Abstract

Background and PurposeTreatment 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.Methods10-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.ResultsOnly 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.ConclusionsPost-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.

Highlights

  • Neonatal hypoxia-ischemia (HI) brain injury significantly contributes to neurological mortality in children [1]

  • This was associated with improved mitochondrial tolerance to Ca2+-induced permeabilization, reduced oxidative brain injury and permanent neuroprotection

  • Interaction of docosahexaenoic acid (DHA) with mitochondria alters reactive oxygen species (ROS) release and improves Ca2+ buffering capacity. This may account for neuroprotective action of post-HI administration of triglyceride emulsions of docosahexaenoic acid (tri-DHA)

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Summary

Introduction

Neonatal hypoxia-ischemia (HI) brain injury significantly contributes to neurological mortality in children [1]. Over the few hours, secondary energy failure takes place and drives the evolution of necrosis and apoptosis [5,6] Mitochondrial dysfunction is known mechanism of secondary energy failure [2,6] During reperfusion, mitochondria are overloaded with Ca2+. This triggers the opening of permeability transition pores (mPTP) in the mitochondrial inner membrane which arrests ATP production secondary to loss of the proton motive force and inhibition of the respiratory chain [2] At the same time, BAX and other pro-apoptotic proteins permeabilize the outer mitochondrial membrane, causing the release of apoptotic proteins [7]. This reduces Ca2+-induced mitochondrial membrane permeabilization and attenuates brain injury.

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