Neural Resilience to Traumatic Brain Injury: Identification of Bioactive Metabolites of Docosahexaenoic Acids Involved in Neuroprotection and Recovery
Abstract
During the entire award period, we tested the effects of n-3 fatty acids on the TBI recovery outcome. We first established a mouse model of TBI and dietary conditions to generate varying degrees of n-3 fatty acid deficiency. Using these models, we tested spontaneous recovery from TBI-induced motor and cognitive deficits in mice raised on n-3 fatty acid deficient diets. We found that extreme n-3 fatty acid deficiency where brain DHA was depleted by>70 significantly exacerbated TBI outcome for which a scientific publication in PLoS One was generated. Moderate depletion of DHA (by 30 ) in the brain also showed the same trend; TBI-inflicted DHA-deficient mice exhibited slower functional recovery. Biochemical markers such as alpha spectrin cleavage, proinflammatory cytokines were elevated in the cortex of TBI-inflicted DHA-deficient mice which also showed less NeuN-positive neurons, resulting in a manuscript is in preparation. Both male and female mice were similarly affected by the DHA-depletion. An in vitro model to evaluate axon regeneration after injury has been established using cortical neuron cultures. Using this model we demonstrated the induction of axonal regrowth by synaptamide, a bioactive metabolite derived from DHA, for which a manuscript was prepared. We have also developed a method to identify DHA metabolites using stable isotope assisted mass spectrometry along with newly developed metabolite identification software, for which a manuscript is in preparation. Using quantitative mass spectrometry, the time course of the bioactive DHA-metabolite production in TBI-inflicted brain was determined. We identified three distinctive groups of metabolites according to the peak time of production after injury. The synaptamide level was steadily increased after TBI up to 48 h. We also observed improvement of TBI-induced motor deficit by directly injecting synaptamide following injury in FAAH KO mice.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2015
- Accession Number
- AD1007389
Entities
People
- Hee-yong Kim
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine