Preserving Cognitive Function with AgingMarch 2009
By Julius Goepp, MD
UMP’s Role in Cognition Enhancement
Another approach to cognition and memory enhancement is the use of a substance known as uridine-5’-monophosphate (UMP), which helps comprise RNA, the DNA-like structure that cells use to create proteins from blueprints in genes. UMP supplementation in animals dramatically increases the production of vital brain cell membrane structural molecules, such as CDP-choline.61 Such structural molecules are vital for cell growth and repair, and even more importantly, for proper function of the synapses, the relay points at which brain and nerve cells communicate with each other.62
UMP supplementation in animals not only increases the synthesis of those vital proteins and phospholipids, but it actually helps stimulate production of neurotransmitters and of the tiny but critical cell outgrowths called neurites63 that are themselves formed and then remodeled in the process of learning64-66 and of cell repair.67
Brain scientists at MIT took those observations to a higher level when they supplemented nutritionally impoverished rats with UMP and studied the effects on memory.68 The animals were given either a control or a UMP-supplemented diet, and assessed for learning and memory skills. As expected, the impoverished animals fed a control diet did poorly on memory-dependent learning tasks, but those deficits were dramatically prevented in the UMP-supplemented group. One result of studies such as this one is the now-routine addition of UMP to infant formulas to promote healthy brain development.69
Declining ability to produce or respond to the neurotransmitter acetylcholine is one of the hallmarks of Alzheimer’s disease and other disorders of memory. In 2007, the MIT research group found that they could increase acetylcholine concentrations in aged rats with UMP supplementation.70 This is a stunning finding, since drugs like Aricept® that are used to treat Alzheimer’s disease work by inhibiting the enzyme that breaks down acetylcholine—an approach that has had mixed success and may cause serious side effects.71
The same MIT researchers, partnering with Turkish neuroscientists, have recently shown that UMP, together with the omega-3 fatty acid docosahexaenoic acid (DHA), can restore function in an animal model of Parkinson’s disease as well.72 And the same team demonstrated in late 2008 that they could actually enhance the learning and memory improvements caused by DHA in gerbils by adding UMP to the supplementation.73 They concluded, “these findings demonstrate that [UMP/DHA supplements] can enhance cognitive functions in normal animals” (emphasis added).74 In other words, one needn’t already have cognitive impairment to enjoy the potential benefits of UMP supplementation on learning and memory—and who wouldn’t want better memory even at baseline?
Ashwagandha Relieves Stress, Enhances Cognition
Numerous herbs from ancient India are reputed to promote physical and mental health, improve defense mechanisms of the body, and enhance longevity. Among the most promising of these for promoting cognitive health is a plant known as ashwagandha.
Indian researchers characterized the powerful antioxidant capabilities of ashwagandha extracts in 1997, showing that they increased concentrations of natural antioxidants in animal brains after supplementation.75 These researchers concluded that their findings explained the anti-stress, immunomodulatory, cognition-facilitating, anti-inflammatory, and anti-aging effects reported by other researchers in animal and clinical studies.
The same group later found that they could reduce the chronic stress effects of a mild, unpredictable foot shock in rats if they first supplemented them with ashwagandha extracts.76 Untreated animals experienced elevated blood sugar, glucose intolerance, increased stress steroid levels, gastric ulcers, male sexual dysfunction, cognitive deficits, and depression—common findings in humans exposed to chronic stress—but administration of ashwagandha extracts an hour before shocks dramatically attenuated all of these outcomes. As we noted with phosphatidylserine above, reduced stress allows increased focus on tasks and therefore better cognitive performance, in addition to simply improving quality of life.
A different Indian scientific group studied ashwagandha in diabetic rats, reasoning that the memory impairment seen in diabetes is in part related to oxidative damage in brain regions that are pivotal in memory and the ability to detect and process new information.77 They found a significant increase in production of oxidation end products in those brain regions, and a decrease in cognitive function, after the rats became diabetic. But following supplementation, the oxidative damage in the relevant brain regions was significantly reduced, as were blood glucose levels. Dramatically, memory impairment and motor dysfunction were also improved in the supplemented animals.
In 2007, further support for the use of ashwagandha extracts in Alzheimer’s disease was provided by the discovery that the extracts are among the most potent inhibitors of acetylcholinesterase, an enzyme that breaks down the vital memory-related neurotransmitter acetylcholine.78 Drugs that block acetylcholine breakdown (such as Aricept®) are utilized in the management of Alzheimer’s disease. The researchers correctly observed that “these results partly substantiate the traditional use of these herbs for improvement of cognition.” Western research into the benefits of ashwagandha is very recent, so stay tuned for additional exciting news on this extract’s memory- and cognition-enhancing properties.
Herbal Extracts Spice up Memory
It is now apparent that many traditional spices, in addition to adding interest to our food, can provide vital anti-inflammatory and antioxidant function that is having an impact on how we think about chronic illness and aging.79 Three of these in particular deserve special mention for their powerful effects on learning and memory.
Ginger is an age-old part of Asian kitchens and pharmacopeias,80 and we focus on it here especially for its ability to regulate platelet aggregation, which contributes not only to cardiovascular disease but also to cerebrovascular disease risk.81-84 Experimental studies demonstrated early in the millennium that ginger extracts could protect cells from the inflammatory action of the Alzheimer’s disease-related protein amyloid-beta.85-87 By its blood pressure-lowering effects, ginger can protect against the chronic brain injury caused by hypertension.82
Rosemary is an herb more familiar in Western kitchens, but has an equally distinguished record as a neuroprotectant through its antioxidant constituent, carnosic acid.88 Rosemary extracts block damaging lipid peroxidation, the destruction of brain cells’ fatty membranes that impairs cognitive performance.89 Rosemary also protects cell nuclei from DNA damage that results from both oxidant stress and ultraviolet light90—such damage is at the root of many cancers, but short of cancer it can impair a cell’s ability to function normally.
Neuroscientists in England recently showed a remarkable capacity of rosemary: humans exposed just to the aroma of its essential oil performed significantly better on overall memory quality compared with controls.91 Subjects also had increased states of alertness compared with controls or those exposed to lavender aroma.
Completing the culinary triad of memory-enhancing herbs is hops, the bitter ingredient of beer. Hops’ value may be primarily in its ability to promote relaxation and sleep—in one study, the combination of hops with valerian compared equally with a Valium®-like, sleep-inducing drug, and had none of the “hangover” effects seen with the drug.92 Similar results were found in another study comparing a Valium®-like drug with a hops/valerian combination: both groups did equally well on sleep, relaxation, and quality of life improvement, but patients experienced withdrawal symptoms when they stopped taking the drug.93
Far from being an “inevitable” consequence of aging, we now understand that cognitive decline and memory deficits are the predictable results of a lifetime of oxidative and inflammatory injury that damages brain cells’ ability to communicate with one another. A vast array of valuable nutrients are available to help block that damage—and in some cases to actually reverse it. Strong evidence abounds that the nutrients described in this review have important roles in improving the quality of life of older adults, keeping their wits sharp and their experiences vivid. These nutrients together, therefore, make up a vital part of any long-term brain health regimen.
If you have any questions on the scientific content of this article, please call a Life Extension Health Advisor at 1-800-226-2370.
1. Butler RN, Forette F, Greengross BS. Maintaining cognitive health in an ageing society. J R Soc Health. 2004 May;124(3):119-21.
2. 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.
3. Egashira T, Takayama F, Yamanaka Y. Effects of bifemelane on muscarinic receptors and choline acetyltransferase in the brains of aged rats following chronic cerebral hypoperfusion induced by permanent occlusion of bilateral carotid arteries. Jpn J Pharmacol. 1996 Sep;72(1):57-65.
4. Joseph JA, Berger RE, Engel BT, Roth GS. Age-related changes in the nigrostriatum: a behavioral and biochemical analysis. J Gerontol. 1978 Sep;33(5):643-9.
5. Joseph JA, Kowatch MA, Maki T, Roth GS. Selective cross-activation/inhibition of second messenger systems and the reduction of age-related deficits in the muscarinic control of dopamine release from perifused rat striata. Brain Res. 1990 Dec 24;537(1-2):40-8.
6. Landfield PW, Eldridge JC. The glucocorticoid hypothesis of age-related hippocampal neurodegeneration: role of dysregulated intraneuronal calcium. Ann NY Acad Sci. 1994 Nov 30;746:308-21.
7. Bartus RT. Drugs to treat age-related neurodegenerative problems. The final frontier of medical science? J Am Geriatr Soc. 1990 Jun;38(6):680-95.
8. Joseph JA, Bartus RT, Clody D, et al. Psychomotor performance in the senescent rodent: reduction of deficits via striatal dopamine receptor up-regulation. Neurobiol Aging. 1983;4(4):313-9.
9. Hauss-Wegrzyniak B, Vannucchi MG, Wenk GL. Behavioral and ultrastructural changes induced by chronic neuroinflammation in young rats. Brain Res. 2000 Mar 17;859(1):157-66.
10. Hauss-Wegrzyniak B, Willard LB, Del SP, Pepeu G, Wenk GL. Peripheral administration of novel anti-inflammatories can attenuate the effects of chronic inflammation within the CNS. Brain Res. 1999 Jan 2;815(1):36-43.
11. Shukitt-Hale B, McEwen JJ, Szprengiel A, Joseph JA. Effect of age on the radial arm water maze-a test of spatial learning and memory. Neurobiol Aging. 2004 Feb;25(2):223-9.
12. Denisova NA, Erat SA, Kelly JF, Roth GS. Differential effect of aging on cholesterol modulation of carbachol-stimulated low-K(m) GTPase in striatal synaptosomes. Exp Gerontol. 1998 May;33(3):249-65.
13. Joseph JA, Erat S, Rabin BM. CNS effects of heavy particle irradiation in space: behavioral implications. Adv Space Res. 1998;22(2):209-16.
14. Joseph JA, Denisova N, Fisher D, et al. Membrane and receptor modifications of oxidative stress vulnerability in aging. Nutritional considerations. Ann NY Acad Sci. 1998 Nov 20;854:268-76.
15. Rozovsky I, Finch CE, Morgan TE. Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of aging, increased proliferation, and resistance to down-regulation. Neurobiol Aging. 1998 Jan;19(1):97-103.
16. McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev. 1995 Sep;21(2):195-218.
17. Chang RC, Chen W, Hudson P, et al. Neurons reduce glial responses to lipopolysaccharide (LPS) and prevent injury of microglial cells from over-activation by LPS. J Neurochem. 2001 Feb;76(4):1042-9.
18. Spaulding CC, Walford RL, Effros RB. Calorie restriction inhibits the age-related dysregulation of the cytokines TNF-alpha and IL-6 in C3B10RF1 mice. Mech Ageing Dev. 1997 Feb;93(1-3):87-94.
19. Barros D, Amaral OB, Izquierdo I, et al. Behavioral and genoprotective effects of Vaccinium berries intake in mice. Pharmacol Biochem Behav. 2006 Jun;84(2):229-34.
20. Ramirez MR, Izquierdo I, do Carmo Bassols RM, et al. Effect of lyophilised Vaccinium berries on memory, anxiety and locomotion in adult rats. Pharmacol Res. 2005 Dec;52(6):457-62.
21. Sato M, Bagchi D, Tosaki A, Das DK. Grape seed proanthocyanidin reduces cardiomyocyte apoptosis by inhibiting ischemia/reperfusion-induced activation of JNK-1 and C-JUN. Free Radic Biol Med. 2001 Sep 15;31(6):729-37.
22. Fillit H, Nash DT, Rundek T, Zuckerman A. Cardiovascular risk factors and dementia. Am J Geriatr Pharmacother. 2008 Jun;6(2):100-18.
23. Sreemantula S, Nammi S, Kolanukonda R, Koppula S, Boini KM. Adaptogenic and nootropic activities of aqueous extract of Vitis vinifera (grape seed): an experimental study in rat model. BMC Complement Altern Med. 2005 Jan 19;51.
24. 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.
25. Kim H, Deshane J, Barnes S, Meleth S. Proteomics analysis of the actions of grape seed extract in rat brain: technological and biological implications for the study of the actions of psychoactive compounds. Life Sci. 2006 Mar 27;78(18):2060-5.
26. Ono K, Condron MM, Ho L, et al. Effects of grape seed-derived polyphenols on amyloid beta-protein self-assembly and cytotoxicity. J Biol Chem. 2008 Nov 21;283(47):32176-87.
27. Wang J, Ho L, Zhao W, et al. Grape-derived polyphenolics prevent Abeta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer’s disease. J Neurosci. 2008 Jun 18;28(25):6388-92.
28. Joseph JA. The putative role of free radicals in the loss of neuronal functioning in senescence. Integr Physiol Behav Sci. 1992 Jul;27(3):216-27.
29. Joseph JA, Denisova N, Fisher D, et al. Age-related neurodegeneration and oxidative stress: putative nutritional intervention. Neurol Clin. 1998 Aug;16(3):747-55.
30. 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.
31. 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.
32. 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.
33. Andres-Lacueva C, Shukitt-Hale B, Galli RL, et al. Anthocyanins in aged blueberry-fed rats are found centrally and may enhance memory. Nutr Neurosci. 2005 Apr;8(2):111-20.
34. Zhu Y, Bickford PC, Sanberg P, Giunta B, Tan J. Blueberry opposes beta-amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activation protein kinase. Rejuvenation Res. 2008 Oct;11(5):891-901.
35. Bailey DM, Evans KA, James PE, et al. Altered free radical metabolism in acute mountain sickness: implications for dynamic cerebral autoregulation and blood-brain barrier function. J Physiol. 2008 Oct 27.
36. Lacombe P, Oligo C, Domenga V, Tournier-Lasserve E, Joutel A. Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy. Stroke. 2005 May;36(5):1053-8.
37. Ogunniyi A, Talabi O. Cerebrovascular complications of hypertension. Niger J Med. 2001 Oct;10(4):158-61.
38. Blokland A, Schreiber R, Prickaerts J. Improving memory: a role for phosphodiesterases. Curr Pharm Des. 2006;12(20):2511-23.
39. Mostafa T. Oral phosphodiesterase type 5 inhibitors: nonerectogenic beneficial uses. J Sex Med. 2008 Nov;5(11):2502-18.
40. Vas A, Gulyas B. Eburnamine derivatives and the brain. Med Res Rev. 2005 Nov;25(6):737-57.
41. Vas A, Gulyas B, Szabo Z, et al. Clinical and non-clinical investigations using positron emission tomography, near infrared spectroscopy and transcranial Doppler methods on the neuroprotective drug vinpocetine: a summary of evidences. J Neurol Sci. 2002 Nov 15;203-204:259-62.
42. Balestreri R, Fontana L, Astengo F. A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction. J Am Geriatr Soc. 1987 May;35(5):425-30.
43. 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.
44. Hadjiev D. Asymptomatic ischemic cerebrovascular disorders and neuroprotection with vinpocetine. Ideggyogy Sz. 2003 May 20;56(5-6):166-72.
45. Kemeny V, Molnar S, Andrejkovics M, Makai A, Csiba L. Acute and chronic effects of vinpocetine on cerebral hemodynamics and neuropsychological performance in multi-infarct patients. J Clin Pharmacol. 2005 Sep;45(9):1048-54.
46. Bagoly E, Feher G, Szapary L. The role of vinpocetine in the treatment of cerebrovascular diseases based in human studies. Orv Hetil. 2007 Jul 22;148(29):1353-8.
47. Valikovics A. Investigation of the effect of vinpocetine on cerebral blood flow and cognitive functions. Ideggyogy Sz. 2007 Jul 30;60(7-8):301-10.
48. Anon. Phosphatidylserine. Monograph. Altern Med Rev. 2008 Sep;13(3):245-7.
49. Araki W, Wurtman RJ. How is membrane phospholipid biosynthesis controlled in neural tissues? J Neurosci Res. 1998 Mar 15;51(6):667-74.
50. Maggioni M, Picotti GB, Bondiolotti GP, et al. Effects of phosphatidylserine therapy in geriatric patients with depressive disorders. Acta Psychiatr Scand. 1990 Mar;81(3):265-70.
51. Crook T, Petrie W, Wells C, Massari DC. Effects of phosphatidylserine in Alzheimer’s disease. Psychopharmacol Bull. 1992;28(1):61-6.
52. Hashioka S, Han YH, Fujii S, et al. Phosphatidylserine and phosphatidylcholine-containing liposomes inhibit amyloid beta and interferon-gamma-induced microglial activation. Free Radic Biol Med. 2007 Apr 1;42(7):945-54.
53. Araujo JA, Landsberg GM, Milgram NW, Miolo A. Improvement of short-term memory performance in aged beagles by a nutraceutical supplement containing phosphatidylserine, Ginkgo biloba, vitamin E, and pyridoxine. Can Vet J. 2008 Apr;49(4):379-85.
54. Baumeister J, Barthel T, Geiss KR, Weiss M. Influence of phosphatidylserine on cognitive performance and cortical activity after induced stress. Nutr Neurosci. 2008 Jun;11(3):103-10.
55. Available at: http://vm.cfsan.fda.gov/~dms/ds-ltr36.html. Accessed December 16, 2008.
56. 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.
57. 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.
58. Cummings JL, et al. Neurobiological basis of behavior. In: Coffey CE, Cummings JL, eds. Textbook of Geriatric Neuropsychiatry. American Psychiatric Press; 1994:72-96.
59. 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.
60. 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.
61. 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.
62. 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.
63. Sakamoto T, Cansev M, Wurtman RJ. Oral supplementation with docosahexaenoic acid and uridine-5’-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain Res. 2007 Nov 28;1182:50-9.
64. Drees F, Gertler FB. Ena/VASP: proteins at the tip of the nervous system. Curr Opin Neurobiol. 2008 Feb;18(1):53-9.
65. Yamauchi T. Molecular mechanism of learning and memory based on the research for Ca2+/calmodulin-dependent protein kinase II. Yakugaku Zasshi. 2007 Aug;127(8):1173-97.
66. Skaper SD. Neuronal growth-promoting and inhibitory cues in neuroprotection and neuroregeneration. Ann NY Acad Sci. 2005 Aug;1053:376-85.
67. Carulli D, Buffo A, Strata P. Reparative mechanisms in the cerebellar cortex. Prog Neurobiol. 2004 Apr;72(6):373-98.
68. 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.
69. Wurtman RJ. Synapse formation and cognitive brain development: effect of docosahexaenoic acid and other dietary constituents. Metabolism. 2008 Oct;57(Suppl 2):S6-10.
70. 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.
71. Hansen RA, Gartlehner G, Webb AP, et al. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. Clin Interv Aging. 2008;3(2):211-25.
72. Cansev M, Ulus IH, Wang L, Maher TJ, Wurtman RJ. Restorative effects of uridine plus docosahexaenoic acid in a rat model of Parkinson’s disease. Neurosci Res. 2008 Nov;62(3):206-9.
73. Holguin S, Huang Y, Liu J, Wurtman R. Chronic administration of DHA and UMP improves the impaired memory of environmentally impoverished rats. Behav Brain Res. 2008 Aug 5;191(1):11-6.
74. Holguin S, Martinez J, Chow C, Wurtman R. Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils. FASEB J. 2008 Nov;22(11):3938-46.
75. Bhattacharya SK, Satyan KS, Ghosal S. Antioxidant activity of glycowithanolides from Withania somnifera. Indian J Exp Biol. 1997 Mar;35(3):236-9.
76. Bhattacharya SK, Muruganandam AV. Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress. Pharmacol Biochem Behav. 2003 Jun;75(3):547-55.
77. Parihar MS, Chaudhary M, Shetty R, Hemnani T. Susceptibility of hippocampus and cerebral cortex to oxidative damage in streptozotocin treated mice: prevention by extracts of Withania somnifera and Aloe vera. J Clin Neurosci. 2004 May;11(4):397-402.
78. Vinutha B, Prashanth D, Salma K, et al. Screening of selected Indian medicinal plants for acetylcholinesterase inhibitory activity. J Ethnopharmacol. 2007 Jan 19;109(2):359-63.
79. Aggarwal BB, Shishodia S. Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning. Ann NY Acad Sci. 2004 Dec;1030:434-41.
80. Hoffman T. Ginger: an ancient remedy and modern miracle drug. Hawaii Med J. 2007 Dec;66(12):326-7.
81. Bordia A, Verma SK, Srivastava KC. Effect of ginger (Zingiber officinale Rosc.) and fenugreek (Trigonella foenumgraecum L.) on blood lipids, blood sugar and platelet aggregation in patients with coronary artery disease. Prostaglandins Leukot Essent Fatty Acids. 1997 May;56(5):379-84.
82. Ghayur MN, Gilani AH, Afridi MB, Houghton PJ. Cardiovascular effects of ginger aqueous extract and its phenolic constituents are mediated through multiple pathways. Vascul Pharmacol. 2005 Oct;43(4):234-41.
83. Koo KL, Ammit AJ, Tran VH, Duke CC, Roufogalis BD. Gingerols and related analogues inhibit arachidonic acid-induced human platelet serotonin release and aggregation. Thromb Res. 2001 Sep 1;103(5):387-97.
84. Young HY, Liao JC, Chang YS, et al. Synergistic effect of ginger and nifedipine on human platelet aggregation: a study in hypertensive patients and normal volunteers. Am J Chin Med. 2006;34(4):545-51.
85. Kim DS, Kim DS, Oppel MN. Shogaols from Zingiber officinale protect IMR32 human neuroblastoma and normal human umbilical vein endothelial cells from beta-amyloid(25-35) insult. Planta Med. 2002 Apr;68(4):375-6.
86. Grzanna R, Phan P, Polotsky A, Lindmark L, Frondoza CG. Ginger extract inhibits beta-amyloid peptide-induced cytokine and chemokine expression in cultured THP-1 monocytes. J Altern Complement Med. 2004 Dec;10(6):1009-13.
87. Kim DS, Kim JY, Han YS. Alzheimer’s disease drug discovery from herbs: neuroprotectivity from beta-amyloid (1-42) insult. J Altern Complement Med. 2007 Apr;13(3):333-40.
88. Aruoma OI, Halliwell B, Aeschbach R, Loligers J. Antioxidant and pro-oxidant properties of active rosemary constituents: carnosol and carnosic acid. Xenobiotica. 1992 Feb;22(2):257-68.
89. Haraguchi H, Saito T, Okamura N, Yagi A. Inhibition of lipid peroxidation and superoxide generation by diterpenoids from Rosmarinus officinalis. Planta Med. 1995 Aug;61(4):333-6.
90. Slamenova D, Kuboskova K, Horvathova E, Robichova S. Rosemary-stimulated reduction of DNA strand breaks and FPG-sensitive sites in mammalian cells treated with H2O2 or visible light-excited Methylene Blue. Cancer Lett. 2002 Mar 28;177(2):145-53.
91. Moss M, Cook J, Wesnes K, Duckett P. Aromas of rosemary and lavender essential oils differentially affect cognition and mood in healthy adults. Int J Neurosci. 2003 Jan;113(1):15-38.
92. Gerhard U, Linnenbrink N, Georghiadou C, Hobi V. Vigilance-decreasing effects of 2 plant-derived sedatives. Praxis Bern. 1994;85:473-81.
93. Schmitz M, Jackel M. Comparative study for assessing quality of life of patients with exogenous sleep disorders (temporary sleep onset and sleep interruption disorders) treated with a hops-valarian preparation and a benzodiazepine drug. Wien Med Wochenschr. 1998;148(13):291-8.
94. 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.
95. 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.
96. 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.
97. 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.
98. 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.
99. 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.