AlphaGenics, Inc. Company Info

The science of NutriGenomics focuses on how gene expression is influenced and shaped by the chemistry of a person’s dietary environment. By understanding how the diet-gene relationships translate into wellness or disease, the prospect is opened to actually manage how genes function by appropriately matching key dietary inputs. This active management process is Directive Genomics.

Ginkgo Biloba is one of the oldest herbal remedies. Its use for a variety of health situations is well documented. This brief paper assembles NutriGenomics relationships for Ginkgo, based upon published scientific literature. These relationships may help explain some of the historical observations. They also may help explain why Ginkgo works in one person and not another, for we are not genetically alike.

Ginkgo Biloba is considered a "living fossil” as it is the oldest surviving plant species on earth. It covered the entire world during the Jurassic Period, but was almost wiped out in the last ice age. The characteristic shape of Ginkgo Biloba leaves (fan-shaped with an indentation in the middle) gave birth to the species name Biloba, a Latin word meaning bi-lobed. Ginkgo Biloba, unlike all other trees, has separate male and female trees. Mature male and female trees commonly stand facing each other at some distance. Pollen from male flowers is carried by the wind to the female tree, which produces ovules that fertilize and develop into yellowish seeds about a half an inch to one inch in length. The Ginkgo fruits have rancid, unpleasant odor, often described as being comparable to vomit. This can be a potential issue when planting young Ginkgo trees for it takes about 50 years before one can with certainty identify whether it is a male or female tree.

Ginkgo survived in Asia as a sacred herb used to treat many ailments. Chinese monks are credited with keeping the tree in existence over the centuries. Ginkgo is also an ingredient of the traditional Hindu medicine called "Soma". Ginkgo was imported from Japan to the Botanical Garden in Utrecht, Holland in 1727, and then to the United States 57 years later.

Ginkgo Biloba is arguably the most interesting medicinal tree in the world. It is considered safe to use and has wide range of benefits that no other tree on earth has. It is also one of the best researched in the world with more than 400 scientific studies conducted on standardized Ginkgo Biloba extracts in the past three decades. Clinical studies demonstrate that daily doses of 120-240 mg of standardized Ginkgo Biloba extract can lead to an improvement many medical conditions mentioned below.

Different countries have established rules governing the sale or use of the herb. In German, for example, Commission E approves Ginkgo Biloba for effective therapy in cases of:

Improvement in the memory loss, depression, and tinnitus could be achieved within 8-12 weeks. In both intermittent claudication and peripheral arterial occlusive disease, symptomatic relief can be achieved by increased circulation.

Small studies have shown that Ginkgo Biloba can also treat infertility in men, impotence, and inability to achieve orgasm stemming from anti-depressant drugs, but should NOT be used to treat this without strict doctor supervision.

While Ginkgo is believed to be one of the safest herbs in the world, side effects have been observed:

These effects are rare and mild and have been known to be caused by people simply taking too much of the herb (the recommended dosage being 40 mg to 240 mg a day). The main groups at risk are infants, pregnant or breast feeding women, people who experience epileptic seizures, and people taking anti-depressants.

Ginkgo Biloba allegedly causes seizures in infant’s that ingest the herb directly or through mother’s milk. One study found that Ginkgo Biloba caused seizures in a 78 year old man and an 84 year old woman, both with a history of epileptic seizures and both taking sodium valproate as an anti-epileptic drug. It is not recommend for patients taking anti-depressants to take Ginkgo to treat sexual dysfunction without strict doctor supervision as there may be complications.

Ginkgo Biloba owes its remarkable abilities to two groups of phytochemicals, the ginkgo flavone glycosides and terpene lactones. They are considered to be the primary active constituents. The ginkgo flavone glycosides include the chemicals quercetin, kaempherol and isorhamnetin. These are believed to be responsible for the antioxidant properties of ginkgo biloba. The terpene lactones include the chemicals ginkgolides A, B and C, as well as bilobalide, and have shown several activities. These activities include neuroprotection from free radicals, improvement of choline (a neurotransmitter) uptake in brain synapses, and a reduction in the tendency of the blood to clot. Ginkgo Biloba extract has been standardized to contain 24% flavonoids and 6% terpenoids.

The chemical Bilobalide-A, found only in Ginkgo Biloba, is known to up-regulate the expression of the gene VEGF, encoding the mitogen (mitosis-inducing protein) vascular endothelial growth factor. Other rare chemicals, Ginkgolide-A, -B, and -C, found in Ginkgo Biloba are all known to down-regulate the expression of VEGF in cardiovascular tissue.

VEGF is known to stimulate the proliferation of endothelial cells and controls blood vessel formation and permeability. Research conducted by Dantz and associates in 2002 showed that VEGF can enable the brain to adapt to neuroglycopenia quickly, and that it maintains neurocognitive function[1]. In another study, it was discovered that VEGF has neurotrophic and neuroprotective effects, promoting cell proliferation which can enhance neural functioning such as memory[2]. It was also found that it inhibits Caspase-3 which induces apoptosis. Further research conducted at the Weill Medical College of Cornell University further revealed that VEGF does in fact induce neurogenesis and improve cognition, learning and memory when it is present and expressed[3]. While VEGF expression is beneficial in the brain, it can be a problem when it is expressed, in some cases at levels that are too high, for other areas of the body like the heart. VEGF is known to make the vascular and endothelial cells more permeable to molecules like LDL, causing problems for coronary tissue and circulation[4]. This also leads to loss of plasma proteins due to the leakage and permeability problem. In addition to neurocognitive functioning and cardiovascular disease, the expression of VEGF is also associated with oxygen-induced retinopathy and neovascularization. Research has been conducted to determine the effects of Ginkgo Biloba on VEGF and the occurrence of retinopathy in mice. Although no specific chemical from Ginkgo Biloba is credited as down-regulating VEGF, when the mice were treated with Gingko Biloba they did not develop retinopathy while those who received no Ginkgo Biloba did in fact develop the condition[5].

With the up-regulation of VEGF in the brain by the Bilobalide-A chemical found in Ginkgo biloba[6], an increase in neurogenesis and neural functioning would result. As a result a person would experience enhanced neurocognitive functioning and memory capabilities. While Bilobalide-A induces higher expression of VEGF in the brain astrocytes, the chemicals Ginkgolide-A, -B, and -C, found in Ginkgo Biloba, all suppress VEGF expression in coronary tissue⁴. Thus, the condition and function of the coronary tissue would be improved, reducing heart disease.

There are several rare chemicals found in Ginkgo Biloba whose effects on the expression of various genes have been studied and identified. One such chemical called Bilobalide-A, found exclusively in Ginkgo Biloba, has been identified as a negative (down) regulator of the human gene BAX (BCL-2 Associated Protein[7]). In other words, in the presence of Bilobalide-A, the BAX gene will lower its activity or be turned off completely (no gene expression).

The BAX protein, encoded for by the BAX gene, is a death affecter required for large proportion of Atm-dependent apoptosis of neurons with genomic damage[8]. It is a cell death-signaling molecule. It seems possible that if BAX is causing more than necessary amounts of apoptosis in an individual, they are more susceptible to diseases like Bipolar disorder. It is also possible that a patient suffering from Bipolar Disorder has a higher level of genomically incorrect neurons than an individual without the disorder. In either case, with the BAX gene activity elevated, cell death would be occurring at a rate that is faster than that of neurogenesis, leaving the patients with a smaller prefrontal cortex of the brain which could lead to Bipolar disorder or make the symptoms more severe.

It was found that patients with Bipolar disorder had a prefrontal cortex 38% smaller than that of an individual without the disorder[9]. In another study conducted by Stanford’s Robert Sapolsky, PhD, it was found that when animals are stressed, like that experienced with mood disorders, the hippocampal neurons undergo cell death or become severely atrophied[10]. This loss of neurons can contribute to the onset of mood disorders. This is resulting from stress-induced release of proteins and neurotransmitters which trigger death effectors (BAX being one such effecter) which kill the cells, leading to problems like Bipolar disorder.

Since Bilobalide-A is known to lower BAX gene expression, it is conceivable that neuronal cell death can be reduced, leaving a patient with more neurons, and reduced symptoms of Bipolar Disorder.

There is another chemical in Ginkgo Biloba that is shown to negatively regulate BAX gene activity. Via a signaling cascade, the chemical 6-Heptadecenylsalicylic-Acid has been found to lead to BAX inhibition, yielding the same effects as Bilobalide-A[11].

Another chemical in Ginkgo Biloba, Apigenin, has been found to positively regulate the function of the human gene JUN (“AP1”)[12]. When Apigenin is present, JUN will be higher regulated or turned on in the cell.

JUN-encoded protein has been found to directly activate the gene transcription within a cell in response to cell stimulation[13]. As reported on the OMIM database, JUN, when accompanied with the N-terminal kinase JNK, is essential for neuronal microtubule assembly and apoptosis. These two processes are known to play a role in mood disorders such as depression and Bipolar Disorder. An in depth explanation of this relationship is explained below with information concerning the gene BAX.

As reported in an article in Molecular Psychiatry, August 2004, factors believed to lead to the development of Bipolar Disorder include improper or incomplete signaling cascades within the cell, and loss of cellular plasticity and cellular hardiness in neurons[14]. Based on the information reported in OMIM, it seems logical that JUN would be a genetic factor for Bipolar Disorder when also considering the information from Molecular Psychiatry. In another study, conducted by Synyal and colleagues, a drosophila model synapse was used to demonstrate that AP1 functions to positively regulate (increase) synaptic strength and synapse number[15]. Greater synaptic strength should mean stronger signaling between cells. Greater cellular signaling, when considering the information above, would seemingly benefit those suffering from brain disorders such as Bipolar disorder.

Since Apigenin is known to positively regulate expression of JUN, it would induce strengthening of the synapse as described above, to alleviate the symptoms experienced by those with Bipolar Disorder.

In addition to Apigenin, the chemical 6-Pentadecenylsalicylic-Acid, found in Ginkgo Biloba, also enhances the expression of JUN[16].

The research done at AlphaGenics Inc. examined the health benefits of Gingko Biloba in the context of how specific Ginkgo phytochemicals influence the activity of different genes. By identifying the phytochemical-gene connection documented in the scientific literature, AlphaGenics was able to link what a gene does to claimed benefits of Ginkgo. The findings provide preliminary genetic validation for Ginkgo Biloba benefits that are historically described. Using computer data search methods, AlphaGenics has come to reasonable explanations about how the remarkable effects of Ginkgo Biloba work at the level of the human genome. All areas of thought and theory were included; folklore, centuries old medical documents, home remedies, medical research and reports from the last 100 years, and genetic information discovered only recently. All of this was combined and analyzed to provide new insights into how Ginkgo Biloba works.

[1] Dantz et al. “Vascular endothelial growth factor: a novel endocrine defensive response to hypoglycemia.” Journal of Clin. Endocr. Metab. 87: 835-840. 2002.

[2] Jin et al. “Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo.” Pro. Nat. Acad. Sci. 99: 11946-11950. 2002.

[3] Cao L et al. “VEGF links hippocampal activity with neurogenesis, learning and memory.” Nat. Genet. August 2004. 36(8): 827-835.

[4] Qui Y et al. “Inhibitory effect of extracts of Ginkgo biloba leaves on VEGF-induced hyperpermeability of bovine coronary endothelial cells in vitro.”Acta. Pharmacol. Sin. October 2004: 25(10): 1306-1311.

[5] Juarez CP. “Experimental retinopathy of prematurity: angiostatic inhibition by nimodipine, ginkgo-biloba, and dipyridamole, and response to different growth factors.” Eur J Ophthalmol. 2000 January-March: 10(1): 51-9.

[6] Zheng SX et al. “Bilobalide promotes expression of glial cell line-derived neurotrophic factor and vascular endothelial growth factor in rat astrocytes.” Acta Pharmacol Sin. February 2000: 21(2): 151-155.

[7] Zhou LJ et al. “Reactive oxygen species-induced apoptosis in PC12 cells and protective effect of bilobalide.” J Pharmacol Exp Ther. 2000 Jun; 293(3):982-8.

[8] Chong et al, 2000.

[9] Kiester, Edward, Jr. “Now We can See- Depressed Brains are Biologically Different.” PittMed. October 2000; 22-27.

[10] McManamy, John. “Forget the Neurotransmitters.” http://www.mcmanweb.com/article-191.htm. 14 September 2004.

[11] Marx, J. L. “'Jun' is bustin' out all over.” Science. 242: 1377-1378, 1988

[12] Frigo DE et al. “Flavonoid phytochemicals regulate activator protein-1 signal transduction pathways in endometrial and kidney stable cell lines.” J Nutr. 2002 Jul; 132(7):1848-53.

[13] Mark et al, 1988

[14] Quiroz JA et al. Molecular Psychiatry. 2004 Aug; 9(8): 756-76.

[15] Synyal et al. 2002

[16] Wu K, Zhao et al. “c-Jun N-terminal kinase is required for vitamin E succinate-induced apoptosis in human gastric cancer cells.” World J Gastroenterol. 2004 Apr 15; 10(8):1110-4.