Ginkgo biloba

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Nonvitamin and Nonmineral Nutritional Supplements. https://doi.org/10.1016/B978-0-12-812491-8.00035-7
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Ginkgo biloba
Tarun Belwal, Lalit Giri, Amit Bahukhandi, Mohd. Tariq, Pushpa Kewlani, Indra D. Bhatt and Ranbeer S. Rawal
Centre for Biodiversity Conservation and Management, G.B. Pant National Institute of Himalayan Environment and Sustainable Development
(GBPNIHESD), Kosi-Katarmal, Almora, India
INTRODUCTION
Herbal medicines have been used for over 1000years and they are one of the most promising sources of new medicines.
One of these sources of newly emerging herbal medicines is Ginkgo biloba L., (of the Ginkgoaceae family; English name,
maidenhair tree), a living fossil which has amazed scientists all over the world with its immense source of bioactive compounds
and medicinal importance. The species is largely used in the treatment of central nervous system (CNS) disorders, such as
Alzheimer’s disease and cognitive deficits (Chan etal., 2007). The common name Ginkgo is a phonetic pronunciation of
a Japanese name for the tree, while the species name “biloba” refers to the two distinct lobes, typical of the tree's leaves
(Fig.3.19.1). Ginkgo is a unique plant due to its distinctive classification in the plant kingdom, one of the oldest seed plants it
is regarded as a “living fossil” (Mohanta etal., 2012). The Ginkgo tree flourished 150 million years ago during the Mesozoic
era. It reached its greatest development during the Jurassic and Cretaceous periods (Kushwaha etal., 2014; Salvador, 1995).
The Ginkgo tree is now cultivated extensively in Asia, Europe, North America, New Zealand, and Argentina (Huh and
Staba, 1992). This tree has a long history of use in medicine by the Chinese, some 2000years (Singh etal., 2008). Ginkgo
leaf extracts are widely used in herbal medicinal products, food and dietary supplements, and botanical and complimentary
medicines. A variety of bioactive compounds such as terpenoids (e.g., ginkgolides, bilobalide), flavonoids (e.g., kaempferol,
quercetin, isorhamnetin), biflavonoids (e.g., sciadopitysin, ginkgetin, isoginkgetin), and organic acids (e.g., ginkgolic acid),
among others, broaden its use in different biological systems (Chan etal., 2007). As such, the standard extract of G. biloba
leaves (EGb 761) is widely used for treating neurological and cardiovascular disorders (Singh etal., 2008; Vellas etal., 2012)
and thus is positioned as one of the most traded medicinal plants (van Beek, 2002; Nakanishi, 2005).
This chapter highlights the distribution of G. biloba, its trade and trends, classes of bioactive compounds, biological
effects and possible molecular mechanisms, toxicity, and interactions with other drugs and food supplements.
GEOGRAPHICAL DISTRIBUTION
The G. biloba tree, which is native to China, Japan, and Korea, is distributed through cultivation in many parts of Europe,
America, and the temperate regions of New Zealand, Argentina, and India (Table3.19.1; Fig.3.19.2). The last wild tree of
G. biloba is reported in Zhejiang Province, China at an elevation of 1506 m a.s.l. (Singh etal., 2008). The wild populations
of G. biloba have only few remaining trees, which place it in the endangered category according to the International Union
for Conservation of Nature and Natural Resources (Endangered B1+2c ver 2.3. Year Published: 1998).
BIOACTIVE COMPOUNDS
The major bioactive compounds of Ginkgo are reported to be terpenoids, flavonoids, biflavonoids, organic acids, polyprenols,
and many others (Table3.19.2). Of these, ginkgolides and bilobalide are the major constituents of G. biloba that exhibit
biological and/or pharmacological activities. Ginkgolides can be classified in five forms (A, B, C, J, and M), all having
the same molecular geometrical skeleton but different numbers and geometric locations of hydroxyl functional groups
(Fig.3.19.3). The flavonoids like quercetin, kaempferol, and isorhamnetin are also the principal flavonoids occurring as
glycoside derivatives in G. biloba (Fig.3.19.3). A standardized leaf extract of G. biloba, known as EGb 761, contains 24%
flavonoid glycosides, 6% terpenoids, 5%–10% organic acids, and other constituents, and are responsible for numerous
health benefits (Chan etal., 2007; Salvador, 1995; Vasseur etal., 1994).
Chapter 3.19

242 PART | III Plant and Algae Extracts
TABLE3.19.1 Native and Non-native Distribution of Ginkgo biloba Across the Globe
Country Map Location State/Region/Province References
Native
China a–j Zhejiang province, Guangxi, Guizhou, Sichuan province,
Hubei, Chongqing, Henan, Shandong, Jiangsu, Fujian
Shen etal. (2005), Sun etal.
(2003), Zhao etal. (2010)
Japan k–o Tsukuba, Ibaraki, Okayama, Tokyo, Fukuoka, Zhao etal. (2010)
Korea p–q Seoul, Incheon Zhao etal. (2010)
Non-native/cultivated
Netherlands 1 Utrecht Zhao etal. (2010)
Austria 2 Vienna University Zhao etal. (2010)
France 3 Montpellier Zhao etal. (2010)
Germany 4 Hannover Zhao etal. (2010)
Italy 5 Padua Zhao etal. (2010)
North America 6–7 Pennsylvania, MA Zhao etal. (2010)
New Zealand 8 — McWhannel (1981)
Argentina 9 — Boelcke (1981)
India 10 Uttarakhand Sati etal. (2013)
FIG.3.19.1 Cultivated Ginkgo biloba tree at the G.B. Pant National Institute of Himalayan Environment and Sustainable Development campus,
Almora, Uttarakhand, India.

Ginkgo biloba Chapter | 3.19 243
THERAPEUTIC EFFECTS
G. biloba has been used in traditional Chinese medicine for many years for the treatment of asthma, bronchitis,
tuberculosis, cognitive dysfunction, stomach pain, etc. (Almeida, 2009) and has been tested and clinically found effective
as a dietary supplement and medication for the improvement of memory, treatment or prevent of Alzheimer's disease and
other neurological disorders, and treatment of cardiovascular disorders through its neuroprotective, immunomodulatory,
antiinflammatory, and antioxidant activities (Herrschaft etal., 2012; Kleijnen and Knipschild, 1992; Kanowski etal., 1997;
Vellas etal., 2012). The molecular mechanism of the bioactive compounds of G. biloba for preventive actions have been
well explored (Fig.3.19.4) and some of these therapeutic effects are discussed in the following text.
TABLE3.19.2 Major Bioactive Components of Ginkgo biloba
Class Plant parts Major chemical constituents
Terpenoids Leaf/root/bark Diterpenes: ginkgolides A, B, C, and J (a)
Root Diterpenes: ginkgolides M (a)
Leaf/bark Sesquiterpene: bilobalide (b)
Leaf/bark Triterpenes: sterols
Flavonoids Leaf Quercetin (c), kaempferol (d), isorhamnetin (e), rutin, luteolin, delphidenon, myricetin
Biflavonoids Leaf Sciadopitysin, ginkgetin, isoginkgetin, amentoflavone, bilobetin, 5’-methoxybilobetin
Organic acids Leaf Benzoic acid derivatives (ginkgolic acid), N-containing acids
Polyprenols Leaf Di-trans-poly-cis-octadecaprenol
Others Leaf Waxes, steroids, 2-hexenal, cardanols, sugars, catechins, proanthocyanidins, phenols,
aliphatic acids, rhamnose
Source: Modified from van Beek, T.A., Bombardelli, E., Morazzoni, P., Peterlongo, F. 1998. Ginkgo biloba L. Fitoterapia 69 (3), 195–244; van Beek, T. A. 2005.
Ginkgolides and bilobalide: their physical, chromatographic and spectroscopic properties. Bioorg. Med. Chem. 13 (17), 5001–5012; DeFeudis, F.V., 1998.
Ginkgo biloba extract (EGb 761): from chemistry to the clinic. Ullstein Medical, Wiesbaden, p. PP400.
FIG.3.19.2 Distribution of Ginkgo biloba showing native and nonnative occurrences across globe (see also Table3.19.1).

244 PART | III Plant and Algae Extracts
Neuroprotective Effect
G. biloba extract prevents neurological damage and it is one of the most popular dietary supplements reported for enhancing
memory (Ahlemeyer and Krieglstein, 2003a,b; Fitzpatrick etal., 2006; Santos-Neto etal., 2006; Ramassamy, 2006). The leaf
extract EGb 761 has been reported to be effective against Alzheimer's at a dose of 240mg/kg/day (Ahlemeyer and Krieglstein,
2003b; Kleijnen and Knipscheld, 1992), which may be due to its antioxidant effect inhibiting Aβ-induced toxicity and cell
death (Bastianetto and Quirion, 2002; Christen, 2000; Ponto and Schuitz, 2003). G. biloba leaf extract was found effective
in reducing the behavioral deficit when tested against 6-hydroxydopamine-induced neurotoxicity in rats (Kim etal., 2004).
The isolated compound sesquiterpene bilobalide at a dose of 3 and 6 mg/kg/day and EGb 761 at 25, 50, and 100 mg/kg/
day, exert effect against gerbil global brain ischemia when administered orally for 7weeks in rats (Chandrasekaran etal.,
2002). The underlying mechanism for the neuroprotective effect was highlighted by CA1 neuron protection from death
and downregulation of COX III mRNA encoded by mitochondrial DNA. The neuroprotective, as well as neurorestorative,
effects of G. biloba extract were also studied in mice (Wu and Zhu, 1999). EGb 761 when administered at 20, 50, and
100 mg/kg per/day intraperitoneal (i.p) for 7days before or after MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine)
treatment, protected nigrostriatal dopaminergic neurotoxicity along with a reduction in monoamine oxidase (MAO) activity
in the brains of mice, suggesting one possible mechanism for the neuroprotective activity of G. biloba. Similarly, the
isolated polysaccharides from G. biloba leaf extract were found to be effective against ischemia/reperfusion (I/R) injury in
rat brains (Yang etal., 2013). Administration of a G. biloba supplement 7days before I/R injury resulted in improvement in
neurological deficits by a reduction in MDA content and proinflammatory cytokinins (TNF-α and IL-1β), while increased
levels of antiinflammatory cytokinin (IL-10), superoxide dismutase (SOD) and myeloperoxidase (MPO) activity have also
been recorded.
FIG.3.19.3 Chemical structures of the major bioactive compounds founds in Ginkgo biloba: (A) ginkgolide; (B) bilobalide; (C) quercetin; (D)
kaempferol; (E) isorhamnetin. Source: From Chan, P.C., Xia, Q., Fu, P.P. 2007. Ginkgo biloba leave extract: biological, medicinal, and toxicological
effects. J. Environ. Sci. Health C 25(3), 211–244.

Ginkgo biloba Chapter | 3.19 245
G. biloba exerts its neuroprotective effect when coadministered with bone marrow derived mesenchymal stem cells (BMSCs)
in an experimental autoimmune encephalomyelitis (EAE) rat model by inhibiting the secretion of proinflammatory cytokinins,
demyelination, and protecting axons and neurons (Hao etal., 2016). G. biloba has been widely consumed to improve memory
and learning power. As such, at 100mg/kg/day, orally administered G. biloba leaf extract, consumed for 4–8 weeks in mice,
resulted in improved memory and learning during appetitive operant conditioning (Winter, 1991). In addition, a 40 mg/kg i.d
dose for 1–3weeks was found to enhance learning in young and aging mice (Cohen-Salmon etal., 1997). The flavonoids and
bilobalide from G. biloba extract showed antioxidant and antiaging properties and exerted its action by scavenging free radicals
and activating antioxidant enzymes (superoxide dismutase, SOD; catalase, CAT; glutathione peroxidase, GPx), which protect
against tissue injuries (Kim etal., 1997).
Antiinflammatory Effect
The antiinflammatory effect of G. biloba extract has been recorded with downregulation of nitric oxide (NO) and PGE2
production along with mRNA expression of iNOS and COX-2 enzymes and proinflammatory cytokinins (IL-1β, IL-6,
and TNF-α) and upregulation of NF-kB factor (Mir and Albaradie, 2015). The effect of G. biloba leaf extract on the
chronic inflammatory condition found in the colons of mice showed that the extract effectively suppresses the activation
of macrophages and downregulates inflammation (iNOS, COX-2, and TNF-α) and inflammatory stress markers (p53
and p53-phospho-serine 15). Also the numbers of T cells (CD4+/CD25−/FOXp3) were reduced during this treatment
(Kotakadi etal., 2008). In a similar study, G. biloba extract was found to be effective in helping rats recover from colitis by
significantly reducing macroscopic and histological damage, elevating the activity of antioxidant enzymes, and reducing
MDA content (Zhou etal., 2006). This colon tissue was also examined for inflammatory markers and revealed that G.
biloba extract inhibited mRNA expression of TNF-α, NF-kBp65, and IL-6. Upregulation of antiinflammatory markers
(IL-10 and IL-20R) in an atherosclerosis rat model was also recorded with administration of 100 mg/kg per/day of G.
biloba leaf extract for 8weeks along with a downregulation of the mRNA expression of IL-1β and TNF-α in comparison
to a control group (Pietri etal., 1997).
FIG.3.19.4 Molecular mechanism underling different therapeutic effects of Ginkgo biloba. Aβ, Amyloid beta; AST, aminotransferase; BCl-2,
B-cell lymphoma 2; CAT, catalase; COX III, cyclooxygenase 3; CYP19, aromatase gene; ERK, extracellular signal-regulated kinases; GPx, glutathione
peroxidase; GSH, glutathione; Il-1β, interleukin 1 beta; Il-10, interleukin 10; Il-20R, interleukin 20R; iNOS, nitric oxide synthase; KSR1, kinase suppressor
of Ras 1; LDH, lactate dehydrogenase; LPK, L-pyruvate kinase; LPO, lipid hydroperoxide; MAO, monoamino oxidase; MAPK, mitogen-activated protein
kinase; MDA, malondialdehyde; MPO, myeloperoxidase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NO, nitric oxide; p53, tumor protein p53;
PGE2, prostaglandin E2; SOD, superoxide dismutase; TNF-α, tumor necrosis factor α.

246 PART | III Plant and Algae Extracts
Cardioprotective Effect
G. biloba extract was found to improve blood flow, prevent hypoxia and platelet aggregation, improve blood rheology,
and reduce capillary permeability through the release of NO and prostaglandins (DeFeudis, 1998; Pietri etal., 1997).
G. biloba leaf extract, terpenoids (ginkgolide A and B), and a terpene-free extract was examined for its cardioprotective
activity on isolated ischemic and reperfused rat hearts. The result revealed that both G. biloba extract and isolated
terpenoids delayed the onset of contracture during ischemia and postischemia and improved functional recovery
(Liebgott etal., 2000). G. biloba extract also showed cardioprotective activity on a cardiac necrosis model of rats. A
G. biloba phytosome (GBP) formulation was administered orally for 21days at 100 and 200 mg/kg per day which
significantly reduced the level of marker enzymes (AST, LDH, LPK, and lipid peroxidase) and increased GSH, SOD,
CAT, GPx, and GR antioxidant enzymes, as well as playing a preventive role against myocardial necrosis (Panda and
Naik, 2008). Hyperglycemia is a key initiating factor in diabetes-associated diseases. Diabetic cardiomyopathy is
one factor which is induced by diabetic oxidative stress resulting in an opening of MPTP, leading to disfunctioning
myocardium. G. biloba extract attenuates the oxidative stress and improves antioxidant enzyme levels, acting as a
blocker of MPTP in animal models. When coadministered with atractyloside (an mPTP opener), the preventive effect
is reversed (Saini etal., 2014).
Anticancer Activity
The antitumogenic effect of EGb 761 using an invitro cell model and an invivo xenograft model has been investigated
(Park etal., 2016) and the extract was found effective as an antitumor agent by inhibiting aromatase activity in MCF-7
cells. In addition, CYP19 mRNA and CYP19 promoter 1.3 and PII expression was decreased in the treated cell model.
In an invivo experiment, aromatase overexpressing MCF-7 cells were implanted in BALB/c nude mice and given oral
EGb 761 treatment for 3weeks. Their tumor sizes were found to significantly decrease along with the downregulation
of CYP19 mRNA expression. G. biloba extract was also found effective at preventing gastric cancer cell proliferation
and at inducing apoptosis with a significant increase in caspase 3 and P53 and a decrease in antiapoptotic Bcl-2 levels
(Bai etal., 2015). It has been well documented that the kinase suppressor of Ras1 (KSR1) is responsible for activation
of oncogenic mitogen activated protein kinase (MAPK) and the extracellular signal-related kinase (ERK) signaling
pathway, which contributes to the tumerogenesis and chemoresistance of human gastric cells (Roberts and Der, 2007).
EGb 761 was found to be effective at increasing the sensitivity of chemotherapy and reversing chemoresistance
by inhibiting the KSR1-mediated ERK1/2 pathway (Liu etal., 2015). G. biloba flavanoid compound, kaempferol,
was also tested for cell proliferative and apoptosis activity against pancreatic cancer cells. This flavonoid, at 70 μM
concentration for 4days, was found to significantly inhibit the proliferation of cancer cells. When coadministered
with the anticancer drug, 5-fluorouracil, a synergistic effect was recorded with increased apoptic cell concentrations.
The role of NO in cancer cell proliferation is also downregulated because of alteration of the NO synthase enzyme
expression by G. biloba extract (DeFeudis etal., 2003).
G. biloba also overcomes the toxic side effects of anticancer drugs. As such, when G. biloba extract is coadministered
with cisplatin (an anticancer drug), no significant auditory brainstem response (ABR) threshold shift is recorded. Similarly,
endocochlear potentials (EPs) decreased less than 20% for G. biloba coadministration compared to 50% using cisplatin
alone. Hair cells in both groups remained intact in rats treated with G. biloba extract in combination with cisplatin as
compared to hair loss in rats treated with cisplatin alone (Huang etal., 2007).
Other Effects
Ginkgo has also been used to treat brain function impairment and inner ear disorders such as hearing loss, vertigo, and
tinnitus (Hilton and Stuart, 2004; Salvador, 1995). Diabetic cataracts are one of the earliest secondary complications
of diabetes, eventually leading to loss of vision. The pharmacological effects of G. biloba extract (EGb 761) for
prevention of diabetic-induced cataract conditions in rat lenses, cultured in high-glucose conditions, have been
reported (Lu et al., 2014; Pollreisz and Schmidt–Erfurth, 2010). EGb 761 was found effective in the prevention
of pathological changes of high glucose–induced lens epithelial cells and ameliorated lens opacity with decreased
intensity of oxidative stress, aldose reductase activation, and levels of advanced glycosylation end products. It also
was found to suppress transforming growth factor β2 or Smad pathway activation, increase E-cadherin, and decreases
α smooth muscle actin expression, all of which makes G. biloba an potential drug candidate for the prevention of
diabetes-induced cataracts.

Ginkgo biloba Chapter | 3.19 247
INTERACTIONS AND TOXICITY
G. biloba extract was found to increased bleeding and coagulation time (Kohler etal., 2004) and when coadministered with
antiplatelet and anticoagulant drugs the antiplatelet activity was found to increase (Bent, 2008; Koch, 2005; Ryu etal.,
2009). Interaction of G. biloba extract with drug-metabolizing enzymes has been well explored. As such, nicardipine (a
calcium channel blocker), an antihypertensive drug when coadministered with EGb 761, causes a decrease in the rate of
drug metabolism due to an inhibition of CYP3A which decreases the hypotensive action of nicardipine (Yoshioka etal.,
2004a, b). Similarly, another calcium channel blocker drug, talinolol, which is a substrate drug for PGAP transporter in
humans was found ineffective when coadministered with G. biloba extract (Fan etal., 2009a, b). Clinical studies suggest
that drugs which are commonly metabolized by CYP3A4, that is, diltiazem, midazolam, fexofenadine, valproic acid,
propanol, omeprazole, theophylline, and human immunodeficiency virus (HIV) protease inhibitor, when coadministered
with G. biloba extract have their bioavailability affected with concurrent effects (Deng etal., 2008; Numa etal., 2007;
Ohnishi etal., 2003; Robertson etal., 2008; Tang etal., 2007; Yin etal., 2004; Zhao etal., 2006). Interaction between CYP
and G. biloba results in molecular changes. As such, in a study by Yeung etal. (2008), rat hepatocytes culture cells when
treated with G. biloba extract, had their mRNA expression of the CYP3A23 gene upregulated. This is a target gene for the
rat pregnane X receptor (transcription factor, role in drug metabolism, and transport). Similarly, ginkgolides A and B and
flavonoids activated the pregnane X receptor and resulted in a change in the activity of hepatic drug–metabolizing enzymes
(Li etal., 2009). Also, the pregnane X receptor, which constitutes androstane and aryl hydrocarbon receptors, activated
by ginkgolides A and B and flavonoids, resulted in change in the activity of hepatic drug–metabolizing enzymes and
transporters (Li etal., 2009). All this clinical evidence shows that drugs which are metabolized mainly by CYP enzymes
need to be avoided or taken with precaution along with G. biloba extract. However, no side effects have been seen when
G. biloba leaf extract is administered alone for 1–3months at a dose of 120–160 mg/day (Kleijnen and Knipschild, 1992).
In a similar study, when Ginkgo extract was administered at 120 mg/day for 52weeks, gastrointestinal complications were
reported (Le Bars etal., 2007). 4-O-methylpyridoxin (ginkgotoxin), a toxic chemical compound found in G. biloba leaf
extract was reported to interfere with pyridoxine (vitamin B6) metabolism, leading to neurotoxicity, seizures, and loss of
consciousness (Arenz etal., 1996). According to a recent study by the National Institute of Health, under the National
Toxicology Program, G. biloba leaf extract exerts potential toxic and cancer-related consequences such as lesions including
hypertrophy in the liver and thyroid gland, liver hyperplasia, hyperkeratosis, and stomach ulcers (Rider etal., 2014).
TRENDS IN TRADE
Trends in using plant-based products are shifting back to their roots with over 20% of the population using herbal cosmetics,
dietary supplements, and medicines (Bent, 2008). In this context, the medicinal properties of G. biloba have attracted a global
market for its potential applications in health, food, and supplements. The leaf extract of Ginkgo contains pharmaceutically
imperative flavonoids, glycosides, and ginkgolides along with other bioactive compounds which have wider applications
(Table3.19.3). The standard leaf extract of Ginkgo biloba is EGb 761, which is one of the most commonly used herbal
dietary remedies in many countries, including China, the United States, France, and Germany. EGb 761, also called Tebonin,
Tanakan, Rokan, or Kaveri, is marketed in Europe as a medicine for cardiovascular disease. In the United States, Nature's
Way, Inc., USA has exclusive distribution rights for EGb 761 and markets this product as a dietary supplement under the
trade name Ginkgold (Huh and Staba, 1992; Salvador, 1995). The use of G. biloba has been growing at a very rapid rate in
the open world's commercial markets and some of them are mentioned in Table3.19.3.
CONCLUSIONS
The use of plant-based food and dietary supplements, botanicals and complementary medicine, cosmetics, and other
products are gaining popularity all across the globe. G. biloba, considered by some as a living fossil, plays a role in the three
“cals,” that is, cosmeceuticals, nutraceuticals, and pharmaceuticals (CNP). The reported uses and therapeutic potential of
this tree positions it at a “wonder tree with multifarious uses.” The presence of ginkgolides and other bioactive contents
in the tree, particularly its leaves, has shown its effectiveness in neuroprotection, cardioprotection, and cancer protection;
however, its long-term use and side effects are yet to be investigated. Therefore, knowledge of the long-term use of these
bioactives, particularly ginkgolides, will be useful in understanding its mechanisms of protection and side effects, if any
exist. Since the number of Alzheimer's patients is increasing along with patients with other brain-related problems, the use
of G. biloba to overcome these health-related problems will be very useful. However, its availability in the wild is negligible
and only commercially planted trees are available. In such circumstances, it is important to reintroduce the species in its
natural habitat so that conservation of this species can be ensured together with its beneficial utilization.

248 PART | III Plant and Algae Extracts
REFERENCES
Ahlemeyer, B., Krieglstein, J., 2003a. Neuroprotective effects of Ginkgo biloba extract. Cell. Mol. Life Sci. 60 (9), 1779–1792.
Ahlemeyer, B., Krieglstein, J., 2003b. Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer’s disease.
Pharmacopsychiatry 36 (S1), 8–14.
Almeida, E.R., 2009. Plantas adaptógenas e com ação no sistema nervoso central. Biblioteca, São Paulo. 24.
Arenz, A., Klein, M., Fiehe, K., Groß, J., Drewke, C., Hemscheidt, T., Leistner, E., 1996. Occurrence of neurotoxic 4′-O-methylpyridoxine in Ginkgo
biloba leaves, Ginkgo medications and Japanese Ginkgo food. Planta Med. 62 (6), 548–551.
Bai, Y., Zhao, F., Li, Y., Wang, L., Fang, X.J., Wang, C.Y., 2015. Ginkgo biloba extract induce cell apoptosis and G0/G1 cycle arrest in gastric cancer cells.
Int. J. Clin. Exp. Med. 8 (11), 20977–20982.
Bastianetto, S., Quirion, R., 2002. EGb 761 is a neuroprotective agent against beta-amyloid toxicity. Cell. Mol. Biol. 48 (6), 693–697.
Bent, S., 2008. Herbal medicine in the United States: review of efficacy, safety, and regulation. J. Gen. Intern. Med. 23 (6), 854–859.
Boelcke, O. 1981. Plantus vasculares de la Argentina. Nativus y Exoticas Editorial Hemisferio Sur S.A., pp. 28–29.
TABLE3.19.3 List of Commercially Available Ginkgo biloba Products
Product name Manufacture Uses
Approximate
price ($)
Zenith Nutrition Ginkgo biloba 60 mg Zenith Nutrition Pvt. Ltd., India Improving blood circulation 7.32
Vista Nutritions Ginkgo biloba 60 mg Vista Nutrition's Pvt. Ltd., India Improving memory and mental
alertness
6.57
NUTRILITE Siberian Ginseng with Ginkgo
Biloba (500 gm)
Amway, USA Endurance and mental
sharpness
34.63
Doctor's Best, Extra Strength Ginkgo,
120 mg
Doctor's Best Inc., USA Promote mental function and
alertness
21.22
Goicoechea Lotion, Gingkobiloba, 13.5
Fluid Ounce
Goicoechea, Argentina Nourishing and refreshing skin 52.42
Antioxidant Vitamin C Creme with
Gingkobiloba
Pree Cosmetics Inc., USA Neutralize free radicals, skin
moisture
61.12
Nature Made Ginkgo biloba 30 mg Nature Made Inc., USA Herbal supplement 127.95
Nature's Way, Ginkgold Eyes, 60 Tablets Nature's WayInc., USA Improving visual Function and
optimal night vision
35.04
Solgar, Bilberry Ginkgo Eyebright Complex
Plus Lutein, 60 Veggie Caps
Solgar Inc., USA Eye health, antioxidant support 23.32
Nature's bounty Ginkgo biloba 120 mg
100 capsules
Nature's Bounty Inc., USA Supports healthy brain
functions and circulation
33.68
Healthvit Ginkgo biloba (60 mg), capsule Healthvit Ltd., India Promote healthy brain function,
supports sharpened alertness
11.43
Forever ginkgo plus 60 tablets Forever Living Inc., USA Helps support circulation,
energy level booster
19.15
Puritans Pride Ginkgobiloba 120 mg-100
Capsules
Puritans Pride Inc., USA Supports healthy brain
functioning
24.64
Ginkgo biloba powder (100 g) Raw Living Ltd., England Reduces the stickiness of
platelets
6.10
Qi Teas Organic Fairtrade Green Tea with
Ginkgo
Holland and Barrett Retail Ltd.,
UK
Helps in uplifting of body and
mind
2.45
Tebonin Egb 761 Dr. Schwabe, Germany Symptomatic relief and
management of Tinnitus and
Vertigo
40.69
Source: amazon.in, amazon.com, iherb.com, healthcart.com.

Ginkgo biloba Chapter | 3.19 249
Chan, P.C., Xia, Q., Fu, P.P., 2007. Ginkgo biloba leave extract: biological, medicinal, and toxicological effects. J. Environ. Sci. Health C 25 (3), 211–244.
Chandrasekaran, K., Mehrabian, Z., Spinnewyn, B., Chinopoulos, C., Drieu, K., Fiskum, G., 2002. Bilobalide, a component of the Ginkgo biloba extract
(EGb 761), protects against neuronal death in global brain ischemia and in glutamate-induced excitotoxicity. Cell. Mol. Biol. 48 (6), 663–669.
Christen, Y., 2000. Oxidative stress and Alzheimer disease. Am. J. Clin. Nutr. 71 (2), 621s–629s.
Cohen-Salmon, C., Venault, P., Martin, B., Raffalli-Sebille, M.J., Barkats, M., Clostre, F., Pardon, M.C., Christen, Y., Chapouthier, G., 1997. Effects of
Ginkgo biloba extract (EGb 761) on learning and possible actions on aging. J. Physiol. 91 (6), 291–300.
DeFeudis, F.V., 1998. Ginkgo biloba Extract (EGb 761): from Chemistry to the Clinic. Ullstein Medical, Wiesbaden. PP400.
DeFeudis, F.V., Papadopoulos, V., Drieu, K., 2003. Ginkgo biloba extracts and cancer: a research area in its infancy. Fundam. Clin. Pharmacol. 17 (4), 405–417.
Deng, Y., Bi, H.C., Zhao, L.Z., He, F., Liu, Y.Q., Yu, J.J., Ou, Z.M., Ding, L., Chen, X., Huang, Z.Y., Huang, M., 2008. Induction of cytochrome P450s by
terpene trilactones and flavonoids of the Ginkgo biloba extract EGb 761 in rats. Xenobiotica 38 (5), 465–481.
Fan, L., Mao, X.Q., Tao, G.Y., Wang, G., Jiang, F., Chen, Y., Li, Q., Zhang, W., Lei, H.P., Hu, D.L., Huang, Y.F., 2009a. Effect of Schisandra chinensis
extract and Ginkgo biloba extract on the pharmacokinetics of talinolol in healthy volunteers. Xenobiotica 39 (3), 249–254.
Fan, L., Tao, G.Y., Wang, G., Chen, Y., Zhang, W., He, Y.J., Li, Q., Lei, H.P., Jiang, F., Hu, D.L., Huang, Y.F., 2009b. Effects of Ginkgo biloba extract
ingestion on the pharmacokinetics of talinolol in healthy Chinese volunteers. Ann. Pharmacother. 43 (5), 944–949.
Fitzpatrick, A.L., Fried, L.P., Williamson, J., Crowley, P., Posey, D., Kwong, L., Furberg, C.D., 2006. Recruitment of the elderly into a pharmacologic
prevention trial: the Ginkgo Evaluation of Memory Study experience. Contemp. Clin. Trials 27 (6), 541–553.
Hao, F., Li, A., Yu, H., Liu, M., Wang, Y., Liu, J., Liang, Z., 2016. Enhanced neuroprotective effects of combination therapy with bone marrow-derived mesenchymal
stem cells and Ginkgo biloba extract (EGb 761) in a rat model of experimental autoimmune encephalomyelitis. Neuroimmunomodulation 23, 41–57.
Herrschaft, H., Nacu, A., Likhachev, S., Sholomov, I., Hoerr, R., Schlaefke, S., 2012. Ginkgo biloba extract EGb 761® in dementia with neuropsychiatric
features: a randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J. Psychiatr. Res. 46 (6), 716–723.
Hilton, M.P., Stuart, E.L., 2004. Ginkgo biloba for Tinnitus. Cochrane Database Syst. Rev. 2, CD003852.
Huang, X., Whitworth, C.A., Rybak, L., 2007. Ginkgo biloba extract (EGb 761) protects against cisplatin-induced toxicity in rats. Otol. Neurotol. 28 (6), 828–833.
Huh, H., Staba, E.J., 1992. The botany and chemistry of Ginkgo biloba L. J. Herbs Spices Med. Plants 1 (1–2), 91–124.
Kanowski, S., Herrmann, W.M., Stephan, K., Wierich, W., Hörr, R., 1997. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients
suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Phytomedicine 4 (1), 3–13.
Kim, M.S., Lee, J.I., Lee, W.Y., Kim, S.E., 2004. Neuroprotective effect of Ginkgo biloba L. extract in a rat model of Parkinson’s disease. Phytother. Res.
18 (8), 663–666.
Kim, S.J., Lim, M.H., Chun, I.K., Won, Y.H., 1997. Effects of flavonoids of Ginkgo biloba on proliferation of human skin fibroblast. Skin Pharmacol.
Physiol. 10 (4), 200–205.
Kleijnen, J., Knipschild, P., 1992. Ginkgo biloba for cerebral insufficiency. Br. J. Clin. Pharmacol. 34 (4), 352–358.
Koch, E., 2005. Inhibition of platelet activating factor (PAF)-induced aggregation of human thrombocytes by ginkgolides: considerations on possible
bleeding complications after oral intake of Ginkgo biloba extracts. Phytomedicine 12 (1), 10–16.
Kohler, S., Funk, P., Kieser, M., 2004. Influence of a 7-day treatment with Ginkgo biloba special extract EGb761 on bleeding time and coagulation:
randomized, placebo-controlled, double-blind study in healthy volunteers. Blood Coagul. Fibrinolysis 15 (4), 303–309.
Kotakadi, V.S., Jin, Y., Hofseth, A.B., Ying, L., Cui, X., Volate, S., Chumanevich, A., Wood, P.A., Price, R.L., McNeal, A., Singh, U.P., 2008. Ginkgo biloba
extract EGb 761 has anti-inflammatory properties and ameliorates colitis in mice by driving effector T cell apoptosis. Carcinogenesis 29 (9), 1799–1806.
Kushwaha, S.K., Sharma, C.S., Singh, H.P., Ankalgi, A., Ranawat, M.S., Mehtab, R., 2014. Ginkgo biloba a source of bioactive natural products: a review.
Indo Am. J. Pharmaceut. Res. 4 (12), 5622–5629.
Le Bars, P.L., Katz, M.M., Berman, N., Itil, T.M., Freedman, A.M., Schatzberg, A.F., 2007. A placebo-controlled, double-blind, randomized trial of an
extract of Ginkgo biloba for dementia. JAMA 278 (16), 1327–1332.
Li, L., Stanton, J.D., Tolson, A.H., Luo, Y., Wang, H., 2009. Bioactive terpenoids and flavonoids from Ginkgo biloba extract induce the expression of
hepatic drug-metabolizing enzymes through pregnane X receptor, constitutive androstane receptor, and aryl hydrocarbon receptor-mediated pathways.
Pharmaceut. Res. 26 (4), 872.
Liebgott, T., Miollan, M., Berchadsky, Y., Drieu, K., Culcasi, M., Pietri, S., 2000. Complementary cardioprotective effects of flavonoid metabolites and
terpenoid constituents of Ginkgo biloba extract (EGb 761) during ischemia and reperfusion. Basic Res. Cardiol. 95 (5), 368–377.
Liu, S.Q., Xu, C.Y., Qin, M.B., Tan, L., Zhuge, C.F., Mao, Y.B., Lai, M.Y., Huang, J.A., 2015. Ginkgo biloba extract enhances chemotherapy sensitivity
and reverses chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells. Oncol. Rep. 33 (6), 2871–2882.
Lu, Q., Yang, T., Zhang, M., Du, L., Liu, L., Zhang, N., Guo, H., Zhang, F., Hu, G., Yin, X., 2014. Preventative effects of Ginkgo biloba extract (EGb 761)
on high glucose-cultured opacity of rat lens. Phytother. Res. 28 (5), 767–773.
McWhannel, R., 1981. Ginkgo fruiting in New Zealand. Garden (London) 106, 517.
Mir, M.A., Albaradie, R.S., 2015. Immunomodulation of inflammatory markers in activated macrophages by leaf extracts of Gingko biloba. Adv.
Neuroimmune Biol. 6 (1), 9–17.
Mohanta, T.K., Occhipinti, A., Zebelo, S.A., Foti, M., Fliegmann, J., Bossi, S., Maffei, M.E., Bertea, C.M., 2012. Ginkgo biloba responds to herbivory by
activating early signaling and direct defenses. PLoS One 7 (3), e32822.
Nakanishi, K., 2005. Terpene trilactones from Gingko biloba: from ancient times to the 21st century. Bioorg. Med. Chem. 13 (17), 4987–5000.
Numa, A.M., Abbott, F.S., Chang, T.K., 2007. Effect of Ginkgo biloba extract on oxidative metabolism of valproic acid in hepatic microsomes from
donors with the CYP2C9* 1/* 1 genotype. Can. J. Physiol. Pharmacol. 85 (9), 848–855.
Ohnishi, N., Kusuhara, M., Yoshioka, M., Kuroda, K., Soga, A., Nishikawa, F., Koishi, T., Nakagawa, M., Hori, S., Matsumoto, T., Yamashita, M., 2003.
Studies on interactions between functional foods or dietary supplements and medicines. I. Effects of Ginkgo biloba leaf extract on the pharmacokinetics
of diltiazem in rats. Biol. Pharmaceut. Bull. 26 (9), 1315–1320.

250 PART | III Plant and Algae Extracts
Panda, V.S., Naik, S.R., 2008. Cardioprotective activity of Ginkgo biloba phytosomes in isoproterenol-induced myocardial necrosis in rats: a biochemical
and histoarchitectural evaluation. Exp. Toxicol. Pathol. 60 (4), 397–404.
Park, Y.J., Ahn, H.Y., Kim, H.R., Chung, K.H., Oh, S.M., 2016. Ginkgo biloba extract EGb 761-mediated inhibition of aromatase for the treatment of
hormone-dependent breast cancer. Food Chem. Toxicol. 87, 157–165.
Pietri, S., Maurelli, E., Drieu, K., Culcasi, M., 1997. Cardioprotective and anti-oxidant effects of the terpenoid constituents of Ginkgo biloba extract (EGb
761). J. Mol. Cell. Cardiol. 29 (2), 733–742.
Pollreisz, A., Schmidt-Erfurth, U., 2010. Diabetic cataract: athogenesis, epidemiology and treatment. J. Ophthalmol. 2010.
Ponto, L.L.B., Schultz, S.K., 2003. Ginkgo biloba extract: review of CNS effects. Ann. Clin. Psychiatry 15 (2), 109–119.
Ramassamy, C., 2006. Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: a review of their intracellular targets.
Eur. J. Pharmacol. 545 (1), 51–64.
Rider, C.V., Nyska, A., Cora, M.C., Kissling, G.E., Smith, C., Travlos, G.S., Hejtmancik, M.R., Fomby, L.M., Colleton, C.A., Ryan, M.J., Kooistra, L., 2014.
Toxicity and carcinogenicity studies of Ginkgo biloba extract in rat and mouse: liver, thyroid, and nose are targets. Toxicol. Pathol. 42 (5), 830–843.
Roberts, P.J., Der, C.J., 2007. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26, 3291–3310.
Robertson, S.M., Davey, R.T., Voell, J., Formentini, E., Alfaro, R.M., Penzak, S.R., 2008. Effect of Ginkgo biloba extract on lopinavir, midazolam and
fexofenadine pharmacokinetics in healthy subjects. Curr. Med. Res. Opin. 24 (2), 591–599.
Ryu, K.H., Han, H.Y., Lee, S.Y., Jeon, S.D., Im, G.J., Lee, B.Y., Kim, K., Lim, K.M., Chung, J.H., 2009. Ginkgo biloba extract enhances antiplatelet and
antithrombotic effects of cilostazol without prolongation of bleeding time. Thrombosis Res. 124 (3), 328–334.
Saini, A.S., Taliyan, R., Sharma, P.L., 2014. Protective effect and mechanism of Ginkgo biloba extract EGb 761 on STZ-induced diabetic cardiomyopathy
in rats. Pharmacogn. Mag. 10 (38), 172.
Salvador, R.L., 1995. Herbal medicine: Ginkgo. CPJ/RPC 52 (July–August), 39–41.
Santos-Neto, L.L.D., de Vilhena Toledo, M.A., Medeiros-Souza, P., de Souza, G.A., 2006. The use of herbal medicine in Alzheimer’s disease—a
systematic review. Evid. Based Complement. Alternat. Med. 3 (4), 441–445.
Sati, P., Pandey, A., Rawat, S., Rani, A., 2013. Phytochemicals and antioxidant in leaf extracts of Gingko biloba with reference to location, seasonal
variation and solvent system. J. Pharm. Res. 7, 804–809.
Shen, L., Chen, X.Y., Zhang, X., Li, Y.Y., Fu, C.X., Qui, Y.X., 2005. Genetic variation of G. biloba L (Ginkgoaceae) based on cpDNA PCR-RFLPs;
inference of glacial refugia. Heredity 94 (4), 396–401.
Singh, B., Kaur, P., Singh, R.D., Ahuja, P.S., 2008. Biology and chemistry of Ginkgo biloba. Fitoterapia 79 (6), 401–418.
Sun, B., Dilcher, D.L., Beerling, D.J., Zhang, C., Yan, D., Kowalski, E., 2003. Variation in Ginkgo biloba L. leaf characters across a climatic gradient in
China. Proc. Natl. Acad. Sci. 100 (12), 7141–7146.
Tang, J., Sun, J., Zhang, Y., Li, L., Cui, F., He, Z., 2007. Herb–drug interactions: effect of Ginkgo biloba extract on the pharmacokinetics of theophylline
in rats. Food Chem. Toxicol. 45 (12), 2441–2445.
van Beek, T.A., 2002. Chemical analysis of Ginkgo biloba leaves and extracts. J. Chromatogr. A 967 (1), 21–55.
Vasseur, M., Jean, T., Defeudis, F.V., Drieu, K., 1994. Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761), bilobalide and ginkgolide
B on the electrical activity of pancreatic β cells of normal or alloxan-diabetic mice: an exvivo study with intracellular microelectrodes. Gen.
Pharmacol. 25 (1), 31–46.
Vellas, B., Coley, N., Ousset, P.J., Berrut, G., Dartigues, J.F., Dubois, B., Grandjean, H., Pasquier, F., Piette, F., Robert, P., Touchon, J., 2012. Long-term
use of standardized Ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol.
11 (10), 851–859.
Winter, E., 1991. Effects of an extract of Ginkgo biloba on learning and memory in mice. Pharmacol. Biochem. Behav. 38 (1), 109–114.
Wu, W.R., Zhu, X.Z., 1999. Involvement of monoamine oxidase inhibition in neuroprotective and neurorestorative effects of Ginkgo biloba extract against
MPTP-induced nigrostriatal dopaminergic toxicity in C57 mice. Life Sci. 65 (2), 157–164.
Yang, Y., Liu, P., Chen, L., Liu, Z., Zhang, H., Wang, J., Sun, X., Zhong, W., Wang, N., Tian, K., Zhao, J., 2013. Therapeutic effect of Ginkgo biloba
polysaccharide in rats with focal cerebral ischemia/reperfusion (I/R) injury. Carbohydr. Polym. 98 (2), 1383–1388.
Yeung, E.Y., Sueyoshi, T., Negishi, M., Chang, T.K., 2008. Identification of Ginkgo biloba as a novel activator of pregnane X receptor. Drug Metab.
Dispos. 36 (11), 2270–2276.
Yin, O., Tomlinson, B., Waye, M., Chow, A., Chow, M., 2004. Pharmacogenetics and herb–drug interactions: experience with Ginkgo biloba and
omeprazole. Pharmacogenetics 14 (12), 841–850.
Yoshioka, M., Ohnishi, N., Koishi, T., Obata, Y., Nakagawa, M., Matsumoto, T., Tagagi, K., Takara, K., Ohkuni, T., Yokoyama, T., Kuroda, K.,
2004a. Studies on interactions between functional foods or dietary supplements and medicines. IV. Effects of Ginkgo biloba leaf extract on the
pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers. Biol. Pharmaceut. Bull. 27 (12), 2006–2009.
Yoshioka, M., Ohnishi, N., Sone, N., Egami, S., Takara, K., Yokoyama, T., Kuroda, K., 2004b. Studies on interactions between functional foods or dietary
supplements and medicines. III. Effects of Ginkgo biloba leaf extract on the pharmacokinetics of nifedipine in rats. Biol. Pharmaceut. Bull. 27 (12),
2042–2045.
Zhao, L.Z., Huang, M., Chen, J., Rachel Ee, P.L., Chan, E., Duan, W., Guan, Y.Y., Chen, X., Zhou, S., 2006. Induction of propranolol metabolism by
Ginkgo biloba extract EGb 761 in rats. Curr. Drug Metab. 7 (6), 577–587.
Zhou, Y.H., Yu, J.P., Liu, Y.F., Teng, X.J., Ming, M., Lv, P., An, P., Liu, S.Q., Yu, H.G., 2006. Effects of Ginkgo biloba extract on inflammatory mediators
(SOD, MDA, TNF-α, NF-kBp65. IL-6) in TNBS-induced colitis in rats. Mediators Inflamm. 10, 1–9.
Zhao, Y., Paule, J., Fu, C., Koch, M.A., 2010. Out of China: distribution history of Ginkgo biloba L. Taxon 59 (2), 495–504.