Research Article| Volume 162, 102176, November 2020

Acute injection of a DHA triglyceride emulsion after hypoxic-ischemic brain injury in mice increases both DHA and EPA levels in blood and brain

  • Denny Joseph Manual Kollareth
    Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY
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  • Richard J. Deckelbaum
    Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY

    Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
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  • Zequn Liu
    Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY
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  • Rajasekhar Ramakrishnan
    Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY

    Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
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  • Charlotte Jouvene
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America
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  • Charles N. Serhan
    Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America
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  • Vadim S. Ten
    Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
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  • Hylde Zirpoli
    Correspondence should be addressed to: Hylde Zirpoli, PhD, Institute of Human Nutrition, Columbia University Irving Medical Center, 630 West 168th Street, pH-East-1512, New York, NY 10032.
    Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY
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Published:September 24, 2020DOI:


      • DHA injected as triglyceride emulsion (tri-DHA) was associated with highest uptake in the liver while brain has the lowest.
      • Rapid increases in plasma LPC-DHA levels were observed in animals subjected to ischemic injury and acutely treated with tri-DHA.
      • Tri-DHA administration increased DHA derived SPMs in brain after ischemic injury.
      • Tri-DHA administration increased EPA and EPA derived SPMs and pathway markers in plasma lipid pools and in brain.


      We recently reported that acute injection of docosahexaenoic acid (DHA) triglyceride emulsions (tri-DHA) conferred neuroprotection after hypoxic-ischemic (HI) injury in a neonatal mouse stroke model. We showed that exogenous DHA increased concentrations of DHA in brain mitochondria as well as DHA-derived specialized pro-resolving mediator (SPM) levels in the brain. The objective of the present study was to investigate the distribution of emulsion particles and changes in plasma lipid profiles after tri-DHA injection in naïve mice and in animals subjected to HI injury. We also examined whether tri-DHA injection would change DHA- and eicosapentaenoic acid (EPA)-derived SPM levels in the brain. To address this, neonatal (10-day-old) naïve and HI mice were injected with radiolabeled tri-DHA emulsion (0.375 g tri-DHA/kg bw), and blood clearance and tissue distribution were analyzed. Among all the organs assayed, the lowest uptake of emulsion particles was in the brain (<0.4% recovered dose) in both naïve and HI mice, while the liver had the highest uptake. Tri-DHA administration increased DHA concentrations in plasma lysophosphatidylcholine and non-esterified fatty acids. Additionally, treatment with tri-DHA after HI injury significantly elevated the levels of DHA-derived SPMs and monohydroxy-containing DHA-derived products in the brain. Further, tri-DHA administration increased resolvin E2 (RvE2, 5S,18R-dihydroxy-eicosa-6E,8Z,11Z,14Z,16E-pentaenoic acid) and monohydroxy-containing EPA-derived products in the brain. These results suggest that the transfer of DHA through plasma lipid pools plays an important role in DHA brain transport in neonatal mice subjected to HI injury. Furthermore, increases in EPA and EPA-derived SPMs following tri-DHA injection demonstrate interlinked metabolism of these two fatty acids. Hence, changes in both EPA and DHA profile patterns need to be considered when studying the protective effects of DHA after HI brain injury. Our results highlight the need for further investigation to differentiate the effects of DHA from EPA on neuroprotective pathways following HI damage. Such information could contribute to the development of specific DHA-EPA formulations to improve clinical endpoints and modulate potential biomarkers in ischemic brain injury.

      Graphical abstract



      [3H]CEt ([3H] cholesteryl hexadecyl ether), DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), FA (fatty acids), LPC (lysophosphatidylcholine), NEFA (non-esterified fatty acids), SPM (specialized pro-resolving mediator), TG (triglyceride), PL (phospholipids), PUFA (polyunsaturated fatty acids), 7S,14S-diHDHA (7S,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid), 4S,14S-diHDHA (4S,14S-dihydroxy-docosa-5E,7Z,10Z,12E,16Z,19Z-hexaenoic acid), Maresin 1 (7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid), Resolvin E2 (RvE2, 5S,18R-dihydroxy-eicosa-6E,8Z,11Z,14Z,16E-pentaenoic acid), 17-HDHA (17-hydroxy-docosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid), 14-HDHA (14S-hydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid), 7-HDHA (7-hydroxy-docosa-4Z,8E,10Z,13Z,16Z,19Z-hexaenoic acid), 4-HDHA (4-hydroxy-docosa-5E,7Z,10Z,13Z,16Z,19Z-hexaenoic acid), 18-HEPE (18-hydroxy-eicosa-5Z,8Z,11Z,14Z,16E-pentaenoic acid), 15-HEPE (15-hydroxy-eicosa-5Z,8Z,11Z,13E,17Z-pentaenoic acid), 12-HEPE (12-hydroxy-eicosa-5Z,8Z,10E,14Z,17Z-pentaenoic acid), 5-HEPE (5-hydroxy-eicosa-6E,8Z,11Z,14Z,17Z-pentaenoic acid)
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