title: DHA but Not EPA Emulsions Preserve Neurological and Mitochondrial Function after Brain Hypoxia-Ischemia in Neonatal Mice.
abstract: OBJECTIVE
  Treatment with triglyceride emulsions of docosahexaenoic acid (tri-DHA) protected neonatal mice against hypoxia-ischemia (HI) brain injury. The mechanism of this neuroprotection remains unclear. We hypothesized that administration of tri-DHA enriches HI-brains with DHA/DHA metabolites. This reduces Ca2+-induced mitochondrial membrane permeabilization and attenuates brain injury.
  
  
  METHODS
  10-day-old C57BL/6J mice following HI-brain injury received tri-DHA, tri-EPA or vehicle. At 4-5 hours of reperfusion, mitochondrial fatty acid composition and Ca2+ buffering capacity were analyzed. At 24 hours and at 8-9 weeks of recovery, oxidative injury, neurofunctional and neuropathological outcomes were evaluated. In vitro, hyperoxia-induced mitochondrial generation of reactive oxygen species (ROS) and Ca2+ buffering capacity were measured in the presence or absence of DHA or EPA.
  
  
  RESULTS
  Only post-treatment with tri-DHA reduced oxidative damage and improved short- and long-term neurological outcomes. This was associated with increased content of DHA in brain mitochondria and DHA-derived bioactive metabolites in cerebral tissue. After tri-DHA administration HI mitochondria were resistant to Ca2+-induced membrane permeabilization. In vitro, hyperoxia increased mitochondrial ROS production and reduced Ca2+ buffering capacity; DHA, but not EPA, significantly attenuated these effects of hyperoxia.
  
  
  CONCLUSIONS
  Post-treatment with tri-DHA resulted in significant accumulation of DHA and DHA derived bioactive metabolites in the HI-brain. This was associated with improved mitochondrial tolerance to Ca2+-induced permeabilization, reduced oxidative brain injury and permanent neuroprotection. Interaction of DHA with mitochondria alters ROS release and improves Ca2+ buffering capacity. This may account for neuroprotective action of post-HI administration of tri-DHA.
authors: Institute of Human Nutrition, Columbia University, New York, New York, United States of America.
authors: Korapat
authors: K
authors: Mayurasakorn
authors: Department of Pediatrics, Columbia University, New York, New York, United States of America.
authors: Zoya V
authors: ZV
authors: Niatsetskaya
authors: Department of Pediatrics, Columbia University, New York, New York, United States of America.
authors: Sergey A
authors: SA
authors: Sosunov
authors: Institute of Human Nutrition, Columbia University, New York, New York, United States of America.
authors: Jill J
authors: JJ
authors: Williams
authors: Institute of Human Nutrition, Columbia University, New York, New York, United States of America.
authors: Hylde
authors: H
authors: Zirpoli
authors: 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.
authors: Iliyan
authors: I
authors: Vlasakov
authors: Institute of Human Nutrition, Columbia University, New York, New York, United States of America.|Department of Pediatrics, Columbia University, New York, New York, United States of America.
authors: Richard J
authors: RJ
authors: Deckelbaum
authors: Department of Pediatrics, Columbia University, New York, New York, United States of America.
authors: Vadim S
authors: VS
authors: Ten
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000627:therapeutic use*; D015118:Eicosapentaenoic Acid / Q000627:therapeutic use*; D004655:Emulsions; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004655:Emulsions; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D002118:Calcium