Boost Brain Function
Key Nutrients Support The Growth of Brain Cell Neurites and Dendrites
By VRP Staff
There are two basic cell populations in the human body—the dividing (or mitotic) cell populations and the non-dividing (or post-mitotic) cell types. Brain cells, or neurons, for a long time were considered non-dividing post-mitotic cells that formed during embryogenesis and never replaced themselves.
We now know that brain cells can, under certain conditions, renew themselves and regrow their neural communications networks. What is especially true is that neurites and dendrites, the long filament or root-like terminal branches that are extensions of the brain cells themselves, can be supported in growth when given the proper nutrients. Neurites and dendrites comprise the wiring communications network that allows brain cells to communicate with each other. Loss of brain cells with age is a normal process, but the loss of neurites and dendrites disrupts the neural communications network, preventing brain cell “cross-talk”. Senescence of the central nervous system is characterized by a loss of neurons, neurites and dendrites and results in physiological and behavioral imbalances. It is believed that reductions in the levels of growth factors, like nerve growth factor and other trophic growth factors may lead to suboptimal brain cell performance and affect health in diverse areas.1 The good news is that certain supplements act as growth factors or stimulate the brain to produce growth factors to maintain and rebuild the neural communications network.
In a study conducted in 1991, it was discovered that the presence of acetyl carnitine enhanced the effects of nerve growth factor on the outgrowth of neurites from rat brain cells 100 times greater than when just nerve growth factor itself was present. This was an interesting observation at the time, but nerve growth factor is an internally produced protein in the brain, and it was not really known how to stimulate or regulate its production.2
In another study conducted in 1995, it was discovered that the supplement acetyl carnitine arginate mimicked the effect of nerve growth factor and supported neurite outgrowth of PC12 cells “in a manner similar to that elicited by nerve growth factor (itself).”3 Synergy between acetyl carnitine arginate and acetyl carnitine had earlier been demonstrated when both were tested separately and together on brain cells and found to be highly synergistic in the production of the neurotransmitters GABA, glutamate, somatostatin and other brain peptides.4
Synergistic Action on Brain Cell Regrowth
The mechanism by which the two carnitines work synergistically on brain cell regrowth was delineated from the study observation that acetyl carnitine creates nerve growth factor receptors for nerve growth factor or its mimic acetyl carnitine arginate to act on.2 So, the one carnitine supported the synthesis of receptors that NGF acted on, thereby supporting neurite regrowth, and the other compound mimicked the effects of nerve growth factor itself. The two pieces of the puzzle were finally put into place.2-3
Acetyl carnitine and acetyl carnitine arginate are two synergists that were shown in one study to stimulate regrowth in brain cell neurites and dendrites so powerfully that the average length of neurites produced by the acetyl carnitine arginine amide (ST-857) resulted in a 19.5 percent increase in neurite outgrowth with the ST-857, compared to neurite outgrowth of 5.6 percent using acetyl carnitine alone in brain cell cultures.3
In addition, acetyl carnitine arginate protects neurons against the effects of exposure to beta amyloid found in aging brain cells.5 Beta amyloid production is strongly implicated in the development of some forms of age-related cognitive decline and is found in great abundance in aging brains. When beta amyloid was added to healthy brain cell cultures, neurotoxicity took place in 5 days and cell death occurred within 8 days. Acetyl carnitine arginate added at the same time mitigated the effects of beta amyloid exposure by preventing its disrupting effect on the normal brain cell’s calcium balance, or homeostasis.5
In one study conducted in 1988, it was demonstrated that the buildup of lipofuscin, another oxidized protein found in all older cells, became more balanced in brain cells when acetyl carnitine was fed to rats as they aged.6-7 Acetyl carnitine also supported healthy emotions in older rats, like decreased rearing behavior and decreased locomotor activity.8
Other studies have demonstrated that acetyl carnitine supports the structural integrity of the hippocampus in the aging brain and supports receptor balance in various areas across the brain. Within seven days, treatment with acetyl carnitine enhanced serotonin and dopamine output in rat brains. Acetyl carnitine also enhances the rats’ ability to deal with the emotional effects of a stress reaction called escape behavior.9
In several human trials, acetyl carnitine improved pain, nerve regeneration and sensory perceptions.10 A meta-analysis, or a summary of all the studies until 2003 using acetyl carnitine for cognitive health, showed significant benefits.11 Acetyl carnitine in randomized studies was successfully used to enhance energy.12-13 It also was used successfully to enhance mood and support healthy cerebrovascular circulation.14-17
In many early studies, acetyl carnitine has been proposed to support healthy brain aging,8,18 and given its successful clinical history in the brain since these proposals, it is a shining star in the field of cognitive health. It also has demonstrated itself in brain rejuvenation in animal and human brain cell studies. Together with the documented synergy between acetyl carnitine arginate and acetyl carnitine in supporting the regrowth in neurites and dendrites, it is a vitally important dietary supplement for the brain.
Other Brain-Cell Supporting Nutrients
Uridine, or its most common salt, uridine-5-monophosphate, UMP, is a building block of RNA and DNA and, like acetyl carnitine arginate and acetyl carnitine, it is important to brain health. Uridine-5-monophosphate is the usual dietary source of uridine, found in the milk of mammals. Recent research is increasingly showing that uridine is essential for growth and development in rats.19 It was once thought that only infants needed uridine during early developmental stages, since mature mammals are capable of synthesizing their own uridine. Uridine monophosphate is still routinely added to all infant and most parenteral formulas. Uridine monophosphate has the phosphate group removed in the body by the phosphatases and, when uridine is transported into the brain, the body again adds the phosphate group to cross the blood-brain barrier.20
In the 1960s, it was discovered that uridine is an essential ingredient for adult brain functioning. In 1968, one researcher found that uridine is the real dietary source of cytidine, a building block of the cell membrane component and signaling agent, phosphatidylcholine, which is necessary for memory and is a major component of cell membranes.21 Phosphatidylcholine levels decline with age in all mammals, and these declining levels appear to play a major role in age-related memory concerns.
A great deal of brain research, especially when it comes to memory and cognition, is conducted with gerbils and rats because they have close similarities to human brain structure. Gerbils, in particular, lose cognition in a manner strikingly similar to humans.22
Research in the 1970s showed that rats that watched visual stimuli and then were required to perform training tasks took up more uridine into their brains than rats not required to perform tasks. It was also shown that rats that were exposed to visual stimuli had increased uptake of uridine into the hippocampal areas of the brain and needed uridine for memory in responding to the visual stimuli. It was becoming apparent that uridine plays an important role in memory retention.23
In a study conducted in 2000, researchers observed that human brain cells had increased neurite outgrowth and neurofilament expression when exposed to uridine for 4 days. A variety of chemicals that prevented incorporation of nucleotides into brain cells all prevented the neurite outgrowth in the brain cells caused by uridine, showing that uridine was responsible for the neural regeneration.24
In 2005, a study demonstrated that uridine added to brain cell cultures stimulated neurite outgrowth branching and increased the number of new neurites per cell. The researchers found that uridine stimulated neurite outgrowth and branching by two different pathways—it enhanced phosphatidylcholine synthesis, as was previously shown in the earlier studies, but it also blocked receptors that stopped neurites from growing.25
In the same year, a study showed that orally administered uridine-5-monophosphate given to aged rats supported the release of dopamine in the right striatum of their brains to a level of 341 compared to a control group level of 221, a 35 percent increase. Biomarkers of neurite outgrowth, neurofilament-70 and neurofilament-M protein levels increased to 182 percent and 221 percent higher than in the control rats. The study demonstrated that even in old rats, oral uridine intake supported neurotransmitter release and neurite outgrowth in vivo.19
Gotu kola (Centella asiatica)
Gotu kola is a perennial plant native to India and has been used in Ayurvedic traditional medicine for thousands of years. It is mentioned in the ancient Chinese Shennong Herbal during the Tang dynasty 2,000 years ago. Gotu kola and its extracts have been incorporated into the Indian pharmacopeia in the early 1800s and have been used in France for decades.
Traditionally, Gotu kola has been used as a brain tonic to support memory. It has been called a “brain food” and has been recommended for overstressed people, mood, to improve reflexes and to support feelings of calmness. Gotu kola has also been studied in humans and was found to have a positive influence on enhancing peripheral circulation.26
Scientific research into Gotu kola extracts and its effects on the brain really only began in earnest in the past decade. In 2002, Gotu kola water extracts were administered to rats, where it improved their cognitive function in terms of learning and memory in a standard shuttle box avoidance and step through test. Brain levels of malondialdehyde (MDA), an indicator of overall oxidative stress, was reduced, and brain levels of the endogenous antioxidant glutathione were increased.27
In 2003, the same researchers again showed enhanced cognitive function in rats in two well-accepted tests for improved intelligence. They confirmed the reduced MDA brain levels and increased brain glutathione levels.28
A breakthrough year occurred in 2005 regarding the number of studies published using Gotu kola extracts on brain function and their support of healthy brain structure. In one study, where Gotu kola was given to mice during postnatal development stage, the extract supported healthy brain cell dendrite growth and branching of dendrites in the hippocampal area of the brain. This showed the extract “can influence the neuronal morphology and promote the higher brain function of juvenile and young adult mice.” In other words, structural out-branching of the neural network of the brain was observed, and this resulted in higher brain functioning.29-30
In the same year, another study showed that Gotu kola alcohol extract stimulated a positive effect on neurite outgrowth in the presence of nerve growth factor in human brain cells. It was shown than many different fractions of Gotu kola extracts supported neurite branching and outgrowth from the human cells, demonstrating that there are several active principles in Gotu kola promoting this growth. One of the active principals was identified as asiatic acid. When the alcohol extract was added to the drinking water of old rats, “(they) demonstrated more functional recovery and increased axonal regeneration (of neurites and dendrites), larger calibers of axons and greater numbers of myelinated (sheath-covered) axons.” The authors concluded that components in Centella (Gotu kola) ethanolic extract may promote neuron health.”31
The most desirable Gotu kola extract to use is a hydro-alcoholic extract standardized to a much higher percentage of active asiaticoside principles than the vast majority of Gotu kola extracts.
Acetyl carnitine increases the effects of nerve growth factor 100 times when in NGF’s presence. It supports the expression of nerve growth factor receptor sites, which nerve growth factor acts on to promote healthy neurite and dendrite outgrowth. Acetyl carnitine arginate mimics the effects of nerve growth factor itself. The two supplements act synergistically.
Uridine is another supplement that has been shown to support neurites and dendrites during growth and development stages in vivo orally. It has been shown to stimulate neurite-dendrite outgrowth in older animals, too, while supporting their mental abilities.
Gotu kola supports healthy cognition in older animals while stimulating neurite-dendrite growth and out branching in key areas of the brain because of the presence of several active principals called asiaticosides. It enhances cognition and outgrowth in older animals and also during the growth and development stages of younger animals.
1. Sarter, M, Bruno, JP. Developmental origins of the age-related decline in cortical cholinergic function and associated cognitive abilities. Neurobiol Aging. 2004 Oct;25(9):1127-39.
2. Tagliatatela G, Angelucci L, Ramacci MT, Werrbach-Perez K, et al. Acetyl-L-carnitine enhances the response of PC-12 cells to nerve growth factor. Brain Res Dev Brain Res. 1991 Apr 24;59(2):221-30.
3. Taglialatela, G, Navarra D, Olivi A, Ramacci MT, Werrbach-Perez K, et al. Neurite outgrowth in PC12 cells stimulated by acetyl-L- carnitine arginine amide. Neurochem Res. 1995 Jan;20(1):1-9.
4. Westlund KN, Lu Y, Werrbach-Perez K, Hulsebosch CE, Morgan B, et al. Effects of nerve growth factor and acetyl-L-carnitine arginyl amide on the human neuronal line HCN-1A. Int J Dev Neurosci. 1992 Oct;10(5):361-73.
5. Scorziello A, Meucci O, Calvani M, Schettini G. Acetyl-L-carnitine arginine amide prevents beta 25-35-induced neurotoxicity in cerebellar granule cells. Neurochem Res. 1997 Mar;22(3);257-65.
6. Amenta, F, Ferrante F, Lucreziotti R, Ricci A, Ramacci MT. Reduced lipofucscin accumulation in senescent rat brain by long term acetyl-L-carnitine treatment. Arch Gerontol Geriatr. 1989 Sep-Oct;9(2):147-53.
7. Ramacci, MT, De Rossi M, Lucreziotti, MR, Mione MC, Amenta F. Effect of long-term treatment with acetyl-L-carnitine on structural changes of ageing rat brain. Drugs Exp Clin Res. 1988;14(9):593-601.
8. Kohjimoto Y, Ogawa T, Matsumoto M, Shirakawa K, Kuwaki T, Yasuda H, et al. Effects of acetyl-L-carnitine on the brain lipofucscin content and emotional behavior in aged rats. Jpn J Pharmacol. 1988 Nov;48(3):365-71.
9. Tolu P, Masi F, Leggio B, Schleggl S, Tagliamonte A, de Montia MG. Effects of long-term acetyl-L-carnitine administration in rats: I. Increased dopamine output in mesocorticolimbic areas and protection toward acute stress exposure. Neuropsychopharmacology. 2002 Sep;27(3):410-20.
10. Sima AA, Calvani , Mehra M, Amato A. Acetyl-L-carnitine Study Group. Acetyl-l-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care. 2005 Jan;28(1):89-94.
11. Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double-blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol. 2003 Mar;18(2):61-71.
12. Vermeulen RC, Scholte HR. Exploratory open label, randomized study of acetyl and propionylcarnitine in chronic fatigue syndrome. Psychosom Med. 2004 Mar-Apr;66(2):276-82.
13. Tomassini V, Pozzilli C, Onesti E, Pasqualetti P, Marinelli F, Pisani A, et al. Comparison of the effects of acetyl-L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomized, double-blind, crossover trial. J. Neurol Sci. 2004 Mar 15;218(1-2):103-8.
14. Garzya G, Corallo D, Fiore A, Lecciso G, Petrelli G, Zotti C. Evaluation of the effects of L-acetylcarnitine on senile patients suffering from depression. Drugs Exp Clin Res. 1990;16(2):101-6.
15. Tempesta E, Troncon R, Janiri L, Colusso L, Riscica P, Saraceni G, et al. Role of acetyl-L-carnitine in the treatment of cognitive deficit in chronic alcoholism. Int J Clin Pharmacol Res. 1990;10(1-2):101-7.
16. Herrmann WM, Dietrich R, Hiersemenzel R. Pharmaco-electroencephalographic and clinical effects of the cholinergic substance-acetyl-L-carnitine-in patients with organic brain syndrome. Int J Clin Pharmacol Res. 1990;10(1-2):81-4.
17. Arrigo A, Casale R, Buonocore M, Ciano C. Effects of acetyl-L-carnitine on reaction times in patients with cerebrovascular insufficiency. Int J Clin Pharmacol res. 1990;10(1-2):133-7.
18. Fiora L, Rampello L. L-acetylcarnitine attenuates the age-dependent decrease of NMDA-sensitive glutamate receptors in rat hippocampus. Acta Neurol (Napoli) 1989 Oct;11(5):346-50.
19. Wang, L, Pooler AM, Albrecht MA, Wurtman, RJ. Dietary uridine-5’-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. J Mol Neurosci. 2005;27(1):137-45.
20. Wang L, Albrecht MA, Wurtman RJ. Dietary supplementation with uridine-5’-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat. Brain Res. 2007 Feb 16;1133(1):42-8.
21. Dawson DM. Enzymatic conversion of uridine nucleotide to cytidine nucleotide by rat brain. J Neurochem. 1968 Jan;15(1):31-4.
22. Delbarre G, Delbarre B, Casset-Senon D. The use of the Mongolian gerbil as a model for cerebrovascular involvement. Paroi Arterielle. 1980;6(3):161-5.
23. Smith JE. Distribution of 3H-uridine-5 in rat brain areas after exposure to various training tasks-an autoradiographic analysis. Pharmacol Biochem Behav. 1975 May-Jun:3(3):463-70.
24. Silei V, Politi V, Lauro GM. Uridine induces differentiation in human neuroblastoma cells via protein kinase C epsilon. J Neurosci Res. 2000 Jul 15;61(2):206-11.
25. Pooler AM, Guez DH, Benedictus R, Wurtman RJ. Uridine enhances neurite outgrowth in nerve growth factor-differentiated PC 12 (corrected). Neuroscience. 2005;134(1):207-14.
26. Pointel JP, Boccalon H, Cloarec M, Ledevehat C, Joubert M. Titrated extract of Centella asiatica (TECA) in the treatment of venous insufficiency of the lower limbs. Angiology. 1987 Jan;38(1 Pt 1):46-50.
27. Veerendra Kumar MH, Gupta YK. Effect of different extracts of Centella asiatica on cognition and markers of oxidative stress in rats. J. Ethnopharmacol. 2002 Feb;79(2):253-60.
28. Veerendra Kumar MH, Gupta YK. Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer’s disease in rats. Clin Exp Pharmacol Physiol. 2003 May-Jun;30(5-6):336-42.
29. Rao SB, Chetana M, Uma Devi P. Centella asiatica treatment during postnatal period enhances learning and memory in mice. Physiol Behav. 2005 Nov 15;86(4):449-57.
30. Soumyanath A, Zhong YP, Gold SA, Yu X, Koop DR, Bourdette D, Gold BG. Centella asiatica accelerates nerve regeneration upon oral administration and contains multiple active fractions increasing neurite elongation in-vitro. J Pharm Pharmacol. 2005 Sept;57(9):1221-9.
31. Garcia-Alloza M, Dodwell SA, Meyer-Luehmann M, Hyman BT, Bacskai BJ. Plaque-derived oxidative stress mediates distorted neurite trajectories in the Alzheimer mouse model. J Neuropathol Exp Neurol. 2006 Nov;65(11):1082-9.