Brain Uptake and Metabolism of Eicosapentaenoic Acid in Rodents

Omega-3 polyunsaturated fatty acids (n-3 PUFA) are currently being investigated as a potential therapy in mood disorders including depressive disorder and bipolar disorder. Clinical trials that used relatively pure EPA were more effective in alleviating depressive symptoms compared to relatively pure DHA supplementations. However, this poses a potential paradox as EPA levels in the brain are 250 to 300-fold lower than DHA, a finding consistent across mammals. The large difference in brain EPA and DHA levels may be explained by either selective differences in their uptake or metabolism upon entry into the brain. Based on the literature, EPA and DHA can passively diffuse across the blood-brain barrier at similar rate suggesting that the uptake of n-3 PUFA into the brain is non-selective. Therefore, I hypothesize that the difference between EPA and DHA concentrations might be explained by metabolic differences which are yet to be elucidated. First, we characterized the difference in EPA and DHA β-oxidation via in situ cerebral perfusion. We found that EPA was 2.5-fold more readily β-oxidized than DHA. Upon in vivo kinetic modeling in the rat, we observed a 3-fold lower esterification and 154-fold lower recycling of EPA in brain phospholipids as compared to DHA. This corresponded to a 7-fold increase in EPA loss from brain phospholipids compared to DHA in the rat brain. Moreover, upon inhibiting mitochondrial fatty acid β-oxidation, we observed a further reduction in EPA recycling and increased EPA elongation to n-3 docosapentaenoic acid (n-3 DPA) suggesting multiple redundant pathways are present to maintain low levels of EPA in the brain. In conclusion, the low levels of EPA in brain phospholipids, as compared to DHA, are maintained by increased β-oxidation, decreased esterification, increased conversion to n-3 DPA, decreased recycling and increased loss.Ph.D