Evaluating the therapeutic efficiency and drug targeting ability of alkaloids present in Rauwolfia serpentina

Abstract

Rauwolfia serpentina is reported in an Ayurvedic medicinal system for centuries, for the treatment of various ailments such as snakebites, insomnia, hypertension, and insanity. Scientific evaluation of these documents can be valuable for finding new potential use in neurological disorders. The work presents the brief overview of R. serpentina including a description of the plant, its active chemical constituents and pharmacological properties with the major emphasis on cardiovascular and central nervous system disorders. This review compiles information available in the scientific literature from databases such as Science Direct, PubMed, India bioscience.org, Herbs - Medicinal plant usage and Identification Database, Database on medicinal plants used in Ayurveda and Siddha, Missouri Botanical Garden, National Medicinal Plants Board, and the International Plant Names Index. Information gathered from the literature has shown that the alkaloids are the major constituents of the plant imparting various pharmacological properties. Reserpine, the Indole alkaloid, is the most active compound of R. serpentine. The plant is known to possess antidiarrheal, antimicrobial activity apart from using it for the treatment of circulatory disorders, rheumatism, hypertension, insanity, epilepsy, and leaves are used in the removal of opacities of the cornea. Research shows that R. serpentine is a potential source of compounds pertaining medicinal applications. It provides an interesting subject in the search for new drugs of natural origin.

Full text

International Journal of Green Pharmacy • Jul-Sep 2017 • 11 (3) | 132
Evaluating the therapeutic efficiency and
drug targeting ability of alkaloids present
in Rauwolfia serpentina
Manisha Singh, Ramneek Kaur, Rashi Rajput, Garima Mathur
Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
Abstract
Rauwolfia serpentina is reported in an Ayurvedic medicinal system for centuries, for the treatment of various
ailments such as snakebites, insomnia, hypertension, and insanity. Scientific evaluation of these documents
can be valuable for finding new potential use in neurological disorders. The work presents the brief overview
of R. serpentina including a description of the plant, its active chemical constituents and pharmacological
properties with the major emphasis on cardiovascular and central nervous system disorders. This review compiles
information available in the scientific literature from databases such as Science Direct, PubMed, India bioscience.
org, Herbs - Medicinal plant usage and Identification Database, Database on medicinal plants used in Ayurveda
and Siddha, Missouri Botanical Garden, National Medicinal Plants Board, and the International Plant Names
Index. Information gathered from the literature has shown that the alkaloids are the major constituents of the
plant imparting various pharmacological properties. Reserpine, the Indole alkaloid, is the most active compound
of R. serpentine. The plant is known to possess antidiarrheal, antimicrobial activity apart from using it for the
treatment of circulatory disorders, rheumatism, hypertension, insanity, epilepsy, and leaves are used in the removal
of opacities of the cornea. Research shows that R. serpentine is a potential source of compounds pertaining
medicinal applications. It provides an interesting subject in the search for new drugs of natural origin.
Key words: Reserpine, alkaloids, hypertension, neuropsychiatry disorders, vasodilatation
Address for correspondence:
Dr. Manisha Singh, Department of Biotechnology, Jaypee
Institute of Information Technology, Noida,
Uttar Pradesh, India.
E-mail: manishasingh1295@gmail.com
Received: 04-05-2017
Revised: 06-06-2017
Accepted: 23-06-2017
INTRODUCTION
India has a rich heritage of traditional
Ayurvedic medicine, and a recent surge in the
demand for plant-derived drugs has gained
momentum. Plants have played a significant role
in maintaining human health and improving the
quality of human life for thousands of years.[1] The
World Health Organization estimated that <80%
of the world’s population relies on traditional
medicine for their primary health-care requirement
most of them are derived from plant extracts or
their active components. Herbal remedies and
herbal drugs playing a key role in curing central
nervous system (CNS) disorders.[2] There are
certain potential herbal medicines specifically for
CNS disorders which exhibit a pharmacological
potency and clinical efficacy of synthetic drugs
in neurological disorders. Rauwolfia serpentina
is reported as an Ayurvedic medicine which is
also named Sarpgandha or Chandra which refers
to use as an antidote for snakebite.[3] It is one of
the first neuroleptic compounds that are used in
the history of medical science.[4] The plant’s more
formal introduction is attributed to physicians:
Bose and Sen, (in 1931 paper) “R. serpentina, a new Indian drug
for insanity and high blood pressure”[5] which was published
in Indian medical journal. However, it soon became apparent
that it could cause depression and even suicides. Therefore,
because of the side effects, the use of drug for antipsychotics
was eclipsed especially by chlorpromazine.
As reported in the ancient Ayurvedic literature, R. serpentina
has been used for the treatment of skin cancer, eczema[6]
psychosis phenomenon, hysterical neurosis, and high blood
pressure, schizophrenia, and angiospastic attacks due to
peripheral vascular disorders.[7] This paper summarizes the
knowledge on pharmacological properties, major chemical
constituents, therapeutic actions, presymptomatic studies,
REVIEW ARTICLE

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International Journal of Green Pharmacy • Jul-Sep 2017 • 11 (3) | 133
safety and this paper summarizes the knowledge on
pharmacological properties, major chemical constituents,
therapeutic actions, pre symptomatic studies, possible mode
of action and safety of R. serpentina which is of historical
interest drug.[8]
In modern medical science, its active constituent is used
effectively as commercial drugs. It is one of the essential
compounds; Reserpine is used as an antihypertensive,
anthelmintic drug.[9] It plays an important role in dysentery,
ecbolic, fever, diarrhea, cornea’s opacity, and epilepsy.[10] It
is used to treat high blood pressure,[11] arrhythmia,[12] breast
cancer, cardiovascular diseases,[13] hypertension,[14] mental
disorders,[15] and leukemia.[16] Due to the presence of
Alseroxylon alkaloid (fat soluble, extracted from roots),
it is known to cure many circulatory disorders.[17] The root
extract or decoction extracts is known to treat and relieves
the abdomen, liver pain, and gastrointestinal disorders. The
leaves, flower buds, and roots are dried and crushed into
milk, and the crude paste is used externally on affected areas
to treat burns, body aches, eczema, and scabies.[18]
DESCRIPTION OF THE PLANT
R. serpentina belongs to the family Apocynaceae.[19] The
genus name was selected in honor of Dr Leonhard Rauwolf,
a 16th-century German botanist, Physician and explorer,
who reported this plant as a potential source of therapeutic
alkaloid.[14] The discovery of genus Rauwolfia dates back to
the 16th century and around 130 species are known till now
among which the most useful variant available in India of
commercial importance is R. serpentine.[20]
R. serpentina is a climbing evergreen, perennial shrub
grows up to a height of 60 cm and has cylindrical stem.[21]
Its roots are tuberous with pale brown cork. Plant leaves
are in whorls of three, elliptic to lanceolate or obovate,
base tapering, and slender. Flowers are in many irregular
corymbose cymes.[22] Its fruits are Drupe, single or two-
fold, shining black, the inflorescence with red pedicels and
calyx and white corolla. Corolla is longer than calyx, tube
slender, swollen a little above the middle, three-lobed, and
elliptic-oblong. The flowering time is from March to May
in Indian conditions.[23]
The root occurs as segments, subcylindrical to tapering,
tortuous or curved, rarely branched, occasionally bearing
twisted rootlets, which are larger, more abundant, and more
rigid and woody on the thicker parts of the roots. Root odor
is indistinct, earthy, reminiscent of stored white potatoes, and
the taste is bitter. Bark separates easily from the wood on
scraping. The wood is hard and of relatively low density.[10,24]
Figure 1 depicts the various parts of the plant. The plant
inhabits the hot and humid regions of South and South-East
Asian countries mainly Ceylon, Burma, Indonesia, and India.
In India, it is widely distributed in the tropical Himalayas,
Sikkim, North Bihar, Assam, and Deccan Peninsula. It is
also found in the lower hills of Gangetic Plains, Eastern and
Western Ghats and Andamans. It is mostly found in moist
deciduous forests at altitudes ranging from sea level to an
altitude of 1200 m high.[25]
Distinctly, focusing on the root extract of R. serpentine, which
possesses high therapeutic properties and is potent in treating
chronic hives, malnutrition, that was earlier unresponsive
to high energy diets or high proteins.[8] The other effective
remedial properties are in treating and relieving conditions
such as - Hysteria, Urticaria, and instant lowering of high
blood pressure.[26] Furthermore, these roots contain a high
quantity of starch, resin and some micronutrients such as
- phosphate, silicate, manganese, potassium carbonate,
and traces of iron.[27] The phytochemical content of
roots is Reserpine, serpentine, reserpiline, ajmalicine,
ajmaline, aricine, ajmalimine, deserpidine, corynanthine,
rescinnamidine, rescinnamine, isoreserpiline, isoreserpine,
indobinine, indobine, yohimbine, serpentine apart from these
contents there are various indole alkaloids that are identified
in the roots, namely, isorauhimbinic acid, yohimbinic acid,
N(b)-methylajmaline, 3 hydroxysarpagine, and N(b)-
methylisoajmaline. The most potent and essential ingredient
found in R. serpentina roots is “reserpine.”[28] Harisaranraj
evaluated the chemical composition, minerals and vitamins
of R. serpentine. Tables 1-3 provide a brief description of the
chemical composition.[29]
The plant is enriched with vitamins, particularly, ascorbic acid
(vitamin acid), which was found to be 44.03 ± 0.20 mg/100 g
in R. serpentina. Other vitamins were also found to be present
in the plant, namely, riboflavin, thiamine, and niacin.[30] The
plant may be an antimicrobial agent because of the presence
of phenolics compound in it. Phenols are responsible for
the antioxidant properties of the plant.[31] Alkaloids and its
derivatives are used as medicinal agents because of their
antispasmodic, analgesic, and bactericidal effects.[32] They
Figure 1: Images of Rauwolfia serpentina, showing various
parts (a) R. serpentina whole plant, (b) flower sproutings,
(c) dried seed, (d) dried roots
c
b
a
e

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show marked physiological activity when administered to
animals. Flavonoids are the free radical scavengers and water
soluble antioxidants which have strong anticancer activity and
prevent oxidative stress to the cells. Further, the flavonoids in
the intestine decrease the risk of heart diseases.[33] Flavonoids
have antioxidant and anti-inflammatory activities which are
used in the treatment of diseases in herbal medicine.[34]
Tannins, on the other hand, have peculiar properties and
increase the healing of inflamed mucous membrane and
wounds. The lower sodium content of the plant is an added
advantage because of the direct relationship between
hypertension and sodium intake in humans.[35] The plant
plays an important role in the management of diabetes
because of the presence of zinc.[36] The plant is a good source
of riboflavin, niacin, ascorbic acid, and thiamin.[37] Due to
the presence of ascorbic acid in the plant, it is used in herbal
medicines to treat many diseases.[38] Lack of ascorbic acid
hinders the normal synthesis of intercellular substances in
the body, which includes, tooth dentin, collagen, and bone
matrix.[39] Ascorbic acid is essential for body’s performance.[40]
Anemia, weakening of the endothelial wall of capillaries and
pain in the joint can be related to the association of normal
connective tissue metabolism and ascorbic acid.[41]
MEDICINALLY ACTIVE CHEMICAL
CONSTITUENTS OF R. SERPENTINE
Reserpine, the major pure crystalline alkaloid isolated from
root, stem and leaves of the plant, is the most active compound
of R. serpentine.[42] It is an indole alkaloid, and chemically
it is 11, 17 α-Dimethoxy-18 β-[(3,4,5-Trimethoxybenzoyl)
Oxy]-3 β, 20 α-yohimban-16 β-carboxylic acid methyl
ester.[43] The concentration of reserpine varies from 1.7% to
3.0% depending on geographical location and the season of
plant collection with December being the favorite month for
maximum alkaloid yield.[44]
The age of the plant has no effect on the percentage of alkaloid
content. It contains not <0.15% of reserpine - rescinnamine
group alkaloids, calculated as reserpine. Apart from reserpine,
other minor alkaloids present in the plant are ajmalicine,
ajmaline, isoajmaline, chandrine, rauwolfinine, renoxidine,
rescinnamine, reserpiline, sarpagine, tetraphyllicine, and
yohimbine.[45,46] The root contains ophioxylin, resin, starch,
and wax.[20] The whole root contains over 50 alkaloids.[47]
These alkaloids are categorized based on basic strength and
solubility in organic solvents as shown in Table 4.
Commercially available preparations of R. serpentina
generally contain 0.15-0.25% active alkaloids (reserpine and
rescinnamine) by weight. Reserpine is most commonly used
alkaloid for treating mild to moderate essential hypertension[48]
and is approved by FDA (1953) as an antihypertensive
drug molecule. Besides this, reports have shown its effects
against Staphylococcus aureus[49] and a potential commercial
antipsychotic drug.[50] Moreover, other alkaloids have also
been reported for treatment of hypertension and other cardiac
disorders.[51] Ajmaline (known by trade names Aritmina,
Ritmos, Gilurytmal) is used as an antiarrhythmic agent
(class 1a).[52] It is used to lower the ST elevations in patients
suffering from Brugada syndrome.[53] This compound was
named after Hakim Ajmal Khan, a Unani medical practitioner
from South Asia.[54] It is found in Catharanthus roseus[55]
and most species of Rauwolfia genus but its concentration
is too low when extracted from the root part and also its
bioavailability is lesser[56] hence, a semisynthetic propyl
derivative called prajmaline was developed that had a better
absorption and bioavailability as compared to Ajmaline.[57]
MECHANISMS OF ACTION
On the basis of experimental and clinical studies, the root of
R. serpentina attributed to many pharmacological actions.[58]
Table 1: Phytochemical composition of
R. serpentine (expressed as mg/100 g dry wt.)
Phytochemicals R. serpentine
Phenols 1.86±0.11
Flavonoids 1.72±0.11
Alkaloids 1.48±0.02
Tannins 0.51±0.20
R. serpentine: Rauwolfia serpentina
Table 2: Macro and microelement composition of
R. serpentine (expressed as mg/100g dry wt.)
Minerals R. serpentine
Macroelements
Calcium 0.32±0.10
Phosphorus 0.18±0.22
Magnesium 0.10±0.20
Potassium 0.04±0.11
Sodium 0.02±0.10
Microelements
Zinc 5.38±0.11
Iron 1.85±0.20
R. serpentine: Rauwolfia serpentina
Table 3: Vitamin composition of
R. serpentine (expressed as mg/100g dry wt.)
Vitamins R. serpentine
Ascorbic acid 44.03±0.20
Riboflavin 0.42±0.10
Thiamine 0.18±0.02
Niacin 0.02±0.10
R. serpentine: Rauwolfia serpentina

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It leads to generalized vasodilation acting directly on the
vasomotor center, resulting in lowering of blood pressure.
It’s been also reported for depressant action on the cerebral
centers, it exerts a sedative action[59] on the gastric mucosa
and a stimulating action on the plain musculature of the
intestinal tract.[22] It stimulates the bronchial musculature.
The principal action of the drug appears to be an alteration
of the sympathetic-parasympathetic balance by the partial
suppression of sympathetic predominance at the hypothalamic
level.[60]
Ajmaline, another alkaloid isolated from Rauwolfia has a
potent antiarrhythmic effect and lowering of blood pressure.
Studies have shown that ajmaline specifically depresses
intraventricular conduction, suggesting this would be
particularly effective in the treatment of re-entrant ventricular
arrhythmias. In one study of 100 patients with essential
hypertension, it was determined that serum cadmium levels
were 643% higher and serum zinc levels 28% lower in
hypertensives when compared with normotensive controls.
When the patients were put on ajmaline, blood pressure
was lowered significantly. It also appeared to decrease the
elevated serum cadmium levels in these individuals.[61]
Ajmaline group acts as a general depressant to the heart
but has been reported to stimulate respiration and intestinal
movements while serpentine group causes paralysis of
respiration, depression of the nerves, and stimulation of the
heart.[62] Rauwolfinine has hypotensive properties on the
autolysis of rat brain and liver tissue.[63] Isoajmaline and
neoajmaline causes lowering of blood pressure in intact,
spinal and decerebrate animals with or without experimentally
induced hypertension.[64] It is also reported for the enhanced
glucose tolerance in Wister mice, methanolic root extract of
R. serpentine shows significant antidiabetic, antiatherogenic,
and hypolipidemic effects in alloxan-induced diabetic mice
which could be due to the presence of total flavonoids
[Table 5].[9,65]
Table 4: Properties of major alkaloids present in R. serpentina[62]
Alkaloid Molecular
formula
Nature Chemical structure Functions Melting
point
Reserpine C33H40N2O9Indole alkaloid, soluble in chloroform Antipsychotic
antihypertensive
264.5°C
Rescinnamine C35H42N2O9Weakly basic Indole Alkaloids Antihypertensive 238°C
Reserpiline C23H28N2O5Indoline Alkaloids of intermediate
basicity
Antihypertensive 207°C
Ajmaline C20H26N2O2Alkaloid, miscible in water Antiarrhythmic 158°C
Ajmalicine C21H24N2O3Indoline Alkaloids Vasodilator 250°C
Serpentine C20H21N2O3Basic anhydronium alkaloids Tranquilizer 153°C
Alstonine C21H20N2O3Indole alkaloid Antipsychotic 348°C

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R. SERPENTINA AND
NEURODEGENERATIVE DISEASES (NDD)
The main strategy against Alzheimer’s disease (AD) is the
inhibition of acetylcholine esterase (AChE). In addition to
currently approved drugs, many phytochemicals derived
from the plant are used for the treatment of NDD. Apart from
NMDA antagonist memantine, the only approved drugs for
the treatment of AD are rivastigmine, galantamine, and
donepezil till 2014.[69] Inhibition of AChE is known to be
a promising strategy for treatment of Parkinson’s disease,
glaucoma, dementia, myasthenia gravis in addition to AD.
Various plant species from worldwide have been screened
for the AChE activity.[70] Formation of reactive oxygen
species, reactive nitrogen species is another important
neurotoxic pathway in AD, which leads to neuronal injury
and death.[71]
Various plant species are used by the ayurvedic system of
medicine since 4000 years for the treatment of CNS disorders
and to improve cognitive function and memory. Mathew et
al. conducted a study wherein R. serpentina was used to
screen anti-cholinesterase and antioxidant activity.[72] The
results revealed that R. serpentine showed high antioxidant
activity with IC50 of 96 ± 7.8 µg/ml using DPPH assay[73] and
IC50 for AChE inhibitor was 22 ± 4.9 µg/ml using Ellman’s
colorimetric methodology.[70] Thus, R. serpentina was an
effective candidate as a source of antioxidants and AChE
inhibitors.[74]
In another study by Saharia et al, reserpine efficacy in the
treatment of AD was evaluated.[75] They reported that AChE is
responsible for increasing the reserpine mediated lifespan[76]
and reduction in Aβ toxicity.[75] In Caenorhabditis elegans
(an established model of AD), Aβ toxicity causes paralysis[75]
Table 5: Detailed pharmaceutical information of different constituents of R. serpentina plant
Name of
compound
Category of drug Bioavailability Patent information Generic name/brand name
Ajmaline
(C20H26N2O2)
Indole alkaloids
antiarrhythmics (class I
and III)
antiarrhythmic agent,
cardiovascular
system, membrane
transport modulators,
secologanin tryptamine
alkaloids, sodium
channel blocker,
voltage‑gated sodium
channel blocker
50% U.S. Patent
US4175078, issued
on May 1975.[66]
The patent covers
Ajmaline derivatives:
Cardenolide and
Bufadienolide and the
process of production
The derivatives
produce two
therapeutically
important effects:
Tonicizingcardiac’s
activity
Relieving Cardiac
arrhythmia
Generic name
Ajmaline (OS: DCF, JAN)
Rauwolfia (IS)
Ajmalina (PH: F.U. IX)
Ajmaline (PH: BP 1980, JP XVI)
Ajmalinum (PH: Ph. Helv. VI)
Brand name
Gilurytmal
Reserpine
(C33H40N2O9)
Indole alkaloids
antihypertensive agent,
adrenergic uptake
inhibitor, antipsychotic
agent, hypotensive
agent, membrane
transport modulator,
neurotransmitter
agent (OCT2
substrates)
50% U.S. Patent US
2788309 An issued on
9 April, 1957.[67]
The patent covers
composition
for reserpine
for parenteral
administration
Brand name
Demi‑Regroton, Regroton
Diuretic Ap‑Es, Serathide,
Ser‑Ap‑Es, Serpazide
Hydropres‑25, Hydroserpine 1,
Hydroserpine, Hydropres‑50
Salutensin, Salutensin‑Demi
Rescinnamine
(C35H42N2O9)
Alkaloid angiotensin
converting enzyme
inhibitor cardiovascular
system indoles
antihypertensive agent
yohimbine indole
alkaloid
0 U.S. Patent US
3898215 A issued on
5 August,[68] 1975
The patent covers
rescinnamine‑like
compounds and a
process for producing
the same.
Generic names:
Rescinnamina (OS: DCIT)
Rescinnamine (OS: BAN, DCF,
JAN)
3,4,5‑ Trimethoxycinnamic
acid ester of methyl
reserpate (IS: WHO)
Reserpyletrimethoxycinnamate (IS)
BRAND NAME
Tsuruselpi S

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and is expressed in muscles. It was observed that reserpine
alleviated pathogenesis of AD in model worms by delaying
the paralysis mediated by Aβ expression. Furthermore, there
was not the significant alteration in the deposits of Aβ in vivo.
Reserpine was able to extend the lifespan and increased the
stress tolerance in C. elegans. Hence, reserpine provides
protection against AD pathogenesis in C. elegans.[77]
DRUG TARGETS FOR ALKALOIDS
PRESENT IN R. SERPENTINA
Reserpine
The antihypertensive property of R. serpentina is due to the
presence of reserpine (3, 4, 5-trimethyl benzoic acid ester of
reserpic acid, an indole derivative of 18-hydroxy yohimbine
type).[78] It is the most significant of all alkaloids present in
R. serpentina with good documentation about its therapeutic
properties of being a natural tranquilizer and antihypertensive
agent.[79] Physiologically, it binds with protein receptors
vesicular monoamine transporters (VMATS) in membranes
of specialized secretory vesicles of presynaptic neurons
leading to pre synaptic closure of calcium-gated ion channels
and preventing intracellular neuro transmitters from binding
to VMAT proteins therefore, stopping secretory vesicles from
up taking neurotransmitters [Figure 2].[80] Thus, causing a
limited release of neurotransmitters from pre synaptic neurons
subsequently, governing the nerve impulse transmission in
postsynaptic neurons. Reserpine has the higher affinity for
VMAT2 and binds irreversibly to their receptors.[81] It acts
on both central and the peripheral nervous systems to deplete
stores of neurotransmitters: Dopamine and nor epinephrine
at central and peripheral synapses, epinephrine in the
adrenal glands, and serotonin (5-HT) in the CNS[82] and its
higher doses cause a low release of neurotransmitters. This
compound also damages the intracellular vesicles in which
neurotransmitters are stored permanently, leading to spillage
of neurotransmitters inside the neuron which are destroyed
by monoamine oxidase. It is also used to treat symptoms of
dyskinesia in patients suffering from Huntington’s disease[83]
by depleting catecholamine stores within the peripheral
vascular adrenergic nerve endings, thus indirectly acting
sympathomimetics and are unable to trigger the release of
catecholamine.[84] The reserpine-induced catecholamine
release increases sensitivity to the effects of direct-acting
sympathomimetics.[85] It has sedative and tranquillizing
effects, as it depletes catecholamine from the CNS.
The tranquillizing effects of R. serpentine can result from
the depletion of amino stores in the CNS; by depressant
action on the cerebral centers, it relaxes the general nervous
system.[86,87] Thereafter, effect of reserpine in the vasomotor
center causes diminished reflex in vasomotor responses
leading to generalized vasodilatation, with a lowering of
blood pressure.[86]
Rescinnamine
Rescinnamine binds and inhibits angiotensin converting
enzyme and competes with Angiotensin I thus, blocking the
conversion of Angiotensin I-II.[88] Angiotensin II is a negative
feedback mediator of renin activity and a vasoconstrictor
[Figure 3].[89] Therefore, rescinnamine helps in lowering
the concentration of angiotensin II therefore, decreasing
the blood pressure and stimulation of baroreceptor reflex
mechanisms, leading to decreased aldosterone secretion and
vasopressor activity.[90]
Figure 2: Schematic representation of reserpine neural mechanism at neuromuscular junction

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Reserpiline
It is a 10, 11 dimethoxy stereo isomer of Ajmalicine. It has an
amorphous base and is extracted out from R. serpentina after
extracting ajmalicine. Isoreserpiline and reserpiline coexist.
It is useful extract for the treatment of psychosis. It increases
the binding affinity for dopaminergic-B2, muscarinic and
serotonergic receptors.[91]
Ajmaline
Ajmaline is an antiarrhythmic agent (Class I) that acts
by altering the shape and threshold of the cardiac action
potential. It blocks sodium channel and a very short half-life
makes it a very suitable drug for acute intravenous treatments.
The mechanism of action of Ajmaline is that it depresses
intraventricular conduction.[92] It leads to prolongation of
P-Q interval, Q-T interval, QRS complex, and widening
of R wave.[93] It does not deplete catecholamine content of
heart, has a negative ionotropic effect[94] and sympatholytic
activity. Cellular stimulation was observed in the heart
muscle of guinea pigs that received therapeutic ajmaline.[95]
The drug is very famous in some countries for the treatment
tolerated monomorphic ventricular tachycardias and atrial
fibrillation in patients with the Wolff-Parkinson-White
syndrome.[96] It has also been used as a drug to challenge
the conduction system of the heart in cases of syncope and
bundle branch block. It is used to diagnose Brugada disorder
(genetic cardiac syndrome) and helps to distinguish the
subtypes between patients with the syndrome.[97] On the basis
of the molecular mechanism, these agents are classified into
four groups, i.e. beta-adrenergic blockage, sodium channel
blockade, calcium channel blockade, and repolarization
prolongation.[98] It is reported to stimulate intestinal
movements and respiration. Its action on pulmonary and
systemic blood pressure is similar to that of serpentine.[43]
Ajmalicine
Ajmalicine has application in the treatment of circulatory
diseases by providing relief to normal cerebral blood flow.
It effects in preventing strokes, lowering blood pressure,
and affects the function the function of smooth muscles.[99]
Approximately, 3500 Kg of Ajmalicine is isolated from either
Rauvolfia and Catharanthus spp. for the treatment of circulatory
diseases.[100] The synthesis of Ajmalicine starts with geraniol
through irdotrial and iridodial by the formation of loganin,
which on oxidation converts loganin into secoloanin.[101] This
helps tryptamine to synthesise corynanthe type nucleus that
results in the formation of ajmalicine.[102] The ajmalicine is
derived from tryptophan which is converted to tryptamine via
strictosidine, cathenamine, and secologanin.[103] The enzyme
tryptophan decarboxylase and NADH reduces cathenamine
to ajmalicine. The enzyme involved in the synthesis of
ajmalicine is decarboxylase.[104]
Serpentine
Serpentine is an inhibitor of topoisomerase (Type II) and
has antipsychotic properties. For oxidation of ajmalicine to
ajmalicine, an enzyme (PER) peroxidase[105] is responsible for
it by catalyzing bisindole alkaloid localized in the vacuole.
Side Effects
Orally, the roots of the plant may cause adverse reactions
including nasal congestion, abdominal cramps, diarrhea,
nausea, vomiting, anorexia, increased gastric acid secretion,
drowsiness, fatigue, lethargy, slowed reflexes, and sexual
dysfunction. Basically, the concomitant use of R. serpentina
can increase the risk of bradycardia and arrhythmias. Although
there are few reports in allergic responses from the use of
plant root, it may precipitate asthma.
The dosage in larger amounts can precipitate mental
depression and in extremely large amounts, Parkinson-like
symptoms, extrapyramidal reactions, and convulsions may
occur.[46,106] Recently, the studies are focused toward the high
affinity of plant extract toward central a2 and dopamine D2
receptors inducing hypolocomotion by nigral dopaminergic
dysfunction producing an effect on peripheral movements,
rearing, grooming, immobility, and defecation.[107] Hence,
these intriguing findings will likely stimulate further interest
in R. serpentine.[108] Some of the side effects of R. serpentina
are faintness or drowsiness, lack of weakness or energy,
inability to concentrate or mental depression, anxiety or
depression, early morning sleeplessness, and impotence.[109]
FUTURE PERSPECTIVE
Phytomedicine holds a great medical and public interest as
a source of the novel lead compound and neutraceuticals
for drug development. The roots of R. serpentina have
been used for insanity and other illnesses such as vomiting,
fever, and snakebites for more than 3000 years in Indian
traditional medicine set up. Furthermore, it was the first
reported antipsychotic drug but due to its side effects,
Figure 3: Role of rescinnamine in inhibiting angiotensin‑renin
system

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International Journal of Green Pharmacy • Jul-Sep 2017 • 11 (3) | 139
it was been withdrawn back from this use although, the
intensive and systematic research is pending with this regard.
Therefore, evolution of phytomedicine and plant-based
chemical molecules needs more intense and multivariant
research approaches, right from procuring and screening of
plant extracts to phyto preparation and developing secured
and efficient delivery system, till evaluating the safety
and efficacy of the developed formulation. These targeted
delivery systems will not only improve on the bioavailability
of the phyto compounds, but their stability as well. Another
approach to enhance the efficacy of these phytomedicine can
be formulating them into nanoformulations or encapsulating
them into nanoparticles or nanoemulsion forms, which is
nowadays is a crucial field of nanomedicine.
CONCLUSION
R. serpentina is well documented to exhibit potential medical
values for treatment of hypertensive and neurological
disorders. Extensive research has been carried out exploring
its antihypertensive properties; however, limited literature
is presently available on its neuropharmacological activities
despite it being reported as the first neuroleptic compound.
Although it was later reported for many CNS disorders,
therefore R. serpentina covering the broad spectrum array
of pharmacological activity proves to be an ideal therapeutic
target for neurological disorders.
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Source of Support: Nil. Conflict of Interest: None declared.