Traumatic brain injury (TBI) is the leading cause of death and disability in children, resulting in life-long neurologic dysfunction for which there is o specific therapy. Dietary docosahexaenoic acid (DHA) improved neurologic outcome after severe TBI in adult rats and in our pediatric TBI model. However, the mechanism of DHA's neuroprotection is not understood. TBI activates microglia, the brain's resident macrophages, into a spectrum ranging between M1 and M2 activation. M1 promotes oxidative stress, while M2 decreases oxidative stress. In adult animals, M2 activation is associated with improved outcome. It is not known if M2 activation after TBI is associated with improved outcome in the immature brain, nor how such polarization may be fostered. Our preliminary data suggests that DHA decreases microglial activation in our pediatric TBI model, controlled cortical impact (CCI) in rat pups. Our DHA diet increases brain gene expression downstream of a microglial transcription factor that regulates polarization, the Peroxisome Proliferator Activated Receptor (PPAR?). PPAR? agonists polarize microglia towards M2. Our results led us to ask if DHA's neuroprotection depends on promoting microglial M2 polarization via a PPAR?-dependent pathway. Of concern, DHA is readily oxidized. Large amounts of oxidized DHA could cause oxidative injury by depleting the immature brain's limited antioxidant reserve. On the other hand, DHA could decrease oxidative injury by directly absorbing reactive oxygen species and decreasing microglial free radical production. Oxidative injury may be assessed using total antioxidant capacity (TAC). In sum, mechanistic preclinical studies of DHA safety and mechanism are needed. We hypothesize that DHA will polarize activated microglia towards the M2 phenotype and increase brain TAC in rat pups after experimental TBI, via a PPAR?-dependent mechanism, associated with improved neurologic outcome. To test this, we will expose rat pups to DHA or regular (REG) diet after CCI or SHAM surgery and inject them daily with either a PPAR? antagonist or vehicle. We will use imaging and gene expression to characterize M2 activation, TAC to assess oxidation, and histology/cognitive function testing to assess outcome. We anticipate that DHA will increase M2 polarization and TAC in rat pup brains after TBI, abrogated by PPAR? antagonism and associated with decreased lesion volume and cognitive impairment. Our proposal will provide new knowledge on the time course, and functional importance, of M2 microglial polarization in the immature brain after TBI, and whether these are modified by DHA. While the availability and apparent safety of DHA make it an appealing candidate therapy for children after severe TBI, its clinical use is hindered by important knowledge deficits regarding its mechanism of action and safety in the immature brain after TBI. Our proposal will lead to focused pre-clinical studies that will guide clinical trials o DHA in children after severe TBI and potentially decrease the burden of neurologic disability after childhood TBI.

Public Health Relevance

Neurologic impairment in children after traumatic brain injury (TBI) is an important problem for which there are no specific therapies. Docosahexaenoic acid (DHA), a nutrient in fish oil, decreases neurologic impairment in adults and immature rats; however, knowledge deficits regarding its mechanism of action and safety in the immature brain after injury erect barriers to the clinical use of DHA for children after TBI. The studies in our proposal will yield knowledge essential for designing clinical trials of DHA safety and efficacy in children after severe TBI.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bellgowan, Patrick S F
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University of Utah
Schools of Medicine
Salt Lake City
United States
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