of SCI show that significant neuroprotection can be obtained by combining an initial acute i.v. injection of DHA with a sustained dietary supplementation. Given that the safety and tolerability of preparations enriched in omega-3 fatty acids is already well-documented, such a combined DHA treatment regime deserves consideration as a very promising approach to SCI management.
Key Words: docosahexaenoic acid; omega-3 fatty acids; spinal cord injury; inflammation; oxidative stress
Abbreviations: AA, arachidonic acid; APC, adenomatous polyposis coli tumour suppressor protein; ß-APP, ß-amyloid precursor protein; BBB, Basso, Beattie and Bresnahan; COX, cyclooxygenase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; i.v., intravenous; NeuN, neuronal nuclei; 8-OHG, 8-hydroxyguanosine; PBS, phosphate buffered saline; PUFA, polyunsaturated fatty acid; RT, room temperature; SCI, spinal cord injury
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Received June 12, 2007. Revised August 20, 2007. Accepted August 22, 2007.
*These authors contributed equally to this work.
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