Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils

Abstract

Synthesis of phosphatidylcholine, the most abundant brain membrane phosphatide, requires three circulating precursors: choline; a pyrimidine (e.g. uridine); and a polyunsaturated fatty acid. Supplementing a choline-containing diet with the uridine source uridine-5'-monophosphate (UMP) or, especially, with UMP plus the omega-3 fatty acid docosahexaenoic acid (given by gavage), produces substantial increases in membrane phosphatide and synaptic protein levels within gerbil brain. We now compare the effects of various polyunsaturated fatty acids, given alone or with UMP, on these synaptic membrane constituents. Gerbils received, daily for 4 weeks, a diet containing choline chloride with or without UMP and/or, by gavage, an omega-3 (docosahexaenoic or eicosapentaenoic acid) or omega-6 (arachidonic acid) fatty acid. Both of the omega-3 fatty acids elevated major brain phosphatide levels (by 18-28%, and 21-27%) and giving UMP along with them enhanced their effects significantly. Arachidonic acid, given alone or with UMP, was without effect. After UMP plus docosahexaenoic acid treatment, total brain phospholipid levels and those of each individual phosphatide increased significantly in all brain regions examined (cortex, striatum, hippocampus, brain stem, and cerebellum). The increases in brain phosphatides in gerbils receiving an omega-3 (but not omega-6) fatty acid, with or without UMP, were accompanied by parallel elevations in levels of pre- and post-synaptic proteins (syntaxin-3, PSD-95 and synapsin-1) but not in those of a ubiquitous structural protein, beta-tubulin. Hence administering omega-3 polyunsaturated fatty acids can enhance synaptic membrane levels in gerbils, and may do so in patients with neurodegenerative diseases, especially when given with a uridine source, while the omega-6 polyunsaturated fatty acid arachidonic acid is ineffective.

Figure 1

Phosphatidylcholine (PC) biosynthesis via the Kennedy cycle. In rats, plasma cytidine is the major circulating pyrimidine; in gerbils and humans the primary circulating pyrimidine is uridine. Only small amounts of circulating cytidine are converted to brain CTP, since the blood-brain barrier (BBB) high-affinity transporter for pyrimidines (CNT2) has a very low affinity for cytidine; uridine, in contrast, readily enters the brain via CNT2, yielding UTP which can then be converted to CTP by CTP synthase (Cansev, 2006). CTP then reacts with phosphocholine to form endogenous CDP-choline, which combines with diacylglycerol (DAG), preferentially species containing PUFAs like DHA, EPA or AA, (Holub, 1978; Morisaki et al., 1983) to form PC. Boxes indicate the compounds that are obtained from the circulation.

Figure 2

Effects of AA, DHA or EPA, alone or in combination with a UMP-supplemented diet, on levels of the presynaptic or postsynaptic proteins PSD-95 (a1, a2); Synapsin-1 (b1, b2) and Syntaxin-3 (c1, c2). CV, control diet + vehicle; CA, control diet + AA; CD, control diet + DHA; CE, control diet + EPA; UV, UMP-supplemented diet + vehicle; UA, UMP-supplemented diet + AA; UD, UMP-supplemented diet + DHA; UE, UMP-supplemented diet + EPA. *P<0.05; **P<0.01; and ***P<0.001 compared with CV, and ^aP<0.05 compared with CA on the left-sided columns (a1, b1, and c1) using One Way ANOVA. *P<0.05; **P<0.01; and ***P<0.001 compared with UV, and ^xP<0.05; and ^yP<0.01 compared with UA on the right-sided columns (a2, b2, and c2) using One Way ANOVA.