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Preclinical studies

Preclinical research has demonstrated that specific nutrients support synapse formation, with the greatest effects observed when these nutrients are used in combination.

Overview of preclinical research providing the scientific rationale behind Souvenaid [1-20].

Preclinical research providing the scientific rational behind Souvenaid

The scientific rationale behind the mechanism of action of Souvenaid is based on the ability of specific nutrients to support neuronal membrane synthesis and synapse formation, leading to the hypothesis that combinations of these nutrients could provide clinically relevant benefits to early Alzheimer’s disease patients.

The development of Souvenaid is the result of over 10 years of research. Preclinical work conducted by scientists at the Massachusetts Institute of Technology (MIT) formed the basis for our clinical research programme [1-20]. 

 

Nutrients working together to support synapse formation

Preclinical research demonstrates that enhancing the diet with key nutrients increases brain dendritic spines, synaptic proteins and neurite outgrowth, all of which are prerequisites for brain synapse formation [7,9,21]. In vitro studies have shown that uridine, B vitamins, choline and omega-3 fatty acids increase phospholipid synthesis, and promote neurite outgrowth [5,9,22-24].

The greatest benefits on synapse formation are observed when specific nutrients are used in combination [5-7]. The combination of UMP and DHA was shown to increase levels of brain phospholipids, dendritic spine density and synaptic proteins in in vitro studies [5-7]. In animal models, the combination of uridine and choline has been shown to improve learning and memory [17].  

Collectively, this preclinical research supports the mechanism of action of Souvenaid. By providing the specific nutrients required for key processes involved in synapse formation [25], Souvenaid can improve memory in patients with early Alzheimer’s disease, as demonstrated by the results of the Souvenaid clinical trial programme [26,27].

 

  • Uridine promotes neurite outgrowth

    Uridine promotes neurite outgrowth

    In vitro data demonstrates the link between uridine concentrations and the mean number of neurites [5,9,22-24]. The dietary precursor uridine increases neurite outgrowth in vitro: blue: nucleus; green: actin cytoskeleton. Pictures with permission from Dr Verheijen, VU Free University Amsterdam.

  • Uridine monophosphate (UMP) and docosahexaenoic acid (DHA) increase brain phospholipid levels

    Uridine monophosphate (UMP) and docosahexaenoic acid (DHA) increase brain phospholipid levels

    In preclinical models, the combination of UMP and DHA resulted in a greater increase in levels of brain phospholipids than with either nutrient alone [7].

  • Uridine monophosphate (UMP) and docosahexaenoic acid (DHA) increase dendritic spine density

    Uridine monophosphate (UMP) and docosahexaenoic acid (DHA) increase dendritic spine density

    In preclinical studies, the combined effect of UMP and DHA on dendritic spine density was greater than with either nutrient alone [7].

  • Uridine monophosphate (UMP) and docosahexaenoic acid (DHA) increase synaptic proteins

    Uridine monophosphate (UMP) and docosahexaenoic acid (DHA) increase synaptic proteins

    In preclinical studies, the combination of UMP and DHA resulted in a greater increase in synaptic proteins than that achieved with either nutrient alone [7].

  • Spontaneously hypertensive rat* model of cognitive deficit – shorter latency indicates improved learning and memory

    Spontaneously hypertensive rat* model of cognitive deficit – shorter latency indicates improved learning and memory

    In an animal model, UMP combined with choline improves learning and memory.

References

  1. van Wijk N, et al. Plasma choline concentration varies with different dietary levels of vitamins B6, B12 and folic acid in rats maintained on choline-adequate diets. Br J Nutr. 2012;107:1408-12.
  2. van Wijk et al. Combined dietary folate, vitamin B-12, and vitamin B-6 intake influences plasma docosahexaenoic acid concentration in rats. Nutr Metab (Lond). 2012;30;9:49.
  3. Cansev M, et al. Oral uridine-5'-monophosphate (UMP) increases brain CDP-choline levels in gerbils. Brain Res. 2005;1058:101-108.
  4. Ulus IH, et al. Cytidine and uridine increase striatal CDP-choline levels without decreasing acetylcholine synthesis or release. Cell Mol Neurobiol. 2006;26:563-577.
  5. Wurtman RJ, et al. Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Res. 2006;1088:83-92.
  6. Cansev M, Wurtman RJ. 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. Neuroscience. 2007;148:421-431.
  7. Sakamoto T, et al. Oral supplementation with docosahexaenoic acid and uridine-5'-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain Res. 2007;1182:50-59.
  8. Wang L, et al. Dietary uridine-5'-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. J Mol Neurosci. 2005;27:137-145.
  9. Pooler AM, et al. Uridine enhances neurite outgrowth in nerve growth factor-differentiated PC12. Neuroscience. 2005;134:207-214.
  10. Cansev M, et al.  Giving uridine and/or docosahexaenoic acid orally to rat dams during gestation and nursing increases synaptic elements in brains of weanling pups. Dev Neurosci. 2009;31:181-192.
  11. Farkas E, et al. Dietary long chain PUFAs differentially affect hippocampal muscarinic 1 and serotonergic 1A receptors in experimental cerebral hypoperfusion. Brain Res. 2002;954:32-41.
  12. Wang L, et al.Dietary supplementation with uridine-5'-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat. Brain Res. 2007;1133:42-48.
  13. Savelkoul P, et al. A specific multi-nutrient formulation enhances M1 muscarinic acetylcholine receptor responses in vitro. J Neurochem. 2012;120:631-640.
  14. Teather LA, Wurtman RJ. Chronic administration of UMP ameliorates the impairment of hippocampal-dependent memory in impoverished rats. J Nutr. 2006;136:2834-2837.
  15. de Wilde MC, et al. Dietary fatty acids alter blood pressure, behavior and brain membrane composition of hypertensive rats.Brain Res. 2003;988:9-19.
  16. de Wilde MC, et al. The effect of n-3 polyunsaturated fatty acid-rich diets on cognitive and cerebrovascular parameters in chronic cerebral hypoperfusion Brain Res. 2002 Aug 30;947(2):166-73.
  17. De Bruin NM, et al. Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats. Neurobiol Learn Mem. 2003;80:63-79.
  18. Holguin S, et al. Chronic administration of DHA and UMP improves the impaired memory of environmentally impoverished rats. Behav Brain Res. 2008;191:11-16.
  19. Broersen L, et al. Special lipid-based diets alleviate cognitive deficits in the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease independent of brain amyloid deposition. Alzheimers Dement. 2011;7:S650.
  20. de Wilde MC, et al. Neuroprotective effects of a specific multi-nutrient intervention against Aβ42-induced toxicity in rats. J Alzheimers Dis. 2011;27:327-339.
  21. Cansev M, et al.Restorative effects of uridine plus docosahexaenoic acid in a rat model of Parkinson's disease. Neurosci Res. 2008;62:206-209.
  22. Darios F, et al. Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3. Nature. 2006;440:813-817.
  23. Wang CS, Lee RK. Choline plus cytidine stimulate phospholipid production, and the expression and secretion of amyloid precursor protein in rat PC12 cells. Neurosci Lett. 2000;283:25-28.
  24. Calderon F, Kim HY. Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J Neurochem. 2004;90:979-988.
  25. Kamphuis PJ and Scheltens P. Can nutrients prevent or delay onset of Alzheimer's disease? J Alzheimers Dis. 2010;20:765-775.
  26. Scheltens P, et al. Efficacy of a medical food in mild Alzheimer's disease: A randomized, controlled trial. Alzheimers Dement. 2010;6:1-10.e1.
  27. Scheltens P, et al.Efficacy of Souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial. J Alzheimer’s Dis. 2012;31:225–236.