Efficient Docosahexaenoic Acid Uptake by the Brain from a Structured Phospholipid

Abstract

Docosahexaenoic acid (DHA) is the main essential omega-3 fatty acid in brain tissues required for normal brain development and function. An alteration of brain DHA in neurodegenerative diseases such as Alzheimer's and Parkinson's is observed. Targeted intake of DHA to the brain could compensate for these deficiencies. Blood DHA is transported across the blood-brain barrier more efficiently when esterified at the sn-2 position of lyso-phosphatidylcholine. We used a structured phosphatidylcholine to mimic 2-docosahexaenoyl-lysoPC (lysoPC-DHA), named AceDoPC (1-acetyl,2-docosahexaenoyl-glycerophosphocholine), that may be considered as a stabilized form of the physiological lysoPC-DHA and that is neuroprotective in experimental ischemic stroke. The aim of the present study was to investigate whether AceDoPC is a relevant delivery form of DHA to the brain in comparison with other forms of the fatty acid. By combining in vitro and in vivo experiments, our findings report for the first time that AceDoPC is a privileged and specific carrier of DHA to the brain, when compared with DHA-containing PC and non-esterified DHA. We also show that AceDoPC was hydrolyzed, in part, into lysoPC-DHA. Ex vivo autoradiography of rat brain reveals that DHA from AceDoPC was localized in specific brain regions playing key roles in memory, thoughts, and cognitive functions. Finally, using molecular modeling approaches, we demonstrate that electrostatic and lipophilic potentials are distributed very similarly at the surfaces of AceDoPC and lysoPC-DHA. Our findings identify AceDoPC as an efficient way to specifically target DHA to the brain, which would allow potential preventive and therapeutic approaches for neurological diseases.

AceDoPC, a structured phospholipid to target the brain with docosahexaenoic acid

“…As we found in the past with LysoPC-DHA, [ 14 C]-DHA was higher in the brain when originating from AceDoPC r than from nonesterified DHA (at least double) at each time of analysis (1, 6, 24 and 48 h after injection). In contrast, no difference could be found in plasma, liver, heart and even eyes which are, like the brain, endogenously very rich in DHA (Hachem et al, 2015). These results definitely confirm that AceDoPC r is an efficient vehicle of DHA to the brain.…”

“…The accumulation of labeled DHA in the lower medium and glial cells was then considered as the fraction crossing the blood-brain barrier. Under these conditions, the radioactive DHA which crossed the blood-brain barrier from AceDoPC r was significantly higher than from non-esterified DHA, which was significantly higher than from PC-DHA (Hachem et al, 2015).…”

“…The product, 1-acetyl,2-DHA-PC, has been named AceDoPC r . Recent investigation of the AceDoPC conformation by molecular modelling has confirmed that the acetyl group does not much alter the 3D of the LysoPC-DHA molecule (Hachem et al, 2015).…”

“…The main [ 14 C]-labeled lipids were found in phosphatidyl-choline andethanolamine (around 60% in total), while the label in LysoPC plus AceDoPC r was 15% in endothelial cells and 10% in glial cells. The rest was in the neutral plus non-esterified fatty acid fraction (Hachem et al, 2015). This means that AceDoPC r was highly metabolized after its preferential uptake.…”

“…In contrast, [ 14 C]-DHA remained constant in those heart lipid classes. A big difference was relating to [ 14 C]-DHA accumulation in neutral brain lipids plus the non-esterified fatty acid pool where [ 14 C]-DHA was quite low, while it constantly attained 40% in the heart (Hachem et al, 2015).…”