Life Extension Magazine February 2007
Nutritional Strategies to Preserve Memory and Cognition
By Laurie Barclay, MD
By Laurie Barclay, MD
Ashwagandha: Brain Support Through Stress Relief
The herb ashwagandha (Withania somnifera) has long been used to boost energy and blood supply, reduce inflammation, and increase longevity. Modern science is now uncovering ashwagandha’s benefits for cognitive health.60,61
Ashwagandha has been shown to alleviate stress, which not only influences hormonal status and various bodily systems, but also directly affects brain function. In one study, rats were subjected to stress and evaluated for changes in brain cells, particularly in the hippocampus. Control animals kept under stress-free conditions exhibited no changes; however, in the stressed animals, 85% of brain cells examined showed signs of degeneration. When ashwagandha was administered to stressed subjects, the number of degraded brain cells was reduced by 80%.62
Ashwagandha has shown promise in treating Parkinson’s and Alzheimer’s diseases. For example, a recent study in laboratory animals showed that administering ashwagandha extract significantly and dose-dependently reversed all studied parameters of Parkinson’s-type neurodegeneration.63 In treating Alzheimer’s, physicians often rely on acetylcholinesterase-inhibitor drugs like Aricept®, which block the degradation of the neurotransmitter acetylcholine in order to slow the symptoms and progression of the disease. Ashwagandha extract likewise acts as an acetylcholinesterase inhibitor, and may thus help to preserve cognitive function and memory by protecting acetylcholine from breakdown.64
In any situation of cognitive decline, regeneration of the neuronal network may present a promising therapeutic option. Japanese researchers found that ashwagandha helped promote the regeneration and outgrowth of neurites that facilitate communication between nerve cells. Additionally, ashwagandha produced improvements in memory in a mouse model of Alzheimer’s disease.65
Blueberries: Antioxidant Protection for Brain Health
Neuroscientists are continually searching for natural agents that can protect brain cells from the devastating effects of oxidative stress and inflammation. Blueberries are rich in the powerful antioxidant phytochemicals known as polyphenols, which include proanthocyanidins that are particularly beneficial for brain health.66-69
A recent report found that blueberry extracts exert the same anti-inflammatory and antioxidant activities as the whole fruit.70 Anthocyanidin molecules from such extracts have been shown to cross the blood-brain barrier, making them accessible to neurons.71
When free radicals attack delicate brain cells, they disrupt optimal cellular function and often cause age-related cognitive decline.72 In an experimental rat model, a diet supplemented with plant-derived antioxidants reversed age-related decline in memory and cognition.73 Other studies have shown that increasing dietary intake of antioxidant-rich fruits and vegetables can maintain optimal neuronal function and cognition well into old age.74-76
In one study, scientists discovered that supplementation with blueberries prevented memory loss in aged rats. Researchers fed one group of rats a diet supplemented with blueberries and fed another group a control diet. The animals were then tested for object-recognition memory. The blueberry-fed rats performed significantly better than the control group, suggesting that supplementation with blueberries restored youthful levels of function in the aging brain.75
Intriguingly, the researchers also tested for levels of nuclear factor-kappa beta (NFkB) in the rats after supplementation with blueberries. A naturally occurring compound in cells, NFkB increases production of inflammatory mediators that often initiate degenerative diseases. The scientists found that NFkB levels were significantly lower in rats fed blueberries compared to controls, and that when NFkB levels were lower, the rats scored higher on memory tests.75
Animal studies also indicate that blueberries help maintain high levels of new cell generation in the hippocampus, the brain area that suffers extensive damage in Alzheimer’s disease.77
Oxidative stress is a major factor in the development of Alzheimer’s, along with overproduction of the beta-amyloid protein, which appears to cause cell destruction. The result is damaged cells that are then unable to manufacture or respond normally to the neurotransmitter acetylcholine.
A group of scientists sought to determine whether blueberries have a protective effect on rats bred to have Alzheimer’s disease.78 Astonishingly, they determined that a blueberry-supplemented diet caused Alzheimer’s-bred rats to perform normally on tests of memory and motor behavior. A surprising finding was that levels of destructive beta-amyloid protein in the test animals’ brains did not differ from those of normal rats. The researchers concluded that a diet incorporating blueberries may help overcome genetic predispositions to Alzheimer’s disease.
Other studies of blueberries and cognitive health have found that blueberries provide important protection against destructive inflammation in the brain.79 Brain memory regions of young and old rats fed either a blueberry diet or control diet were subjected to an inflammatory challenge and then examined for production of a protein that would indicate a normal protective response to stress. The protein level in the blueberry-fed aged rats was completely restored within four hours of the inflammatory stimulus. This kind of rapid effect suggests that blueberry supplementation could improve neuroprotective responses to diseases with a mixed oxidative and inflammatory cause, such as Alzheimer’s.
Grape Seed Extract: Guarding Against Senile Plaque Formation
The brain’s extraordinarily complex circuitry generates massive amounts of oxygen free radicals that may play an important role in the impairment of healthy brain activity that commonly accompanies aging.
Rich in polyphenols, grape seed extract is considered one of nature’s most potent antioxidants. Researchers believe that grape seed’s antioxidant properties confer broad-spectrum protection against premature aging, disease, and decay; in fact, grape seed extract packs 20 times more antioxidant power than vitamin E and 50 times more antioxidant power than vitamin C.80 These attributes have led many scientists to suggest that grape seed extract is an essential nutrient for maintaining optimal brain health and function.
Grape seed extract not only improves blood circulation by strengthening capillaries, arteries, and veins, but also prevents the formation of senile plaques that can severely damage the brains of those with dementia.81 For example, South Korean scientists treated the brain cells of rats with grape seed extract before exposing them to the toxic beta-amyloid protein. Beta amyloid promotes the development of plaques that accumulate in the brains of patients with Alzheimer’s disease. Treatment with grape seed extract conferred significant protection on the rat brain cells. While the untreated rat brain cells sustained acute free-radical damage and subsequently died, cells treated with grape seed extract suffered little damage.81
In research published in 2006, Indian scientists sought to evaluate grape seed extract’s effects on the accumulation of oxidative DNA damage seen in normal aging. They administered grape seed extract to young and aged albino rats for 30 days. In rats that received the extract, grape seed extract inhibited the accumulation of age-related oxidative DNA damage in the spinal cord and in various brain regions such as the cerebral cortex, striatum, and hippocampus—the very sites involved in thinking, processing, and memory that are most degraded in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease.82
Conclusion: Prevention Is the Best Brain Medicine
An abundance of scientific evidence indicates that any program to protect the brain from dementia and other ravages of aging should incorporate compounds that have been shown to stimulate brain energy metabolism, boost acetylcholine levels, and protect against inflammation, thrombosis, and oxidative stress. By taking advantage of recent advances in our understanding of nerve cell function, cognition and memory, and how these processes are disrupted during normal aging, health-conscious adults can devise an individualized anti-aging program utilizing the most potent brain-protective nutrients available today.
Supplements such as uridine, GPC, phosphatidylserine, DHA, vinpocetine, ashwagandha, blueberries, and grape seed extract work via numerous mechanisms to provide natural, broad-spectrum support for optimal brain health and function. Because it is so much easier to protect the health of your brain cells than it is to restore their function once damage has manifested, it makes sense to begin a preventive program as soon as possible. When it comes to protecting and preserving brain health, “an ounce of prevention is worth a pound of cure” is truly a no-brainer.
1. Hofman A, Rocca WA, Brayne C, et al. The prevalence of dementia in Europe: a collaborative study of 1980-1990 findings. Eurodem Prevalence Research Group. Int J Epidemiol. 1991 Sep;20(3):736-48.
2. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand. 1987 Nov;76(5):465-79.
3. Burns A, Zaudig M. Mild cognitive impairment in older people. Lancet. 2002 Dec 14;360(9349):1963-5.
4. Klegeris A, McGeer PL. Cyclooxygenase and 5-lipoxygenase inhibitors protect against mononuclear phagocyte neurotoxicity. Neurobiol Aging. 2002 Sep;23(5):787-94.
5. Kidd PM. A review of nutrients and botanicals in the integrative management of cognitive dysfunction. Altern Med Rev. 1999 Jun;4(3):144-61.
6. Parnetti L, Amenta F, Gallai V. Choline alphoscerate in cognitive decline and in acute cerebrovascular disease: an analysis of published clinical data. Mech Ageing Dev. 2001 Nov;122(16):2041-55.
7. Ritchie K, Kildea D. Is senile dementia “age-related” or “ageing-related”?—evidence from meta-analysis of dementia prevalence in the oldest old. Lancet. 1995 Oct 7;346(8980):931-4.
8. Ritchie K, Lovestone S. The dementias. Lancet. 2002 Nov 30;360(9347):1759-66.
9. Paris D, Town T, Parker T, Humphrey J, Mullan M. A beta vasoactivity: an inflammatory reaction. Ann NY Acad Sci. 2000 Apr;903:97-109.
10. Smith JE, Heistad GT, Thompson T. Uptake of 3H-uridine into brain and incorporation into brain RNA of rats exposed to various training tasks - a biochemical analysis. Pharmacol Biochem Behav. 1975 May;3(3):447-54.
11. Itoh T, Quastel JH. Ribonucleic acid biosynthesis in adult and infant rat brain in vitro. Science. 1969 Apr 4;164(875):79-80.
12. MacKinnon PC, Simpson RA, Maclennan C. In vivo and in vitro techniques used in the study of RNA synthesis in the brains of rats and mice at various ages from birth to senility. J Anat. 1969 Mar;104(Pt 2):351-60.
13. Blusztajn JK, Liscovitch M, Richardson UI. Synthesis of acetylcholine from choline derived from phosphatidylcholine in a human neuronal cell line. Proc Natl Acad Sci USA. 1987 Aug;84(15):5474-7.
14. Cansev M, Watkins CJ, van der Beek EM, Wurtman RJ. Oral uridine-5’-monophosphate (UMP) increases brain CDP-choline levels in gerbils. Brain Res. 2005 Oct 5;1058(1-2):101-8.
15. Cansev M. Uridine and cytidine in the brain: their transport and utilization. Brain Res Brain Res Rev. 2006 Sep;52(2):389-97.
16. Wurtman RJ, Ulus IH, Cansev M, et al. Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Res. 2006 May 9;1088(1):83-92.
17. 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.
18. Pooler AM, Guez DH, Benedictus R, Wurtman RJ. Uridine enhances neurite outgrowth in nerve growth factor-differentiated PC12 [corrected]. Neuroscience. 2005;134(1):207-14.
19. De Bruin NM, Kiliaan AJ, De Wilde MC, Broersen LM. Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats. Neurobiol Learn Mem. 2003 Jul;80(1):63-79.
20. Teather LA, Wurtman RJ. Chronic administration of UMP ameliorates the impairment of hippocampal-dependent memory in impoverished rats. J Nutr. 2006 Nov;136(11):2834-7.
21. Carlezon WA, Jr., Mague SD, Parow AM, et al. Antidepressant-like effects of uridine and omega-3 fatty acids are potentiated by combined treatment in rats. Biol Psychiatry. 2005 Feb 15;57(4):343-50.
22. Manev H, Uz T, Sugaya K, Qu T. Putative role of neuronal 5-lipoxygenase in an aging brain. FASEB J. 2000 Jul;14(10):1464-9.
23. Ricci A, Bronzetti E, Vega JA, Amenta F. Oral choline alfoscerate counteracts age-dependent loss of mossy fibres in the rat hippocampus. Mech Ageing Dev. 1992;66(1):81-91.
24. Amenta F, Ferrante F, Vega JA, Zaccheo D. Long term choline alfoscerate treatment counters age-dependent microanatomical changes in rat brain. Prog Neuropsychopharmacol Biol Psychiatry. 1994 Sep;18(5):915-24.
25. Amenta F, Bronzetti E, Ricci A, et al. Nucleus basalis magnocellularis lesions decrease histochemically reactive zinc stores in the rat brain: effect of choline alphoscerate treatment. Eur J Histochem. 1995;39(4):281-8.
26. Amenta F, Franch F, Ricci A, Vega JA. Cholinergic neurotransmission in the hippocampus of aged rats: influence of L-alpha-glycerylphosphorylcholine treatment. Ann NY Acad Sci. 1993 Sep 24;695:311-3.
27. Drago F, Mauceri F, Nardo L, et al. Behavioral effects of L-alpha-glycerylphosphorylcholine: influence on cognitive mechanisms in the rat. Pharmacol Biochem Behav. 1992 Feb;41(2):445-8.
28. Vega JA, Cavallotti C, del Valle ME, Mancini M, Amenta F. Nerve growth factor receptor immunoreactivity in the cerebellar cortex of aged rats: effect of choline alfoscerate treatment. Mech Ageing Dev. 1993 Jun;69(1-2):119-27.
29. Cummings JL, et al. Neurobiological basis of behavior. In: Coffey CE, Cummings JL, eds. Textbook of Geriatric Neuropsychiatry. American Psychiatric Press; 1994: 72-96.
30. Parnetti L, Abate G, Bartorelli L, et al. Multicentre study of l-alpha-glyceryl-phosphorylcholine vs ST200 among patients with probable senile dementia of Alzheimer’s type. Drugs Aging. 1993 Mar;3(2):159-64.
31. Barbagallo SG, Barbagallo M, Giordano M, Meli M, Panzarasa R. alpha-Glycerophosphocholine in the mental recovery of cerebral ischemic attacks. An Italian multicenter clinical trial. Ann NY Acad Sci. 1994 Jun 30;717:253-69.
32. De Jesus Moreno MM. Cognitive improvement in mild to moderate Alzheimer’s dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial. Clin Ther. 2003 Jan;25(1):178-93.
33. Amenta F, Parnetti L, Gallai V, Wallin A. Treatment of cognitive dysfunction associated with Alzheimer’s disease with cholinergic precursors. Ineffective treatments or inappropriate approaches? Mech Ageing Dev. 2001 Nov;122(16):2025-40.
34. Kingsley M. Effects of phosphatidylserine supplementation on exercising humans. Sports Med. 2006;36(8):657-69.
35. Ulmann L, Mimouni V, Roux S, Porsolt R, Poisson JP. Brain and hippocampus fatty acid composition in phospholipid classes of aged-relative cognitive deficit rats. Prostaglandins Leukot Essent Fatty Acids. 2001 Mar;64(3):189-95.
36. Lomnitski L, Oron L, Sklan D, Michaelson DM. Distinct alterations in phospholipid metabolism in brains of apolipoprotein E-deficient mice. J Neurosci Res. 1999 Nov 15;58(4):586-92.
37. Suzuki S, Yamatoya H, Sakai M, et al. Oral administration of soybean lecithin transphosphatidylated phosphatidylserine improves memory impairment in aged rats. J Nutr. 2001 Nov;131(11):2951-6.
38. Castilho JC, Perry JC, Andreatini R, Vital MA. Phosphatidylserine: an antidepressive or a cognitive enhancer? Prog Neuropsychopharmacol Biol Psychiatry. 2004 Jul;28(4):731-8.
39. Pepeu G, Spignoli G. Nootropic drugs and brain cholinergic mechanisms. Prog Neuropsychopharmacol Biol Psychiatry. 1989;13 SupplS77-S88.
40. Schreiber S, Kampf-Sherf O, Gorfine M, et al. An open trial of plant-source derived phosphatydilserine for treatment of age-related cognitive decline. Isr J Psychiatry Relat Sci. 2000;37(4):302-7.
41. Delwaide PJ, Gyselynck-Mambourg AM, Hurlet A, Ylieff M. Double-blind randomized controlled study of phosphatidylserine in senile demented patients. Acta Neurol Scand. 1986 Feb;73(2):136-40.
42. Funfgeld EW, Baggen M, Nedwidek P, Richstein B, Mistlberger G. Double-blind study with phosphatidylserine (PS) in parkinsonian patients with senile dementia of Alzheimer’s type (SDAT). Prog Clin Biol Res. 1989;317:1235-46.
43. McDaniel MA, Maier SF, Einstein GO. “Brain-specific” nutrients: a memory cure? Nutrition. 2003 Nov;19(11-12):957-75.
44. Jorissen BL, Brouns F, Van Boxtel MP, et al. The influence of soy-derived phosphatidylserine on cognition in age-associated memory impairment. Nutr Neurosci. 2001;4(2):121-34.
45. Khalsa DS. Integrated medicine and the prevention and reversal of memory loss. Altern Ther Health Med. 1998 Nov;4(6):38-43.
46. Jorissen BL, Brouns F, Van Boxtel MP, Riedel WJ. Safety of soy-derived phosphatidylserine in elderly people. Nutr Neurosci. 2002 Oct;5(5):337-43.
47. Blokland A, Honig W, Brouns F, Jolles J. Cognition-enhancing properties of subchronic phosphatidylserine (PS) treatment in middle-aged rats: comparison of bovine cortex PS with egg PS and soybean PS. Nutrition. 1999 Oct;15(10):778-83.
48. van den Besselaar AM. Phosphatidylethanolamine and phosphatidylserine synergistically promote heparin’s anticoagulant effect. Blood Coagul Fibrinolysis. 1995 May;6(3):239-44.
49. Horrocks LA, Yeo YK. Health benefits of docosahexaenoic acid (DHA). Pharmacol Res. 1999 Sep;40(3):211-25.
50. Kidd PM. Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management. Altern Med Rev. 2005 Dec;10(4):268-93.
51. Kidd P. Phosphatidylserine: Nature’s Brain Booster for Memory, Mood, and Stress. St. George: Total Health Communications, Inc.; 2005.
52. Unpublished data, Enzymotec Ltd, Israel.
53. Nicholson CD. Pharmacology of nootropics and metabolically active compounds in relation to their use in dementia. Psychopharmacology (Berl). 1990;101(2):147-59.
54. Gaal L, Molnar P. Effect of vinpocetine on noradrenergic neurons in rat locus coeruleus. Eur J Pharmacol. 1990 Oct 23;187(3):537-9.
55. Polich J, Gloria R. Cognitive effects of a Ginkgo biloba/vinpocetine compound in normal adults: systematic assessment of perception, attention and memory. Hum Psychopharmacol. 2001 Jul;16(5):409-16.
56. Hindmarch I, Fuchs HH, Erzigkeit H. Efficacy and tolerance of vinpocetine in ambulant patients suffering from mild to moderate organic psychosyndromes. Int Clin Psychopharmacol. 1991;6(1):31-43.
57. Horvath S. The use of vinpocetine in chronic disorders caused by cerebral hypoperfusion. Orv Hetil. 2001 Feb 25;142(8):383-9.
58. Lendvai B, Zelles T, Rozsa B, Vizi ES. A vinca alkaloid enhances morphological dynamics of dendritic spines of neocortical layer 2/3 pyramidal cells. Brain Res Bull. 2003 Jan 15;59(4):257-60.
59. Hadjiev D. Asymptomatic ischemic cerebrovascular disorders and neuroprotection with vinpocetine. Ideggyogy Sz. 2003 May 20;56(5-6):166-72.
60. Govindarajan R, Vijayakumar M, Pushpangadan P. Antioxidant approach to disease management and the role of ‘Rasayana’ herbs of Ayurveda. J Ethnopharmacol. 2005 Jun 3;99(2):165-78. Epub 2005 Apr 26.
61. [No authors listed] Monograph. Withania somnifera. Altern Med Rev. 2004 Jun;9(2):211-4.
62. Jain S, Shukla SD, Sharma K, Bhatnagar M. Neuroprotective effects of Withania somnifera Dunn. in hippocampal sub-regions of female albino rat. Phytother Res. 2001 Sep;15(6):544-8.
63. Ahmad M, Saleem S, Ahmad AS. Neuroprotective effects of Withania somnifera on 6-hydroxydopamine induced Parkinsonism in rats. Hum Exp Toxicol. 2005 Mar;24(3):137-47.
64. Schliebs R, Liebmann A, Bhattacharya SK, Kumar A, Ghosal S, Bigl V. Systemic administration of defined extracts from Withania somnifera (Indian Ginseng) and Shilajit differentially affects cholinergic but not glutamatergic and GABAergic markers in rat brain. Neurochem Int. 1997 Feb;30(2):181-90.
65. Tohda C, Kuboyama T, Komatsu K. Search for natural products related to regeneration of the neuronal network. Neurosignals. 2005;14(1-2):34-45.
66. Ehlenfeldt MK, Prior RL. Oxygen radical absorbance capacity (ORAC) and phenolic and anthocyanin concentrations in fruit and leaf tissues of highbush blueberry. J Agric Food Chem. 2001 May;49(5):2222-7.
67. Bagchi D, Garg A, Krohn RL, et al. Protective effects of grape seed proanthocyanidins and selected antioxidants against TPA-induced hepatic and brain lipid peroxidation and DNA fragmentation, and peritoneal macrophage activation in mice. Gen Pharmacol. 1998 May;30(5):771-6.
68. Bagchi D, Ray SD, Patel D, Bagchi M. Protection against drug- and chemical-induced multiorgan toxicity by a novel IH636 grape seed proanthocyanidin extract. Drugs Exp Clin Res. 2001;27(1):3-15.
69. Devi A, Jolitha AB, Ishii N. Grape seed proanthocyanidin extract (GSPE) and antioxidant defense in the brain of adult rats. Med Sci Monit. 2006 Apr;12(4):BR124-9.
70. Joseph JA, Shukitt-Hale B, Casadesus G. Reversing the deleterious effects of aging on neuronal communication and behavior: beneficial properties of fruit polyphenolic compounds. Am J Clin Nutr. 2005 Jan;81(1 Suppl):313S-6S.
71. Andres-Lacueva C, Shukitt-Hale B, Galli RL, Jauregui O, Lamuela-Raventos RM, Joseph JA. Anthocyanins in aged blueberry-fed rats are found centrally and may enhance memory. Nutr Neurosci. 2005 Apr;8(2):111-20.
72. Meydani M. Nutrition interventions in aging and age-associated disease. Ann N Y Acad Sci. 2001 Apr;928:226-35.
73. Bickford PC, Gould T, Briederick L, et al. Antioxidant-rich diets improve cerebellar physiology and motor learning in aged rats. Brain Res. 2000 Jun 2b;866(1-2):211-7.
74. Galli RL, Shukitt-Hale B, Youdim KA, Joseph JA.. Fruit polyphenolics and brain aging: nutritional interventions targeting age-related neuronal and behavioral deficits. Ann N Y Acad Sci. 2002 Apr;959:128-32.
75. Goyarzu P, Malin DH, Lau FC, et al. Blueberry supplemented diet: effects on object recognition memory and nuclear factor-kappa B levels in aged rats. Nutr Neurosci. 2004 Apr;7(2):75-83.
76. Joseph JA, Shukitt-Hale B, Denisova NA, et al. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci. 1999 Sep 15;19(18):8114-21.
77. Casadesus G, Shukitt-Hale B, Stellwagen HM, et al. Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats. Nutr Neurosci. 2004 Oct;7(5-6):309-16.
78. Joseph JA, Denisova NA, Arendash G, et al. Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci. 2003 Jun;6(3):153-62.
79. Galli RL, Bielinski DF, Szprengiel A, Shukitt-Hale B, Joseph JA. Blueberry supplemented diet reverses age-related decline in hippocampal HSP70 neuroprotection. Neurobiol Aging. 2006 Feb;27(2):344-50.
80. Shi J, Yu J, Pohorly JE, Kakuda Y. Polyphenolics in grape seeds-biochemistry and functionality. J Med Food. 2003;6(4):291-9.
81. Li MH, Jang JH, Sun B, Surh YJ. Protective effects of oligomers of grape seed polyphenols against beta-amyloid-induced oxidative cell death. Ann NY Acad Sci. 2004 Dec;1030:317-29.
82. Balu M, Sangeetha P, Murali G, Panneerselvam C. Modulatory role of grape seed extract on age-related oxidative DNA damage in central nervous system of rats. Brain Res Bull. 2006 Feb 15;68(6):469-73.
83. Meieran SE, Reus VI, Webster R, Shafton R, Wolkowitz OM. Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. Psychoneuroendocrinology. 2004 May;29(4):486-500.
84. Karishma KK, Herbert J. Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone-induced suppression. Eur J Neurosci. 2002 Aug;16(3):445-53.
85. Goncharova ND, Lapin BA. Effects of aging on hypothalamic-pituitary-adrenal system function in non-human primates. Mech Ageing Dev. 2002 Apr 30;123(8):1191-201.
86. Zietz B, Hrach S, Scholmerich J, Straub RH. Differential age-related changes of hypothalamus - pituitary - adrenal axis hormones in healthy women and men - role of interleukin 6. Exp Clin Endocrinol Diabetes. 2001;109(2):93-101.
87. Mayo W, Lemaire V, Malaterre J, et al. Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus. Neurobiol Aging. 2005 Jan;26(1):103-14.
88. Mayo W, George O, Darbra S, et al. Individual differences in cognitive aging: implication of pregnenolone sulfate. Prog Neurobiol. 2003 Sep;71(1):43-8.