Highlights
- •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.
Abstract
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
Graphical Abstract
Keywords
Abbreviations:
[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)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: September 24, 2020
Accepted:
September 9,
2020
Received in revised form:
July 21,
2020
Received:
May 4,
2020
Footnotes
✰Funding
This work was supported by the National Institutes of Health grant R01 NS088197 (RJD and VST). CNS acknowledges support from the National Institutes of Health (Grant Number P01GM095467).
Identification
Copyright
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