Esterification of Docosahexaenoic Acid Enhances Its Transport to the Brain and Its Potential Therapeutic Use in Brain Diseases

Abstract

Docosahexaenoic acid-containing lysophosphatidylcholine (DHA-LysoPC) is presented as the main transporter of DHA from blood plasma to the brain. This is related to the major facilitator superfamily domain-containing protein 2A (Mfsd2a) symporter expression in the blood–brain barrier that recognizes the various lyso-phospholipids that have choline in their polar head. In order to stabilize the DHA moiety at the sn-2 position of LysoPC, the sn-1 position was esterified by the shortest acetyl chain, creating the structural phospholipid 1-acetyl,2-docosahexaenoyl-glycerophosphocholine (AceDoPC). This small structure modification allows the maintaining of the preferential brain uptake of DHA over non-esterified DHA. Additional properties were found for AceDoPC, such as antioxidant properties, especially due to the aspirin-like acetyl moiety, as well as the capacity to generate acetylcholine in response to the phospholipase D cleavage of the polar head. Esterification of DHA within DHA-LysoPC or AceDoPC could elicit more potent neuroprotective effects against neurological diseases.

Valproic Acid Treatment after Traumatic Brain Injury in Mice Alleviates Neuronal Death and Inflammation in Association with Increased Plasma Lysophosphatidylcholines

“…Hence, obviously, the LPC sources and doses determine the outcome, and it must be considered that LPCs of different chain length and saturation may have differential effects. In our study, LPC species all tended to be increased in VPA groups, but the LPCs of 20 C-atoms were most strongly regulated [76].…”

Ethanolamine and vinyl-ether moieties in brain phospholipids modulate behavior in rats

“…However, previous studies have demonstrated that DHA-containing omega-3 fatty acid supplements and eicosapentaenoic acid (EPA) can improve learning and memory in non-cognitively impaired participants, and that omega-3 fatty acid supplements can also bene t patients with mild cognitive impairment or dementia [21]. In rats, blood lysophosphatidylcholine-DHA (LPC-DHA), which is actively transported into the endothelium of the BBB through the symport major facilitator superfamily domain-containing protein 2A (Mfsd2a), passes through the BBB more effectively than PC-DHA or DHA alone: moreover, DHA from LPC-DHA redistributes into PC and PE in the brain [22,23]. In wild-type rats, dietary DHA from LPC-DHA enriched brain DHA more effectively than dietary PC-DHA even though PC-DHA releases LPC-DHA via the actions of lipoprotein lipases; as a result, only dietary LPC-DHA improved spatial learning in the Morris water maze test [23,24].…”

“…In rats, blood lysophosphatidylcholine-DHA (LPC-DHA), which is actively transported into the endothelium of the BBB through the symport major facilitator superfamily domain-containing protein 2A (Mfsd2a), passes through the BBB more effectively than PC-DHA or DHA alone: moreover, DHA from LPC-DHA redistributes into PC and PE in the brain [22,23]. In wild-type rats, dietary DHA from LPC-DHA enriched brain DHA more effectively than dietary PC-DHA even though PC-DHA releases LPC-DHA via the actions of lipoprotein lipases; as a result, only dietary LPC-DHA improved spatial learning in the Morris water maze test [23,24]. On the other hand, a diet containing 0.5% squid PC, in which DHA and EPA accounted for 35.28% and 11.62% of total fatty acids (FAs), respectively, restored cognitive decline in a scopolamine-induced amnesic model as evidenced by improved Morris water maze performance [25].…”

Ischemic Brain Injury: Involvement of Lipids in the Pathophysiology of Stroke and Therapeutic Strategies

“…A specific protein expressed in brain endothelium called Mfsd2a has been reported to bind LysoPC-DHA, but not free DHA, for its uptake into the brain [ 148 , 149 , 150 ]. AceDoPC (1-acetyl,2-docosahexaenoyl-glycerophosphocholine), a stabilized form of LysoPC-DHA, targets efficiently and specifically DHA to the brain [ 151 , 152 , 153 , 154 ]. It was shown to prevent post-ischemic stroke consequences and to decrease oxidative stress in a stroke animal model of ischemia-reperfusion [ 155 ], to decrease the neuroinflammation induced by lipopolysaccharides in mice and microglia cells [ 156 ], and to stimulate neurogenesis in an in vitro OGD model of ischemia [ 157 ].…”