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.
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References
Saravanan P, Davidson N, Schmidt E, Calder P (2010) Cardiovascular effects of marine omega-3 fatty acids. Lancet 376:540–550
Mozaffarian D, Wu J (2011) Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol 58:2047–2067
Yan Y, Jiang W, Spinetti T, Tardivel A, Castillo R, Bourquin C, Guarda G, Tian Z et al (2013) Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 38:1154–1163
O’Brien J, Sampson E (1965) Fatty acid and fatty aldehyde composition of the major brain lipids in normal human gray matter, white matter, and myelin. J Lipid Res 6:545–551
Bourre JM, Bonneil M, Clément M, Dumont O, Durand G, Lafont H, Nalbone G, Piciotti M (1993) Function of dietary polyunsaturated fatty acids in the nervous system. Prostaglandins Leukot Essent Fatty Acids 48:5–15
Jensen M, Skarsfeldt T, Hoy C (1996) Correlation between level of (n-3) polyunsaturated fatty acids in brain phospholipids and learning ability in rats. A multiple generation study. Biochim Biophys Acta 1300:203–209
Makrides M, Neumann M, Gibson R (1996) Is dietary docosahexaenoic acid essential for term infants? Lipids 31:115–119
Rogers L, Valentine C, Keim S (2013) DHA supplementation: current implications in pregnancy and childhood. Pharmacol Res 70:13–19
Bousquet M, Saint-Pierre M, Julien C, Salem N Jr, Cicchetti F, Calon F (2008) Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson’s disease. FASEB J 22:1213–1225
Hashimoto M, Hossain S (2011) Neuroprotective and ameliorative actions of polyunsaturated fatty acids against neuronal diseases: beneficial effect of docosahexaenoic acid on cognitive decline in Alzheimer’s disease. J Pharmacol Sci 116:150–162
Dacks P, Shineman D, Fillit H (2013) Current evidence for the clinical use of long-chain polyunsaturated n-3 fatty acids to prevent age-related cognitive decline and Alzheimer’s disease. J Nutr Health Aging 17:240–251
Bazinet RP, Layé S (2014) Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci 15(12):771–785
Thies F, Pillon C, Moliere P, Lagarde M, Lecerf J (1994) Preferential incorporation of sn-2 lysoPC DHA over unesterified DHA in the young rat brain. Am J Physiol 267:R1273–R1279
Bernoud N, Fenart L, Molière P, Dehouck MP, Lagarde M, Cecchelli R, Lecerf J (1999) Preferential transfer of 2-docosahexaenoyl-1-lysophosphatidylcholine through an in vitro blood-brain barrier over unesterified docosahexaenoic acid. J Neurochem 72:338–345
Croset M, Brossard N, Polette A, Lagarde M (2000) Characterization of plasma unsaturated lysophosphatidylcholines in human and rat. Biochem J 345(Pt 1):61–67
Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, Wenk MR, Goh EL et al (2014) Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 509:503–506
Polette A, Deshayes C, Chantegrel B, Croset M, Armstrong JM, Lagarde M (1999) Synthesis of acetyl, docosahexaenoyl-glycerophosphocholine and its characterization using nuclear magnetic resonance. Lipids 34:1333–1337
Lagarde M, Hachem M, Bernoud-Hubac N, Picq M, Vericel E, Guichardant M (2015) Biological properties of a DHA-containing structured phospholipid (AceDoPC) to target the brain. Prostaglandins Leukot Essent Fatty Acids 92:63--65
Lagarde M, Guichardant M, Picq M, Michaud S, Doutheau S (2008) Method for preparing acetyl, docosahexaenoyl-glycerophosphocholine and use thereof for delivering polyunsaturated fatty acids WO/2008/068413
Chauveau F, Cho TH, Perez M, Guichardant M, Riou A, Aguettaz P, Picq M, Lagarde M et al (2011) Brain-targeting form of docosahexaenoic acid for experimental stroke treatment: MRI evaluation and anti-oxidant impact. Curr Neurovasc Res 8:95–102
Virto C, Adlercreutz P (2000) Lysophosphatidylcholine synthesis with Candida antarctica lipase B (Novozym 435). Enzyme Microb Technol 26:630–635
Booher J, Sensenbrenner M (1972) Growth and cultivation of dissociated neurons and glial cells from embryonic chick, rat and human brain in flask cultures. Neurobiology 2:97–105
Descamps L, Coisne C, Dehouck B, Cecchelli R, Torpier G (2003) Protective effect of glial cells against lipopolysaccharide-mediated blood-brain barrier injury. Glia 42:46–58
Bornstein MB (1958) Reconstituted rattail collagen used as substrate for tissue cultures on coverslips in Maximow slides and roller tubes. Lab Invest 7:134–137
Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911–917
Folch J, Lees M, Sloane Stanley G (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509
Picq M, Chen P, Perez M, Michaud S, Véricel E, Guichardant M, Lagarde M (2010) DHA metabolism: targeting the brain and lipoxygenation. Mol Neurobiol 42:48–51
Culot M, Lundquist S, Vanuxeem D, Nion S, Landry C, Delplace Y, Dehouck MP, Berezowski V et al (2008) An in vitro blood-brain barrier model for high throughput (HTS) toxicological screening. Toxicol In Vitro 22:799–811
Hallier-Vanuxeem D, Prieto P, Culot M, Diallo H, Landry C, Tahti H, Cecchelli R (2009) New strategy for alerting central nervous system toxicity: integration of blood-brain barrier toxicity and permeability in neurotoxicity assessment. Toxicol In Vitro 23:447–453
Sovic A, Panzenboeck U, Wintersperger A, Kratzer I, Hammer A, Levak-Frank S, Frank S, Rader DJ et al (2005) Regulated expression of endothelial lipase by porcine brain capillary endothelial cells constituting the blood-brain barrier. J Neurochem 94:109–119
Chen S, Subbaiah P (2007) Phospholipid and fatty acid specificity of endothelial lipase: potential role of the enzyme in the delivery of docosahexaenoic acid (DHA) to tissues. Biochim Biophys Acta 1771:1319–1328
Bernoud N, Fenart L, Bénistant C, Pageaux JF, Dehouck MP, Moliere P, Lagarde M, Cecchelli R et al (1998) Astrocytes are mainly responsible for the polyunsaturated fatty acid enrichment in blood-brain barrier endothelial cells in vitro. J Lipid Res 39:1816–1824
LaDu MJ, Gilligan SM, Lukens JR, Cabana VG, Reardon CA, Van Eldik LJ, Holtzman DM (1998) Nascent astrocyte particles differ from lipoproteins in CSF. J Neurochem 70:2070–2081
Ladu MJ, Reardon C, Van Eldik L, Fagan AM, Bu G, Holtzman D, Getz GS (2000) Lipoproteins in the central nervous system. Ann N Y Acad Sci 903:167–175
Xiao Y, Huang Y, Chen Z (2005) Distribution, depletion and recovery of docosahexaenoic acid are region-specific in rat brain. Br J Nutr 94:544–55036
Diau GY, Hsieh AT, Sarkadi-Nagy EA, Wijendran V, Nathanielsz PW, Brenna JT (2005) The influence of long chain polyunsaturate supplementation on docosahexaenoic acid and arachidonic acid in baboon neonate central nervous system. BMC Med 3:11
Thies F, Delachambre M, Bentejac M, Lagarde M, Lecerf J (1992) Unsaturated fatty acids esterified in 2-acyl-l-lysophosphatidylcholine bound to albumin are more efficiently taken up by the young rat brain than the unesterified form. J Neurochem 59:1110–1116
Leaf A, Kang J, Xiao Y, Billman G, Voskuyl R (1999) Functional and electrophysiologic effects of polyunsaturated fatty acids on excitable tissues: heart and brain. Prostaglandins Leukot Essent Fatty Acids 60:307–312
Weylandt K, Kang J, Leaf A (1996) Polyunsaturated fatty acids exert antiarrhythmic actions as free acids rather than in phospholipids. Lipids 31:977–982
Anderson G, Connor W (1988) Uptake of fatty acids by the developing rat brain. Lipids 23:286–290
Onuma Y, Masuzawa Y, Ishima Y, Waku K (1984) Selective incorporation of docosahexaenoic acid in rat brain. Biochim Biophys Acta 793:80–85
Sarda N, Gharib A, Moliere P, Grange E, Bobillier P, Lagarde M (1991) Docosahexaenoic acid (cervonic acid) incorporation into different brain regions in the awake rat. Neurosci Lett 123:57–60
Acknowledgments
This work was supported by grants from Polaris, National Institute of Applied Sciences-Lyon, and National Institute for Health and Medical Research. We thank Pr P. Moulin for its constructive input. We also thank Dr Hayet Kouchi for the technical assistance with brain sectioning with cryostat and for the helpful discussions and Stéphane Nion from Cellial Technologies for the technical assistance with in vitro BBB experiments.
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Hachem, M., Géloën, A., Van, A.L. et al. Efficient Docosahexaenoic Acid Uptake by the Brain from a Structured Phospholipid. Mol Neurobiol 53, 3205–3215 (2016). https://doi.org/10.1007/s12035-015-9228-9
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DOI: https://doi.org/10.1007/s12035-015-9228-9