Posted 15 March 2009 - 06:56 AM
Some more updates on studies combining these three ingredients since this thread was last active...
1: FASEB J. 2008 Nov;22(11):3938-46. Epub 2008 Jul 7.
Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils.
Holguin S, Martinez J, Chow C, Wurtman R.
Massachusetts Institute of Technology, 43 Vassar St., 46-5023, Cambridge, MA 02139, USA.
This study examined the effects on cognitive behaviors of giving normal adult gerbils three compounds, normally in the circulation, which interact to increase brain phosphatides, synaptic proteins, dendritic spines, and neurotransmitter release. Animals received supplemental uridine (as its monophosphate, UMP; 0.5%) and choline (0.1%) via the diet, and docosahexaenoic acid (DHA; 300 mg/kg/day) by gavage, for 4 wk, and then throughout the subsequent period of behavioral training and testing. As shown previously, giving all three compounds caused highly significant (P<0.001) increases in total brain phospholipids and in each major phosphatide; giving DHA or UMP (plus choline) produced smaller increases in some of the phosphatides. DHA plus choline improved performance on the four-arm radial maze, T-maze, and Y-maze tests; coadministering UMP further enhanced these increases. (Uridine probably acts by generating both CTP, which can be limiting in phosphatide synthesis, and UTP, which activates P2Y receptors coupled to neurite outgrowth and protein synthesis. All three compounds also act by enhancing the substrate-saturation of phosphatide-synthesizing enzymes.) These findings demonstrate that a treatment that increases synaptic membrane content can enhance cognitive functions in normal animals.
PMID: 18606862 [PubMed - indexed for MEDLINE]
1: Alzheimers Dement. 2008 Jan;4(1 Suppl 1):S153-68. Epub 2007 Dec 21. Links
Oral administration of circulating precursors for membrane phosphatides can promote the synthesis of new brain synapses.
Cansev M, Wurtman RJ, Sakamoto T, Ulus IH.
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
Although cognitive performance in humans and experimental animals can be improved by administering omega-3 fatty acid docosahexaenoic acid (DHA), the neurochemical mechanisms underlying this effect remain uncertain. In general, nutrients or drugs that modify brain function or behavior do so by affecting synaptic transmission, usually by changing the quantities of particular neurotransmitters present within synaptic clefts or by acting directly on neurotransmitter receptors or signal-transduction molecules. We find that DHA also affects synaptic transmission in mammalian brain. Brain cells of gerbils or rats receiving this fatty acid manifest increased levels of phosphatides and of specific presynaptic or postsynaptic proteins. They also exhibit increased numbers of dendritic spines on postsynaptic neurons. These actions are markedly enhanced in animals that have also received the other two circulating precursors for phosphatidylcholine, uridine (which gives rise to brain uridine diphosphate and cytidine triphosphate) and choline (which gives rise to phosphocholine). The actions of DHA aere reproduced by eicosapentaenoic acid, another omega-3 compound, but not by omega-6 fatty acid arachidonic acid. Administration of circulating phosphatide precursors can also increase neurotransmitter release (acetylcholine, dopamine) and affect animal behavior. Conceivably, this treatment might have use in patients with the synaptic loss that characterizes Alzheimer's disease or other neurodegenerative diseases or occurs after stroke or brain injury.
PMID: 18631994 [PubMed - indexed for MEDLINE]
1: Neurosci Res. 2008 Nov;62(3):206-9. Epub 2008 Aug 3. Links
Restorative effects of uridine plus docosahexaenoic acid in a rat model of Parkinson's disease.
Cansev M, Ulus IH, Wang L, Maher TJ, Wurtman RJ.
Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, Cambridge, MA 02139, USA.
Administering uridine-5'-monophosphate (UMP) and docosahexaenoic acid (DHA) increases synaptic membranes (as characterized by pre- and post-synaptic proteins) and dendritic spines in rodents. We examined their effects on rotational behavior and dopaminergic markers in rats with partial unilateral 6-hydroxydopamine (6-OHDA)-induced striatal lesions. Rats receiving UMP, DHA, both, or neither, daily, and intrastriatal 6-OHDA 3 days after treatment onset, were tested for d-amphetamine-induced rotational behavior and dopaminergic markers after 24 and 28 days, respectively. UMP/DHA treatment reduced ipsilateral rotations by 57% and significantly elevated striatal dopamine, tyrosine hydroxylase (TH) activity, TH protein and synapsin-1 on the lesioned side. Hence, giving uridine and DHA may partially restore dopaminergic neurotransmission in this model of Parkinson's disease.
PMID: 18761383 [PubMed - indexed for MEDLINE]
PMCID: PMC2592845 [Available on 2009/11/01]
1: J Nutr Health Aging. 2009 Mar;13(3):189-97.
Synapse Formation Is Enhanced by Oral Administration of Uridine and DHA, the Circulating Precursors of Brain Phosphatides.
Wurtman RJ, Cansev M, Ulus IH.
R.J. Wurtman, MIT, 77 Massachusetts Ave., Room l46-5023, Cambridge, MA 02139 USA, Phone No.: 617 253 6731, Fax No.: 617 253 6882; Email: email@example.com.
Objective: The loss of cortical and hippocampal synapses is a universal hallmark of Alzheimer's disease, and probably underlies its effects on cognition. Synapses are formed from the interaction of neurites projecting from "presynaptic" neurons with dendritic spines projecting from "postsynaptic" neurons. Both of these structures are vulnerable to the toxic effects of nearby amyloid plaques, and their loss contributes to the decreased number of synapses that characterize the disease. A treatment that increased the formation of neurites and dendritic spines might reverse this loss, thereby increasing the number of synapses and slowing the decline in cognition. Design setting, Participants, Intervention, Measurements and Results: We observe that giving normal rodents uridine and the omega-3 fatty acid docosahexaenoic acid (DHA) orally can enhance dendritic spine levels (3), and cognitive functions (32). Moreover this treatment also increases levels of biochemical markers for neurites (i.e., neurofilament-M and neurofilament-70) (2) in vivo, and uridine alone increases both these markers and the outgrowth of visible neurites by cultured PC-12 cells (9). A phase 2 clinical trial, performed in Europe, is described briefly. Discussion and Conclusion: Uridine and DHA are circulating precursors for the phosphatides in synaptic membranes, and act in part by increasing the substrate-saturation of enzymes that synthesize phosphatidylcholine from CTP (formed from the uridine, via UTP) and from diacylglycerol species that contain DHA: the enzymes have poor affinities for these substrates, and thus are unsaturated with them, and only partially active, under basal conditions. The enhancement by uridine of neurite outgrowth is also mediated in part by UTP serving as a ligand for neuronal P2Y receptors. Moreover administration of uridine with DHA activates many brain genes, among them the gene for the m-1 metabotropic glutamate receptor [Cansev, et al, submitted]. This activation, in turn, increases brain levels of that gene's protein product and of such other synaptic proteins as PSD-95, synapsin-1, syntaxin-3 and F-actin, but not levels of non-synaptic brain proteins like beta-tubulin. Hence it is possible that giving uridine plus DHA triggers a neuronal program that, by accelerating phosphatide and synaptic protein synthesis, controls synaptogenesis. If administering this mix of phosphatide precursors also increases synaptic elements in brains of patients with Alzheimer 's disease, as it does in normal rodents, then this treatment may ameliorate some of the manifestations of the disease.
PMID: 19262950 [PubMed - in process]
1: World Rev Nutr Diet. 2009;99:71-96. Epub 2009 Jan 9.
Administration of docosahexaenoic acid, uridine and choline increases levels of synaptic membranes and dendritic spines in rodent brain.
Wurtman RJ, Cansev M, Sakamoto T, Ulus IH.
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. firstname.lastname@example.org
PMID: 19136840 [PubMed - in process]