Background: In neonatal rats, early post-hypoxia-ischemia (HI) administration of the omega-3 fatty acid docosahexaenoic acid (DHA) improves sensorimotor function, but does not attenuate brain damage. Objective: To determine if DHA administration in addition to hypothermia, now standard care for neonatal asphyxial brain injury, attenuates post-HI damage and sensorimotor deficits. Methods: Seven-day-old (P7) rats underwent right carotid ligation followed by 90 min of 8% O2 exposure. Fifteen minutes later, pups received injections of DHA 2.5 mg/kg (complexed to 25% albumin) or equal volumes of albumin. After a 1-hour recovery, pups were cooled (3 h, 30°C). Sensorimotor and pathology outcomes were initially evaluated on P14. In subsequent experiments, sensorimotor function was evaluated on P14, P21, and P28; histopathology was assessed on P28. Results: At P14, left forepaw function scores (normal: 20/20) were near normal in DHA + hypothermia-treated animals (mean ± SD 19.7 ± 0.7 DHA + hypothermia vs. 12.7 ± 3.5 albumin + hypothermia, p < 0.0001) and brain damage was reduced (mean ± SD right hemisphere damage 38 ± 17% with DHA + hypothermia vs. 56 ± 15% with albumin + hypothermia, p = 0.003). Substantial improvements on three sensorimotor function measures and reduced brain damage were evident up to P28. Conclusion: Unlike post-HI treatment with DHA alone, treatment with DHA + hypothermia produced both sustained functional improvement and reduced brain damage after neonatal HI.

Keywords:
Albumin, Docosahexaenoic acid, Hypothermia
1.
Belayev L, Marcheselli VL, Khoutorova L, Rodriguez de Turco EB, Busto R, Ginsberg MD, Bazan NG: Docosahexaenoic acid complexed to albumin elicits high-grade ischemic neuroprotection. Stroke 2005;36:118-123.
2.
Huang WL, King VR, Curran OE, Dyall SC, Ward RE, Lal N, Priestly JV, Michael-Titus AT: A combination of intravenous and dietary docosahexaenoic acid significantly improves outcome after spinal cord injury. Brain 2007;130:3004-3019.
3.
Pan H, Kao T, Ou Y, Yang DY, Yen YJ, Wang CC, Chuang YH, Liao SL, Raung SL, Wu CW, Chiang AN, Chen CJ: Protective effect of docosahexaenoic acid against brain injury in ischemic rats. J Nutr Biochem 2009;20:715-725.
4.
Berman DR, Mozurkewich E, Liu Y, Barks J: Docosahexaenoic acid pretreatment confers neuroprotection in a rat model of perinatal cerebral hypoxia-ischemia. Am J Obstet Gynecol 2009;200:305.e1-e6.
5.
Berman DR, Liu Y, Barks J, Mozurkewich E: Treatment with docosahexaenoic acid after hypoxia-ischemia improves forepaw placing in a rat model of perinatal hypoxia-ischemia. Am J Obstet Gynecol 2010;203: 385.e1-e5.
6.
Suganuma H, Arai Y, Kitamura Y, Hayashi M, Okumura A, Shimizu T: Maternal docosahexaenoic acid-enriched diet prevents neonatal brain injury. Neuropathology 2010;30:597-605.
7.
Zhang W, Hu X, Yang W, Gao Y, Chen J: Omega-3 polyunsaturated fatty acid supplementation confers long-term neuroprotection against neonatal hypoxic-ischemic brain injury through anti-inflammatory actions. Stroke 2010;41:2341-2347.
8.
Marcheselli V, Hong S, Lukiw W, Tian XH, Gronert K, Musto A, Hardy M, Gimenez JM, Chiang N, Serhan CN, Bazan NG: Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 2003;278:43807-43817.
9.
Bazan NG: Neuroprotectin D1-mediated anti-inflammatory and survival signaling in stroke, retinal degenerations and Alzheimer's disease. J Lipid Res 2009;50(suppl):S400-S405.
10.
Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, Strohm B, Thoresen M, Whitelaw, A, Azzopardi D: Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010;340: c363.
11.
Cilio MR, Ferriero DM: Synergistic neuroprotective therapies with hypothermia. Semin Fetal Neonat Med 2010;15:293-298.
12.
Liu YQ, Barks JD, Xu G, Silverstein FS: Topiramate extends the therapeutic window for hypothermia-mediated neuroprotection after stroke in neonatal rats. Stroke 2004;35:1460-1465.
13.
Barks JD, Liu YQ, Shangguan Y, Silverstein FS: Phenobarbital augments hypothermic neuroprotection. Pediatr Res 2010;67:532-537.
14.
Liu Y, Shangguan Y, Barks JD, Silverstein FS: Bumetanide augments the neuroprotective efficacy of phenobarbital plus hypothermia in a neonatal hypoxia-ischemia model. Pediatr Res 2012;71:559-565.
15.
Rice JE, Vannucci RC, Brierley JB: The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 1981;9:131-141.
16.
Grow JL, Liu YQ, Barks JD: Can lateralizing sensorimotor deficits be identified after neonatal cerebral hypoxia-ischemia in rats? Dev Neurosci 2003;25:394-402.
17.
Pazaiti A, Soubasi V, Spandou E, Karkavelas G, Georgiou T, Karalis P, Guiba-Tziampiri: Evaluation of long-lasting sensorimotor consequences following neonatal hypoxic-ischemic brain injury in rats: the neuroprotective role of MgSO4. Neonatology 2009;95:33-40.
18.
Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST: CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 2000;39:777-787.
19.
Trescher WH, Ishiwa S, Johnston MV: Brief post-hypoxic-ischemic hypothermia markedly delays neonatal brain injury. Brain Dev 1997;19:326-338.
20.
Yang Y, Pan HC, Yen YJ, Wang CC, Chuang YH, Chen SY, Lin SY, Liao SL, Raung SL, Wu CW, Chou MC, Chiang AN, Chen CJ: Detrimental effects of post-treatment with fatty acids on brain injury in ischemic rats. Neurotoxicology 2007;28:1220-1229.
21.
Alva N, Carbonell T, Palomeque J: Hypothermic protection in an acute hypoxia model in rats: acid-base and oxidant/antioxidant profiles. Resuscitation 2010;81;609-616.
22.
Roberts LJ, Montine TJ, Markesbery WR, Tapper AR, Hardy P, Chemtob S, Dettbarn WD, Morrow JD: Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J Biol Chem 1998;273:13605-13612.
23.
Signorini C, Ciccoli L, Leoncini S, Carloni S, Perrone S, Comporti M, Balduini M, Buonocore G: Free iron, total F-isoprostanes and total F-neuroprostanes in a model of neonatal hypoxic-ischemic encephalopathy: neuroprotective effect of melatonin. J Pineal Res 2009;46:148-154.
24.
D'Cruz BJ, Fertig KC, Filiano AJ, Hicks SD, DeFranco DB, Callaway CW: Hypothermic reperfusion after cardiac arrest augments brain-derived neurotrophic factor activation. J Cereb Blood Flow Metab 2002;22:843-851.
25.
Wu A, Ying Z, Gomez-Pinilla F: Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition. Neuroscience 2008;155:751-759.
26.
He C, Qu X, Cui L, Wang J, Kang JX: Improved spatial learning performance of fat-1 mice is associated with enhanced neurogenesis and neuritogenesis by docosahexaenoic acid. Proc Natl Acad Sci USA 2009;106:11370-11375.
27.
Xiong M, Cheng GQ, Ma SM, Yang Y, Shao XM, Zhou WH: Post-ischemic hypothermia promotes generation of neural cells and reduces apoptosis by Bcl-2 in the striatum of neonatal rat brain. Neurochem Int 2011;58:625-633.
28.
Hubbard WK: United States Food and Drug Administration. Letter responding to health claim petition dated November 3, 2003 (Martek petition): Omega-3 fatty acids and reduced risk of coronary heart disease (docket No. 2003Q-0401). Date of issue September 8, 2004. http://www.fda.gov/Food/LabelingNutrition/LabelClaims/QualifiedHealthClaims/ucm072932.htm (accessed September 30, 2011).
29.
Diamond IR, Sterescu A, Pencharz PB, Kim JH, Wales PW: Changing the paradigm: omegaven for the treatment of liver failure in pediatric short bowel syndrome. J Pediatr Gastroenterol Nutr 2009;48:209-215.
© 2013 S. Karger AG, Basel
2013
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.