Research Signpost 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India Handbook of Medicinal Plants and their Bioactive Compounds, 2014: 11-26 ISBN: 978-81-308-0548-1 Editor: Nidhi Gupta 2. Stevia rebaudiana: Beyond sweetness Madhumita Kumari and Sheela Chandra Department of Biotechnology, Birla Institute of Technology, Mesra, Ranchi-835215 Jharkhand, India Abstract. Stevia rebaudiana (Bert.) is a name that flourishes in the medicinal world from hundreds of years. Stevia plant has applications in diverse fields. Leaves of Stevia contains diterpene glycosides (Stevioside and rebaudiosides), which are well known for intense sweetness. Stevioside is approx 300 times sweeter than sucrose but have zero calories. Besides sweetness, steviol glycosides can be used as potential therapeutics against numerous diseases and are proving their potential far better compared to established drugs in the market. Steviosides have antihypertensive, antitumour and vasodilator activity. Isosteviol possess neuroprotective activity. Rebaudioside A and Dulcoside A have been found to be similar in acitivity with Hydrocortisone as anti- inflammatory drug. Rebaudioside C acts on 10 to 100 time’s lower doses as compared to Indomethacin, an anti-inflammatory drug. Similarly isosteviol is comparable with Nimodipine, a neuroprotective drug. In comparision to artificial sweetners available in market, steviosides are 100% natural, zero calories, heat stable, non- discolouring, and have no other side effects. It can be added to tea or coffee and cooked or baked. In India, prevalence of diabetes is rising rapidly, and more than half of the patients have poor glycemic control with vascular complications. So there is a need to develop novel therapeutic agent with multipotential activities. Correspondence/Reprint request: Dr. Sheela Chandra, Department of Biotechnology, Birla Institute of Technology, Mesra, Ranchi-835215, Jharkhand, India. E-mail: [email protected]
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Research Signpost
37/661 (2), Fort P.O.
Trivandrum-695 023
Kerala, India
Handbook of Medicinal Plants and their Bioactive Compounds, 2014: 11-26
ISBN: 978-81-308-0548-1 Editor: Nidhi Gupta
2. Stevia rebaudiana: Beyond sweetness
Madhumita Kumari and Sheela Chandra Department of Biotechnology, Birla Institute of Technology, Mesra, Ranchi-835215
Jharkhand, India
Abstract. Stevia rebaudiana (Bert.) is a name that flourishes in
the medicinal world from hundreds of years. Stevia plant has
applications in diverse fields. Leaves of Stevia contains diterpene
glycosides (Stevioside and rebaudiosides), which are well known
for intense sweetness. Stevioside is approx 300 times sweeter than
sucrose but have zero calories. Besides sweetness, steviol
glycosides can be used as potential therapeutics against numerous
diseases and are proving their potential far better compared to
established drugs in the market. Steviosides have antihypertensive,
antitumour and vasodilator activity. Isosteviol possess
neuroprotective activity. Rebaudioside A and Dulcoside A have
been found to be similar in acitivity with Hydrocortisone as anti-
inflammatory drug. Rebaudioside C acts on 10 to 100 time’s lower
doses as compared to Indomethacin, an anti-inflammatory drug.
Similarly isosteviol is comparable with Nimodipine, a neuroprotective
drug. In comparision to artificial sweetners available in market,
steviosides are 100% natural, zero calories, heat stable, non-
discolouring, and have no other side effects. It can be added to tea
or coffee and cooked or baked. In India, prevalence of diabetes is
rising rapidly, and more than half of the patients have poor
glycemic control with vascular complications. So there is a need
to develop novel therapeutic agent with multipotential activities.
Correspondence/Reprint request: Dr. Sheela Chandra, Department of Biotechnology, Birla Institute of
Technology, Mesra, Ranchi-835215, Jharkhand, India. E-mail: [email protected]
Madhumita Kumari & Sheela Chandra 12
India has suitable climate for Stevia cultivation. Inspite of this, Stevia cultivation has
not been taken up on a large scale and China is dominating the market. Lack of
awareness among the farming fraternity on medicinal values and the commercial
prospects of the crop are lacking. Aim of this review is to create awareness by
exploring the hidden therapeutic potential of steviol glycosides beyond its sweetness
value.
Introduction
Stevia rebaudiana (Bert.) is natural sweetener plant and flourishes in the
medicinal world from years. It is a perennial herb belongs to Asteraceae
family. About 200 species of Stevia are known but Stevia rebaudiana (Bert.)
emerged distinct on the ground of its sweet nature [1].
Stevia is native of Paraguay. The word “Stevia” originates against the
name of Spanish botanist P.J. Stevus, who first studied the different species
of Stevia genus. In 1888 M.S. Bertoni first discovered the plant and its sweet
taste. The plant was scientifically named as Stevia rebaudiana in 1905 after
a Paraguayan chemist Dr.Rebaudi. It is also known as sweet herb of
Paraguay, honey leaf, sweet leaf, sweet herb and candy leaf [2].In 1931, two
chemists isolated the compounds responsible for its sweet taste [3]. These
compounds, Steviosides and Rebaudioside A are diterpene glycosides and
are 250-300 times sweeter than sucrose. These are heat-stable, pH-stable,
and not fermentable[4].
Stevia rebaudiana is a short day plant (Figure 1).It grows easily on
tropical and subtropical areas between the temperature range of 21 to 40
degree with semi humid environment and well-draining soil in pH range of
6.5 to 7.5[5]. First crop of Stevia was domesticated at Japan and used as an
alternative sweetener. Later on, extensive studies on Stevia revealed its
useful effects in human body and this favour its commercialization in several
countries including Latin America, Canada, China, Japan, Indonesia, USA
[6, 7]. In India, Stevia is being cultivated successfully in the states of
Rajasthan, Maharashtra and Kerala.
These natural high intensity sweeteners are non-fermentable,
non-discoloring nature, maintaining heat-stability at 100°C and feature a
long shelf life. The product can be added to tea and coffee, cooked or baked
goods, processed foods and beverages. It is used as a table top sweetener, in
soft drinks, baked goods, pickles, fruit juices, tobacco products,
confectionery goods, jams and jellies, candies, yogurts, pastries, chewing
[18] drug. This chapter includes a comprehensive review on current
understanding of Stevia as potential therapeutics beyond its sweetness and
current market scenario of Stevia products.
Madhumita Kumari & Sheela Chandra 14
Chemical constituents of Stevia rebaudiana (Bert.)
The sweet diterpene glycosides of Stevia have been the subject of a
number of reviews [9, 19]. The leaves of Stevia rebaudiana contain at least
eight diterpene glycosides viz. stevioside and rebaudioside. After recognition
of sweet taste of Stevia, several substances have been isolated from the plant
including stevioside and steviol. In 1931, Isolation of stevioside was done by
Bridel and Lavieille. In 1952, the chemical structure of stevioside (Figure 2)
was established and described as an aglycon, steviol with glycoside of three
glucose molecule [20]. During the 1970s, other compounds were isolated,
including rebaudioside A (Figure 3), also known as rebtose, with a sweet
potency even higher than stevioside [21].
Besides steviol glycosides, other diterpenoids also present in leaves of S.
rebaudiana such as manoyl oxide and labdanescareol. Manoyl oxide shows
anti-inflammatory and anti- parasitic action whereas labdanesclareol, has
anti-tumorous and cytotoxic properties [22].
Wild Stevia leaves have been evaluated for typical proportion of major
glycoside and other biochemical constituents on dry weight basis. Among
steviol glycosides, stevioside have highest proportion and than rebaudioside
A and other glycosides. In addition to steviol glycosides, other minerals,
protein, fat, carbohydrate and ash content has also been estimated (Table 1)
[23].
Figure 2. Stevioside. Figure 3. Rebaudioside A.
Stevia rebaudiana: Beyond sweetness 15
Table 1. Percentage of major glycosides and other biochemical constituents of
Stevia.
Component Sweetening*
(times)
Value (gm/100gm dry
leaf weight)
Stevioside 150-300 4–14%
Rebaudioside A 250-350 2–4%
Rebaudioside C 50-150 1–2%
Dulcoside A 50-150 0.4-0.7%
Rebaudioside D,E,F;
Steviolbioside;
Rubusoside
100-250 ˃0.4%
Carbohydrates 35.2
Proteins 12.0–20.42
Lipids 2.7–4.34
Ash 13.12
*Sweetness is tasted at a series of dilutions to determine the concentration that is as sweet as a given percent sucrose reference. Taste panellists usually are trained to quantitate sweetness on a
15 cm line scale, using 2-15% sucrose solutions as references. For example, if a 1% solution of
sweetener X is as sweet as a 10% sucrose solution, then sweetener X is said to be 10 times as potent as sucrose [24].
Stevia leaves also contain numerous all-natural nutrients that are
medically and commercially important, including chromium, magnesium,
manganese, potassium, selenium, zinc, and vitamin B3(Niacin).
Phytochemical screening has showed that tannins are present in higher
concentrations followed by alkaloids, glycosides, saponins, sterols, and
triterpenes, anthraquinones, and other reducing compounds [25].
Biosynthetic pathway of steviol glycosides
Steviol glycosides biosynthesis is currently an endless area of research
because not much is known about the pathway and it shares some common
steps with GA (Gibberellic acid) biosynthesis [26]. Steviol glycoside
biosynthesis occurs in leaves and transported to different parts [27]. In vivo
labeling with [1-13
C] glucose and NMR spectroscopy showed that main
precursor steviol is synthesized via the plastid localized methylerythritol
Staphylococcus aureus) [49]. Minimum concentration (250µg/ml) of
petroleum ether extract was sufficient enough to completely inhibit the
growth of E. Coli.
Anti-inflammatory
Sufficient evidences are there for anti-inflammatory effect of Stevioside.
For example four different steviol glycosides, stevioside, rebaudiosides A
and C, and dulcoside A, showed strong inhibitory activity against
12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in mice
[50]. Isosteviol inhibits DNA polymerases and human DNA topoisomerase
II, cellular targets for pharmacotherapy of cancer as well as inflammatory
diseases. Moreover, isosteviol also retards growth of three different types of
human cancer cells and inhibits inflammation induced by TPA [51].
Neuroprotective
Stevioside and isosteviol have neuroprotective activity. Stevioside
shows antiamnesic effect on scopolamine (drug for motion sickness) treated
rats. On pre-treatment Stevioside suppresses the scopolamine induced
learning and memory deficit. It also constrict scopolamine induced high
acetylcholine activity and oxidative stress level in brain. So stevioside have a
memory preservative effect in cognitive deficits of rats [52].
Isosteviol have protective effects against ischemia-reperfusion (IR)
after cerebral ischemia. Occlusion of cerebral artery damages the brain
even after reperfusion. Isosteviol is tested in different concentration
(5mg/kg to 20mg/kg) and compared with Nimodipine (drug for prevention
of cerebral ischemia) to determine its potential in preventing IR injury in
Madhumita Kumari & Sheela Chandra 20
brain. It is found that isosteviol is as effective as Nimodipine. Isosteviol
acts by reducing imfarct volume, ameliorated cell death and infilteration
of neutrocytes and finally improved neurolocomotor activity observed
[53].
Antidiarrhoeal activity
Diarrhoea is most commonly caused by pathogenic bacteria or viruses
by either direct invasive damage to intestine or deranged intestinal function
[54].Different types of diarrhoea can occur according to their source, it may
be secretory, osmotic, motility related or exudative diarrhoea [55].Currently
in antidiarrheal drug discovery main focus is on rehydration therapyand
antibiotic treatment, but the antibiotic treatment is not effective in case of
antibiotic resistance.
Application of Stevioside as a therapeutics of diarrhoea originates from
its bactericidal effect [56] as it has antimicrobial activity against broad range
of food borne pathogenic bacteria including enterohemorrhagic E.coli,
known to cause diarrhoea. It also inhibits rotavirus which causes
gastroenteritis in children. [57]
Stevioside has an inhibitory effect on intestinal smooth muscle
contraction, stimulation of which results in hypermotility-associated
diarrhoea. Stevioside inhibits CaCl2 induced contraction of isolated guinea
pig ileum by 40% [13]. The mechanism was related to its inhibitory effect on
Ca2+
influx into muscle cells. Thus Stevioside may be useful in treatment of
diarrhoea resulting from intestinal hypermotility.
Global market of Stevia
Stevia is one of the fastest growing industries in world because of its
good taste of food and drink without any calories or health risks. Its zero
calories do not cause any health problem or tooth decay. Now a day’s Stevia
is approved as food additive or dietary supplement in several countries
(Table 2). It is also popular among food manufacturing companies and
distributed over the world. Cargill and Coca Cola companies distribute their
products under the brand name “Truvia” and PepsiCo Inc. distributes by the
name “Pure Via”.
In view of relatively early stage of Stevia market, global sale of Stevia
varies. Data from Leatherhead Food Research valued the world Stevia
market (including both crude extracts and high purity products such as Reb A)
at US$100m in 2010, up by nearly 27% from $79m in 2009. During this
Stevia rebaudiana: Beyond sweetness 21
Table 2. List of countries where Stevia is approved by regulatory agencies [58-61].
Regulatory agency approved
Food additive Food additive and dietary supplement
Country year Forms of Stevia
Country year Forms of Stevia
Australia,
New
Zealand
2008 Steviol glycosides
extracts
Japan 1970 All steviol
glycosides, leaves
Brazil 1986 Stevioside extracts European
Union
2011 Steviol glycosides
Hong Kong
2010 Steviol glycosides United States 2008 Reb A, Stevia
leaves
Israel 2012 Steviol glycosides Indonesia 2012 Steviol glycosides,
dried leaves
Mexico 2009 Mixed steviol
glycosides
Canada 2012 Steviol glycosides,
dried leaves
Norway 2012 Steviol glycosides
Russian
Federation
2008 Stevioside
Singapore 2005 Steviol glycosides
In some other countries Stevia is available in different forms but not verified by regulatory agencies, which includes Argentina, Chile, China, India, Colombia, Korea, Malaysia, Paraguay,
Peru, Philippines, Saudi Arabia, Taiwan, Thailand, Turkey, United Arab Emirates, Uruguay,
and Vietnam [61].
time, volume sales rose from less than 2,300 tonnes to 2,400 tonnes, with
crude extracts accounting for up to 80% of this figure. Separate data from
Zenith International (another UK-based consultancy) suggests that global
market value reached $285m in 2010, with volume sales worth in the
region of 3,500 tonnes. A report from Packaged Facts of the US estimates
the world Stevia market in 2011 is between $800m and $2bn, up from
just $20m in 2008. For this growth, credit goes to Stevia as it gained
regulatory approval in the large sized US market, where sales of intense
sweeteners such as sucralose and aspartame remain above the global