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ABSTRACT:
The new age of
nutraceuticals is now
embracing the centuries
old herbal extract of
Ginkgo biloba (Mantissa
Plantarum Altera, 1771,
Ginkgoceae). The
standardized preparation
of the Ginkgo leaf
extract (EGb 761)
contained 2main
bioactive constituents,
flavonoid glycosides
(24%) and terpene
lactones (6%), along
with less than 5 ppm of
the allergenic
component, ginkgolic
acid. The Ginkgo leaf
extract has been
reported to have
neuroprotective,
anticancer,
cardioprotective, stress
alleviating, andmemory
enhancing effects and
possible effects on
tinnitus, geriatric
complaints, and
psychiatric disorders.
The therapeutic
mechanisms of action of
the Ginkgo leaf extract
are suggested to be
through its antioxidant,
antiplatelet,
antihypoxic, antiedemic,
hemorrheologic, and
microcirculatory
actions, where the
flavonoid and the
terpenoid constituents
may act in a
complementary manner.
Toxicity studies show
that the Ginkgo leaf
extract is relatively
safe for consumption,
although a few side
effects have been
reported, that is,
intracerbral hemorrhage,
gastrointestinal
disturbances, headaches,
dizziness, and allergic
skin reactions. The use
of Ginkgo leaf extract
may be promising for
treatment of certain
conditions, although its
long-termuse still needs
to be evaluated.
Keywords: flavonoids,
Ginkgo biloba, Ginkgo
leaf extract,
neuroprotective,
terpenoids.
Introduction
Complementary and
alternative medicine is
defined as a “diagnosis,
treatment and/or
prevention which
complements mainstream
medicine by contributing
to a common whole, by
satisfying a demand not
met by orthodoxy or by
diversifying the
conceptual frameworks of
medicine” (Ernst 2000).
Over the past 15 y,
there has been a steady
growing trend of these
unconventional therapies
throughout the globe.
The European and the
U.S. market alone
contributed to about $7
and $5 billion per
annum, respectively, in
1999 (Calixto 2000).
Until 2000, estimates
showed that nearly 50%
to 75% of the U.S.
population have tried
complementary and
alternative medicine (Neldner
2000). NIH broadly
classifies complementary
and alternativemedicine
into 6 categories;
Mind-Body Interventions,
Bioelectromagnetics
Applications,
Alternative Systems of
Medical Practice, Manual
Healing Methods, Herbal
Medicine, and Diet and
Nutrition
(Wootton 2005). The
category of herbal
medicine has grown
faster than any of the
other forms of
alternative treatment
(Ernst 2002).
Traditional Chinese
medicine is a subsection
of herbal medicine
(Wootton 2005). The 12
most commonly used and
best-studied medicinal
herbs are listed in
O’Hara (1998).
Over the past couple of
decades, the Ginkgo leaf
extract has stepped into
the herbal spotlight
mainly because of its
proven benefits for
treating Alzheimer’s
disease (Bastianetto and
others 2000; Zimmermann
and others 2002; Smith
and Luo 2003; Yao and
others 2004). It also
appears promising as a
therapeutic for many
other chronic and acute
forms of diseases.
Ginkgo leaf extract
topped the list of the 7
best selling herbal
products in 1998 with
retail sales of US $150
million (Izzo and Ernst
2001). Ginkgo biloba:
botanical data Ginkgo
biloba L. (Mantissa
Plantarum Altera, 1771,
Ginkgoceae) belongs to
the botanical family of
Ginkgoceae with synonyms
like Salisburia
adiantifolia, Salisburia
macrophylla, and
Pterophylla
salisburiensis. The
ginkgo tree, known to be
among the oldest living
species on this planet,
has flourished in
forests for over 150
million years and hence
it is called a “living
fossil” (McKenna and
others2001). It is a
dioecious tree with the
male and female
reproductive organs on
separate trees. They
have a large trunk with
a girth of
about 7 m and a height
of about 30 m. Young
trees are conifer like
and exhibit branching
dimorphism. Leaves that
growin clusters are
golden yellowin fall
during senescence. The
leathery leaves are very
uniquely shaped with 2
lobes and resemble the
maidenhair fern in shape
and venation. The
pollination process
involves the male
microstrobilli bearing
loosely distributed
sporangiophores
containing microspores
with male gametophytes
and the female pendulous
pairs of ovules borne on
the shoots. These trees
begin to reproduce after
about 20 y by developing
naked seeds (nuts) with
an outer fleshy layer
(fruits). The outer
fleshy layer of the
fruit has a considerable
amount of butanoic and
hexanoic acids, which
are responsible
for the rotting flesh,
fermented odor (McKenna
and others 2001).
History and traditional
uses of Ginkgo biloba
The ginkgo tree is the
only surviving member of
Ginkgoaceae
family, class of
Ginkgoatae, rediscovered
in Asian graced temple
gardens by Kaempfer in
1670. The class of
Ginkgoatae consists of
approximately 15 genera,
and among these, Ginkgo,
Baiera, and Ginkgoites
are the most important (Bilia
2002). The name ginkgo
comes from the Chinese
words sankyo or yin-kuo,
which means a hill
apricot or silver fruit,
due to their apricot
shaped mature fruits and
yellow color (McKennaand
others 2001). Englbert
Kaempfer, a German
surgeon, first used the
term “Ginkgo” in 1712,
but it was Linnaeus who
termed it Ginkgo biloba
in 1771 (Gertz and
Kiefer 2004). Both the
leaves and the nuts of
this tree have been in
use for the past several
centuries in traditional
Chinese medicine. In
fact, the nuts are known
to have a longer history
of usage, being first
mentioned in herbals in
the Yuan dynasty [1280
to 1368 AD], published
in 1350 AD (Goh and
Barlow 2002). For over
5000 y, the seeds (nuts)
have been known to treat
pulmonary disorders
(like asthma, cough, and
enuresis), alcohol
abuse, and bladder
inflammation while the
leaves have been mainly
used to treat heart and
lung dysfunctions and
skin infections (Mahady
2002; Smith and Luo
2004). However, it was
only in the last 20 to
30 y that the use of the
ginkgo leaf and its
standardized extract
formulation, EGb 761,
originated in Germany,
and now is the most used
form of supplement for
cognitive ailments in
the United States (Smith
and Luo 2004). Other
uses of this tree
include the fruit,
prepared by fermentation
and cooking, being a
delicacy in weddings and
feasts (McKenna and
others 2001; Bilia
2002). The roasted or
boiled ginkgo seeds are
also considered a
gourmet delicacy in
Japan, China, Korea, and
Malaysia. The tree is
also grown in many parts
of Europe and the United
States mainly for its
ornamental value. It
grows well in most
places due to such
properties as pest,
pollution, and disease
resistance (McKenna and
others 2001). Ginkgo
leaf extract Since the
constituent composition
of ginkgo leaf undergoes
fluctuating changes with
respect to their origin,
species, and time of
harvest like any other
plant, it is essential
to standardize the
Ginkgo leaf extract to
obtain consistent
bioactivities. The
culturing, harvesting,
and extraction of the
ginkgo leaves are
rigorously standardized
and controlled based on
its known active
components (Smith and
Luo 2004). Typically,
the leaves are collected
during summer
and fall between the
months of July and
September when they are
still green. These
leaves are then dried
and analyzed for the
presence of pollutants
and toxic substances
like heavy metals and
aflatoxins. The crude
dried leaves are then
extracted using an
acetone: water mixture
(35 to 67:1).
Standardization of
Ginkgo leaf extract can
be done by measuring
flavonoids and
terpenoids (Bilia 2002).
The standardized extract
preparation of the
ginkgo leaf, EGb 761,
developed by
Beaufor-Ipsen Pharma
(Paris, France) and Dr.
Willmar Schwabe
Pharmaceuticals
(Karlsruhe, Germany),
contains 24% flavonoid
glycosides, 6% terpene
lactones, and less than
5 ppm ginkgolic acid
(the constituent
proposed to have
allergenic properties)
(Smith and Luo 2004).
Recently, a new method
to evaluate Ginkgo leaf
extract using HPLC-fingerprinting
has been suggested as a
better method to monitor
various preparation of
the Ginkgo leaf extract
(Sun and Liu 2007).
Active components of
Ginkgo biloba leaf The 2
main pharmacologically
active groups of
compounds present in the
Ginkgo leaf extract are
the flavonoids and the
terpenoids (Smith and
Luo 2004). Flavonoids,
also called
phenylbenzopyrones or
phenylchromones, are a
group of low molecular
weight substances that
are widely spread in the
plant kingdom.
Flavonoids present in
the Ginkgo leaf extract
are flavones, flavonols,
tannins, biflavones (amentoflavone,
bilobetol,
5-methoxybilobetol,
ginkgetin, isoginkgetin
and sciadopitysin), and
associated glycosides of
quercitin and kaempferol
attached to
3-rhamnosides,
3-rutinosides, or p-coumaric
esters (McKenna and
others 2001). The
flavonoid content in the
Ginkgo
leaf is known to vary
between seasons; greater
amounts are found in
fall than in spring
(McKenna and others
2001). These compounds
are known to actmainly
as antioxidants/free
radical scavengers,
enzyme
inhibitors, and cation
chelators (DeFeudis and
Drieu 2000). In general,
the bioavailability of
flavonoids is relatively
low due to limited
absorption and rapid
elimination (Goh and
Barlow 2004). Flavonoids
in the glycosidic form
are poorly absorbed in
the intestine; only in
the aglycone form can
they be absorbed
directly (Goh and Barlow
2004). Unabsorbed
flavonoids that reach
the colon may be subject
to metabolism by
bacterial enzymes, and
then absorbed (DeFeudis
and Drieu 2000). Once
absorbed, flavonoids
reach the liver where
they are metabolized to
conjugated derivatives (DeFeudis
and Drieu 2000). It is
known that the
biological activities of
flavonoidmetabolites are
not always the same as
those of the parent
compound (Manach and
others 2004). Two types
of terpenoids are
present in Ginkgo as
lactones (nonsaponifiable
lipids present as cyclic
esters): ginkgolides and
the bilobalide (Smith
and Luo 2004).
Ginkgolides are
diterpenes with 5 types
A, B, C, J, andM, where
types A, B, and C
account for around 3.1%
of the total Ginkgo leaf
extract (DeFeudis and
Drieu 2000). Bilobalide,
a sesquiterpene
trilactone, accounts for
the remaining 2.9% of
the total standardized
Ginkgo leaf extract
(Smith and Luo 2004).
There are no adequate
studies determining the
dose of Ginkgo extract
needed to achieve
beneficial effects,
although the recommended
dose of standardized
extract, EGb 761, is 40
to 60 mg, 3 to 4 times
daily based on clinical
trials (Mahady 2001).
For chronic conditions
the German commission
recommends a minimum
8-wk intake in order to
observe the beneficial
effects of the Ginkgo
leaf extract (McKenna
and others 2001).
Pharmacological effects
of Ginkgo biloba Ginkgo
leaf extract has shown
beneficial effects in
treating
neurodegenerative
diseases like
Alzheimer’s,
cardiovascular diseases,
cancer, stress, memory
loss, tinnitus,
geriatric complaints
like vertigo,
age-related macular
degeneration, and
psychiatric disorders
like schizophrenia (Ramassamy
and others 2007). These
multifaceted activities
of the Ginkgo leaf
extract may work through
various mechanisms of
action. The suggested
mechanisms of the Ginkgo
leaf extract are its
antioxidant effect,
anti-platelet activating
factor (Anti-PAF)
activity for cardio and
cerebral vascular
diseases, inhibition of
beta amyloid peptide (Aβ)
aggregation to reduce
Alzheimer’s progression,
and decreased expression
of peripheral
benzodiazepine receptor
(PBR) for stress
alleviation and
stimulation of
endothelium derived
relaxing factor to
improve blood
circulation (Amri and
others 1996; Pietri and
others 1997a; DeFeudis
and Drieu 2000; Smith
and Luo 2004).
Antioxidant effects. The
underlying principle
behind the therapeutic
action of the Ginkgo
leaf extract on chronic
ailments (such as
neurodegenerative
diseases, cardiovascular
diseases and cancer) has
focused on its
antioxidant properties.
The 2 proposed
mechanisms of action are
(1) directly scavenging
free radicals and (2)
indirectly inhibiting
formation of free
radicals. The Ginkgo
leaf extract can
scavenge reactive oxygen
species (ROS) such as
hydroxyl radicals (OH˙),
peroxyl radical (ROO˙),
superoxide anion radical
(O2−˙), nitric oxide
radical (NO˙), hydrogen
peroxide (H2O2), and
ferryl ion species (Mahady
2002; DeFeudis and
others 2003). The Ginkgo
leaf extract can also
enhance activities of
antioxidant enzymes such
as superoxide distmutase
(SOD), glutathione
peroxidase, catalase,
and/or heme-oxygenase-1,
thereby indirectly
contributing as an
antioxidant (Song and
others 2000; DeFeudis
and others 2003). It has
been suggested that
ginkgo leaf extract
increases expression of
mitochondrial enzymes
like NADH dehydrogenases,
which can influence ROS
generation in the
mitochondria. This is a
protection against
uncoupling of oxidative
phosphorylation, thereby
increasing ATP levels
regulating energy
metabolism
(Janssens and others
1995; Tendi and others
2002). In comparison to
other antioxidants, the
Ginkgo leaf extract (EGb
761) is known to be
regulatory and adaptive,
either dilating or
contracting blood
vessels, or controlling
neurochemicals or
neuroendocrine
indicators according to
the circumstances (Smith
and Luo 2003). The main
constituents implicated
in all these actions are
the flavonoids (quercitin
and kaempferol) and the
terpenoids (ginkgolides
and bilobalide) (Bastianetto
and others 2000;DeFeudis
and others 2003;
Smith and Luo 2004),
where each contributes
their antioxidant
property differently.
The flavonoids are known
to exert their effects
through inhibition of
the cyclooxygenase-2
enzyme, which is a part
of prostaglandin
synthesis, and its
inhibition is known to
reduce colon
carcinogenesis. The
bilobalide increase the
activities of the
antioxidant enzymes (SOD
and catalase) and
improve cell viability
(Watanabe and others
2000; DeFeudis and
others 2003).
However,
proanthocyanidins
(present at about 7% in
Ginkgo leaf extract)
present in the whole
leaf extract bind to
proteins and inactivate
antioxidant enzymes such
as catalase, glutathione
peroxidase, and lactate
dehydrogenase (Pietri
and others 1997a).
Hence, the presence of
these proanthocyanidins
may hinder the
antioxidant effects of
the Ginkgo leaf extract.
Prevention of
neurodegenerative
diseases. Alzheimer’s
disease is a form of
dementia that
progressively
deteriorates
intellectual capacity of
various domains of the
brain, particularly with
aging (Smith and Luo
2003). Alzheimer’s
disease affects about 4%
of the population over
65 and 20% of those over
80 (Zimmermann and
others 2002). Research
has now found links
between
Alzheimer’s disease and
deposition of amyloid
beta peptide (Aβ)
(Bastianetto and others
2000; Yao and others
2004; Ramassamy and
others 2007). Aβ is a
polypeptide with 39 to
43 amino acid residues
and a
major component of
senile plaques and
vascular amyloid
deposits of the brains
of patients suffering
fromAlzheimer’s disease.
Ginkgo leaf extract is
known to inhibit the
formation of Aβ from β-amyloid
precursor protein (APP),
a crucial process in the
pathogenesis of
Alzheimer’s disease (Yao
and others 2004).
Formation of amyloid
precursor protein has
been indirectly linked
to high cholesterol
levels (Koudinov and
Koudinova 2001; Wolozin
2002; Puglielli and
others 2003). It has
been postulated that the
inhibition of Aβ
is through the Ginkgo
leaf extract’s ability
to compete with free
cholesterol for
interaction with Aβ and
thereby decrease their
aggregation (Yao and
others 2004).
Alternatively, the
Ginkgo leaf extract
inhibits ROS
accumulation induced by
Aβ (particularly
flavonol quercitin) and
also reduces neuron
apoptosis, where
apoptosis is considered
to be one of the main
causes for
neurodegenerative
diseases (Bastianetto
and others 2000;
Ahlemeyer and
Krieglstein 2003; Ergun
and others 2005;
Ramassamy and others
2007) and thus help to
relieve Alzheimer’s
disease. Ginkgolide B
and bilobalide are
reported to inhibit
apoptosis induced by
staurosporine (alkaloid
anticancer drug) and
serum deprivation
(Ahlemeyer and
Krieglstein 2003).
Bilobalide also
prevented DNA
fragmentation due to
hydroxyl radical β-amyloid
and hydrogen peroxide (Ahlemeyer
and Krieglstein 2003).
In addition, Ginkgo leaf
has also been reported
to improve cerebral
blood flow by
stimulating
norepinephrine secretion
(Yang and others 2005)
and increased the life
span in a particular
study of rats treated
chronically with EGb
761, due to its
antioxidant action in
reducing oxidative
stress and free radical
production (Winter
1998). Ginkgo leaf
extract is known to
improve memory
complaints as well.
Walesiuk and others
(2005) used EGb 761 at a
dose of 100 mg/kg and
found improvements of
spatial and nonspatial
memory tested in rats
using the maze and
object recognition test.
Not only was EGb761
responsible for memory
response improvement but
was also reported to
improve response
retrieval. Similar
effects on improvement
of cognition, memory
loss, or improved blood
flow which may be
beneficial for
Alzheimer’s disease,
vertigo, dyslexia, and
other neuropsychiatric
disorders were exhibited
in a number of human
clinical trials using
Ginkgo leaf extract (Hopfenmuller
1994; Hartley and others
2003; Smith and Luo
2004; Issing and others
2005; Akhondzadeh and
Abbasi 2006;
Donfrancesco and
Ferrante 2007; Kennedy
and others 2007b;
Napryeyenko and others
2007; Ramassamy and
others 2007; Scripnikov
and others 2007).
However, others showed
no benefit of Ginkgo
leaf extract on
cognitive functions or
memory (van Dongen
and others 2000, 2003;
Carlson and others 2007;
Kennedy and others
2007a; Lovera and others
2007). Although there is
a body of evidence
showing the potentially
beneficial effects of
Ginkgo leaf extract on
neurodegenerative
diseases, it is still
not conclusive whether
Ginkgo leaf extract
supplementation can
improve cognitive
functions in humans.
Cardioprotective
effects. Ischemia,
impaired blood
circulation, is a common
underlying condition of
cardiovascular and
cerebral vascular
diseases. During an
ischemic attack, there
is an increased release
of free radicals and
lipid peroxidation
causing tissue damage
and resulting in chronic
diseases (Mahady 2002).
Cardioprotective effects
ofGinkgo leaf extract
are through antioxidant,
antiplatelet activity
and increased blood flow
through release of
nitric oxide and
prostaglandins (Pietri
and others 1997a, 1997b;
Mahady
2002).
Pietri and others
(1997b) showed that
consumption of Ginkgo
leaf extract prior to
cardiac surgery helped
in reducing reperfusion
induced lipid
peroxidation and
prevented ascorbate
depletion, tissue
necrosis, and cardiac
dysfunction. Moreover,
they also showed that
ginkgolide B reduces 50%
to 60% of the
postischemic production
of ROS (Pietri and
others 1997b). Pietri
and others (1997a) also
showed that reperfused
hearts treated with
terpene constituents
alone recovered
functionally better than
those treatedwith EGb
761
(Pietri and others
1997a). This leads to
the conclusion that
terpene constituents
decreasedmyocardial
vulnerability to
ischemic reperfusion.
The Ginkgo leaf extract
is also known to improve
coronary blood flow
through antiplatelet
activity (by ginkgolide
B) and by improving
contractile functions
which are due to
increased release of
catecholamines from
endogenous liver tissue
reserves by flavonoids
(quercitin, kaempferol,
and isorhamnetin) (Mahady
2002). Anticancer
effects. Cancer is a
disease characterized by
uncontrolled division of
cells and the ability of
these cells to invade
other tissues. The
disease is of
mutifactorial origin
that involves changes in
gene expressions and
aberrations in the cell
signaling pathways.
Ginkgo leaf extract is
known to exhibit a
chemopreventive action
at various levels with
antioxidant,
antiangiogenic
properties, and
influence gene
expression (Sagar and
others 2006). The Ginkgo
leaf extract’s
antioxidant ability
contributes to improving
cellular tolerance to
oxidative stress (Smith
and Luo 2004) as well as
to reduce angiogenesis,
which is blood vessel
formation required for
tumor metastasis (Monte
and others 1994;
DeFeudis and others
2003; Kim and others
2006; Sagar and others
2006). The nitric oxide
(NO) involved in cancer
progression also appears
to be resolved through
the terpenoids of the
Ginkgo leaf extract by
altering the expression
of NO synthase enzymes (DeFeudis
and others 2003). In
addition, Ginkgo leaf
extract is known to
influence the expression
of genes involved in
cell proliferation, cell
differentiation, and
apoptosis at the mRNA
levels in breast and
bladder cancer models (Gohil
and others 2000;
Papadopoulos and others
2000; DeFeudis and
others 2003), thus
providing anticancer
effects. Effects on
stress modification,
mood, and memory.
Anxiety syndromes such
as stress, moods, and
depression are becoming
common in the modern
world. Complementary and
alternative medicine is
becoming popular as a
prophylactic and/or
therapeutic treatment
for these symptoms.
Stress involves a rise
in the levels of
glucocorticoids, and a
subsequent memory
dysfunction, increased
anxiety, decreased
immunity,
gastrointestinal tract
disturbances, myocardial
infarction, or effects
such as increased
vigilance (Walesiuk and
others 2005). Since mood
and emotion are related
to stress, the
alleviating effects of
Ginkgo leaf extract may
result in improving
mood, thus resulting in
antidepressant activity
(DeFeudis and Drieu
2004). Ginkgolides A and
B decreased the ligand
binding capacity,
protein, and mRNA
expression of peripheral
benzodiazepine receptor
(PBR) which led to
decreased corticosteroid
synthesis and
subsequently the
circulating levels of
glucocorticoids (Amri
and others 1996). The
memory enhancing effects
of Ginkgo leaf extract
through prevention of
neuron degeneration are
discussed in the
previous section on
prevention of
neurodegenerative
diseases.
Effects on tinnitus,
geriatric, and
psychiatric disorders.
Tinnitus, or “ringing in
the ears,” is a common
condition observed in
almost 10% of the
population (Drew and
Davies 2001). One of the
common causes for
tinnitus is the
inadequate blood supply
to the inner ear (Ernst
and Stevinson 1999).
Thus, Ginkgo leaf
extract was thought to
have some potential
beneficial effects in
treating tinnitus. There
are a number of clinical
trials discussing the
effects of ginkgo leaf
extract on tinnitus
(Ernst and Stevinson
1999; Drew and
Davies 2001;DeBisschop
2003; Rejali and others
2004).However, effects
of Ginkgo leaf extract
on tinnitus are
inconclusive due to
different commercial
extract samples of the
ginkgo leaf, different
intervention
methods, dosages of the
extract, and use of
different primary end
points to evaluate the
results (Ernst and
Stevinson 1999).
Age-related macular
degeneration is thought
to be one of the common
causes of age-related
visual loss, possibly
due to oxidative damage
to the retina. Ginkgo
has been reported to be
effective
against senilemacular
degeneration due to its
free radical scavenging
effect (Diamond and
others 2000). Vertigo,
which involves a
sensation of movement
when no movement is
occurring, is another
disorder which ginkgo
has been found to be
effective against (Issing
and others 2005).
Schizophrenia is a
mental disorder
involving impairments in
the perception or
expression of reality
and by significant
social or occupational
dysfunction. The
condition is
characterized by
excessive free radical
formation in the brain.
A clinical
trial carried out by
Atmaca and others (2005)
showed a positive effect
in treating
schizophrenia patients
through increase in the
levels of antioxidant
enzymes like SOD,
catalase, and
glutathione peroxidase.
Safety profile Studies
show that a relatively
low risk is associated
with the consumption of
Ginkgo leaf products.
Occasional adverse
effects with excessive
consumption of Ginkgo
leaf extract have been
reported
which include
gastrointestinal
disturbances, headaches,
dizziness, excessive
bleeding, allergic skin
reactions, and
occasional
anaphylaxis-like
reactions (only with
intravenous
administration) (Kleijnen
and Knipschild 1992;
Skogh 1998; Vale 1998;
Benjamin and others
2001; De Smet 2002).
Long-term safety of
Ginkgo leaf extract is
not clear. Chinese and
Japanese cuisines often
involve ginkgo nut
consumption
as a part of their diet.
A particular case study
reported frequent
vomiting and clonic
convulsions in a
36-y-old womanwith no
prior history of
epilepsy after consuming
approximately 70 to 80
nuts over 1meal.
4’-Methoxypyridoxine,
one of the components
present in the nuts, is
suspected to cause
convulsions by
indirectly affecting an
enzyme glutamate
decarboxylase, resulting
in a decrease of the γ -aminobutyric
acid (GABA) level in the
brain (Miwa and others
2001). Hemorrhage or
excessive bleeding
caused by Ginkgo leaf
extract is due to its
inhibitory effects on
PAF. At levels of 120 to
240 mg/d EGb 761 does
not have significant
effects on PAF
antagonistic action;
however, dosages greater
than 100 times are
reported to cause
hemorrhage in rabbits
and humans (Koch
2005).Due to its effect
on PAF, Ginkgo has been
known to interact with
anticoagulant drugs (Lu
and others 2006; Aruna
and Naidu 2007),
although Jiang and
others (2005) did not
observe any significant
effects of Ginkgo in
clotting status in
healthy subjects. Ginkgo
leaf extract also
interacts with
antidepressants (that
is, Trazodone),
antiepileptic,
antidiabetic, diuretics,
and nonsteroidal
anti-inflammatory drugs,
aswell as other herbal
drugs (Matthews 1998;
Uchida and others 2006;
Tang and others 2007).
These interactions are
believed to be affected
mainly by the
flavonoidic glycosides
and the terpenoids by
selectively inhibiting
particular enzymes,
including cytochrome
P450 (Gaudineau and
others 2004).However,
others reported no
effect on clearance of
cytochrome P450
substrates by Ginkgo
leaf extract (Markowitz
and others 2003;
Greenblatt and others
2006; Mohutsky and
others 2006). The
apparent discrepancy has
been suggested to be due
to age-dependent
responses (Gurley and
others 2005).
The other components of
Ginkgo leaf extract are
the ginkgolic acids
(alkyl phenols), which
are considered to be
toxic. They are bilobol,
cardanols, cardols, and
ginkgol and are known to
cause gastrointestinal
and allergic reactions.
All commercial
preparations of Ginkgo
leaf extract must
contain 5 ppm or less of
ginkgolic
acids tominimize these
adverse reactions of
Ginkgo leaf extract use
(McKenna and others
2001). German
authorities report no
side effects on pregnant
and lactating women;
however, data with
respect to effects on
fertility, lactation,
and pregnancy,
particularly near labor,
are inadequate to be
conclusive (McKenna and
others 2001; Dugoua and
others 2006).
Conclusions
The standardized Ginkgo
leaf extract preparation
has been found to
exhibit multifaceted
therapeutic effects that
include effects on
neurodegenerative
diseases, cancer,
cardiovascular diseases,
tinnitus, geriatric
complaints, and
psychiatric disorders.
The main underlying
mechanism of action in
all these cases has been
the antioxidant
properties of the
extract. There are other
principles of action
that include PAF
antagonism, modulation
of the peripheral
benzodiazepine receptor,
and endothelium relaxing
factor improving the
circulatory properties
of blood. Thus, Ginkgo
leaf extract has been
shown to be a promising
herbal dietary
supplement with proven
therapeutic benefits.
However, its long-term
safety needs to be
properly addressed.
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