James P.M. Odell, OMD, ND, L.Ac.
Rauwolfia serpentina (also spelled Rauvolfia serpentina), is a member of the Apocynaceae family and grows in tropical and subtropical regions of the Himalayas, Indian peninsula, Burma, Indonesia, and Sri Lanka. The family includes 50 species, distributed in those regions, however, R. serpentina is the most well researched and used in traditional medicine.1, 2 The plant is also known as Snakeroot, Sarpagandha, Chandrabagha, Chotachand, Chandrika, and Harkaya.3 The roots, leaves, and extracted juice are of medicinal importance as it contains many metabolites, particularly unique alkaloids.
Various parts of this plant have been used in traditional medicine (Ayurvedic medicine) for centuries to treat a variety of ailments including snake bites, fever, general weakness, insomnia, intestinal diseases, liver problems, vertigo, and even mental illness. Currently, R. serpentina is one of the most effective plants for treating hypertension and cardiac disorders. It calms the central nervous system, regulates heart rate, and reduces high blood pressure.4 It is reported that after a hard day’s work, Gandhi always took a cup of soothing Rauwolfia tea. Its ability to treat snake bites has labeled it “Indian Snake Root”.
Rauwolfia serpentina has a most fascinating and deep history. It was written about in the Veda literature of Charak Samhita as early as 1000-800 B.C., who has called it by its Sanskrit name Sarpgandha. It has been historically observed that certain snakes are repelled by the scent of this plant which has long been used as an antidote for cobra, krait, and viper bites. Thus, its name is “snakeroot”. There has also been the traditional observation that mongooses consume leaves of Rauwolfia before fighting with the cobras. The generic name was given in the honor of a French Botanist and a well-known sixteenth-century German physician and author Leonard Rauwolf of Augsburg.
R. serpentina is an evergreen perennial shrub that grows to a height of 60-90 cm. Its leaves are simple, 7.5 cm long and 3.5 – 5 cm broad, elliptic, or lanceolate, glabrous, bright green above and pale green beneath pointed, and occurring in whorls of 3-5. The inflorescence is a many-flowered corymb with white or pink flowers. The fruit is a drupe, 0.5 cm in diameter, and shiny black when fully ripe. The root system consists of a prominent, tuberous, soft tap root reaching a length of 30-50 cm in a 2-year-old plant. Its diameter at the thickest portion varies from 1.2 to 2.5 cm. The root bark, which constitutes 40-60% of the whole root, is rich in alkaloids. It is the root that has been primarily used medicinally. The fresh roots emit a characteristic acrid aroma and are very bitter.5
The various phytochemical compounds or secondary metabolites present in R. serpentina include alkaloids, phenols, tannins, and flavonoids.6 About 80 alkaloids have been isolated from Rauwolfia species they include: ajmaline, ajmalimine, ajmalicine, deserpidine, indobine, indobinine, reserpine, reserpiline, rescinnamine, rescinnamidine, serpentine, serpentinine, yohimbine, and numerous others.7, 8
The antihypertensive properties of R. serpentina are attributed to reserpine (3,4,5-trimethyl benzoic acid ester of reserpic acid, an indole derivative of 18- hydroxy yohimbine type). It is the most prominent of all its alkaloids and is a natural tranquilizer.9, 10 Reserpine functions as a sympatholytic agent and antihypertensive medication by acting as an adrenergic uptake inhibitor. Reserpine binds to the storage vesicles of catecholamines, such as dopamine and norepinephrine. Specifically, reserpine irreversibly blocks VMAT-2 (vesicular monoamine transporter-2) in the adrenergic neurotransmission pathway.11
The inhibition of catecholamine pumps results in blockage of the uptake of serotonin, norepinephrine, and dopamine into presynaptic storage vesicles. This action will then lead to their depletion by cytoplasmic monoamine oxidase from peripheral and central synapses.12
Reserpine is lipid-soluble, so it can cross the blood-brain barrier and slow the activity of the nervous system, resulting in decreased heart rate, decreased cardiac output, decreased peripheral resistance, and lowered blood pressure.13 The main effector regions are the cardiovascular system, central nervous system, and gastrointestinal tract.
Ajmaline Ajmaline is an alkaloid unique to R. serpentina that exhibits antiarrhythmic properties. It also is used as an acute treatment of atrial or ventricular tachycardia. Ajmaline is a sodium channel blocker that shows instant action when given intravenously. It was first discovered to lengthen the refractory period of the heart by blocking sodium ion channels, but it has also been noted that it is able to interfere with the hERG (human Ether-a-go-go-Related Gene) potassium ion channel.14
In both cases, Ajmaline causes the action potential to become longer and ultimately leads to bradycardia. When ajmaline reversibly blocks hERG, repolarization occurs more slowly because it is harder for potassium to get out due to less unblocked channels, therefore making the RS interval longer. Ajmaline also prolongs the QR interval since it can also act as a sodium channel blocker, therefore making it take longer for the membrane to depolarize in the first case. In both cases, ajmaline causes the action potential to become longer. Slower depolarization or repolarization results in a lengthened QT interval (the refractory period), and therefore makes it take more time for the membrane potential to get below the threshold level so the action potential can be re-fired. Even if another stimulus is present, an action potential cannot occur again until after complete repolarization.
This alkaloid has also proven highly useful in diagnosing Brugada Syndrome (hereditary cardiac disorder) and differentiating between subtypes of patients with this disease. The administration of this alkaloid to patients with this type of arrhythmia is known as the “Ajmaline Test”. It has been reported to stimulate respiration and intestinal movements.15, 16
Ajmalicine Another unique alkaloid to R. serpentina is Ajmalicine. It has been shown to restore normal cerebral blood flow by its action on smooth muscles. Ajmalicine is structurally related to yohimbine and other yohimbine derivatives. It acts as an α1-adrenergic receptor antagonist with preferential actions over α2-adrenergic receptors, underlying its hypotensive rather than hypertensive effects.17 Additionally, it is a very strong inhibitor of the CYP2D6 liver enzyme, which is responsible for the breakdown of many drugs.18 It is estimated that about 3500 kilograms of Ajmelicine are isolated from Rauwolfia every year.
R serpentina contains over 70 other unique alkaloids, most of which have not been researched. It is likely that some of these alkaloids may be responsible for its antivenom effects.
Saponins are glycosides of both triterpenes and sterols and have been detected in over 70 families of plants. Some of the characteristics of saponins include the formation of foams in aqueous solutions, hemolytic activity, cholesterol-binding properties, and bitterness. Saponin has the property of coagulating red blood cells. The high saponin content of Rauvolfia serpentina explains its utility in stopping bleeding and in treating wounds.19
R. serpentina also contains β-Stigmasterol which may be in part responsible for its antivenom activity against abundant phospholipase A2 protein of Viper (Daboia russelii) and Cobra (Naja naja) venom.
Phenols Phenols are secondary plant metabolites widely distributed in the plant kingdom mainly in herbs, shrubs, vegetables, and trees. The presence of phenols is considered toxic for the growth and development of various pests and pathogens. The high-quantity polyphenolic compounds in R. serpentina exhibit significant antidiabetic and hypolipidemic properties. Its phenolic compounds also exhibit antimicrobial properties.20
Also, there are several mechanisms through which phenolic compounds act as anti-snake venoms. These include the elimination of free radicals, hydrogen donation, singlet oxygen cooling, metal ion chelation, or as substrates during an attack by superoxides. Another approach for the potent neutralization of snake venom by phenolic compounds could be due to the blocking of one or more enzymatic active sites in the venom toxins or the receptors that are structurally susceptible to chemical attack.
Tannin and Flavonoids R. Serpentina contains tannins that have astringent properties and can hasten the healing of wounds and control inflammation. Flavonoids are known for their wide range of health benefits and are commonly used in various ailments. The polypharmacological profile of flavonoids as anti-inflammatory, anti-mutagenic, and anti-carcinogenic agents is due to their ability to modulate key cellular enzyme functions, for example, xanthine oxidases, cyclooxygenases, and kinases. Thus, its flavonoids are potent water-soluble antioxidants and free radical scavengers and deliver anti-inflammatory and anticancer properties.
R. serpentina contains a large amount of macro and micronutrients. It is rich in calcium and zinc. The potential of R. serpentina to stop bleeding and its use in treating wounds (snake bites) can be also due in part to its high calcium content, as it helps in blood coagulation. The presence of zinc shows that this plant can play a valuable role in the immune system. It is a good source of ascorbic acid (vitamin C), riboflavin, thiamine, and niacin.
High Blood Pressure Rauwolfia serpentina is best known as a safe and effective treatment for hypertension. The plant has been used by physicians for hypertension throughout India and the world for decades. Numerous research has been conducted on its efficacious antihypertensive properties.21, 22, 23, 24,
Snakebites There are many Indian and Himalayan herbal folklores and observations about R. serpentina and its miraculous ability to treat venomous snake bites – particularly cobras, vipers, and kraits. One of which is that a mongoose would first chew upon its leaves to gain power before combating a cobra. Some Indian snake charmers, to defang their pet cobras, place snakeroot in an earthenware pot with the snake. The snake is observed to become stupefied and weakened and is unable to bite. The charmer then can remove its fangs safely.
Generally, investigations into ethnomedicinal plants that have demonstrated anti-venomous properties reveal the presence of unique alkaloids, saponins, tannins, anthraquinones, terpenoids, flavonoids, and steroidal bioactive components. These compounds may act singly or synergistically to bring about their antidotal effects.25
Thus, the antivenom (anti-hemorrhagic) activity of R. serpentina can be in part attributed to the presence of β-Stigmasterol, tannins, certain alkaloids, saponins, and flavonoids, which can chelate the zinc atoms involved in the catalytic activity of the venom’s hemorrhagic metalloproteinases, thereby neutralizing the hemorrhagic activity.
Snake venom phospholipase A2 (PLA2), metalloproteases, and hyaluronidases are the key enzymes involved in snake venom toxicity. Thus, the inactivation of these enzymes is generally considered the fundamental step in the management of snakebites. Polyphenolic compounds such as tannins are specialized metabolites found in many plant species and have been shown to interact with the enzymes of the snake venom by non-specific binding proteins.
Additionally, compounds such as vitamin C, flavonoids, terpenoids, tannins, polyphenols, and some minerals (i.e., zinc) from R. serpentina may have the ability to neutralize free radicals. Hence, they are valuable natural antioxidants that can scavenge and remove oxygen free radicals, stabilize cell membranes, and act as immunomodulators.
Research is scarce on R. serpentina’s anti-venomous effects on snakebites. However, its efficacy in treating cobra, viper, and krait bites has long been observed throughout India and Burma and continues to be used presently. The following 10 sources are a few of the many reports that have been published.
R. serpentina is commonly used against snakebite by traditional medicinal practitioners in three villages of Natore and Rajshahi districts, Bangladesh.26 In Chikmagalur district of Karnataka, India, the macerated root is tied to the snake-bitten area as an antivenom treatment.27 R. serpentina roots and leaf bud are crushed with milk and made into a paste and used internally and externally on the affected snake bitten area by the people of Bhadra wildlife sanctuary in Karnataka.28 It is also used in snakebite, insect, and animal bites by the “kavirajes” (local medical practitioners) of Rampal Upazila of Bagerhat district of Bangladesh.29 R. serpentina roots and leaf decoction are orally given for snakebite in the rural areas of Kanyakumari district, India.30 A root decoction R. serpentina (local name: Patala garuda) is used as an antidote to snake venom in some tribal districts of Orissa, India.31 Crushed roots of R. serpentina are mixed with oil and applied to the snake-bitten area in the villages of Narayanpur, Kalidaskhali, Durduria, Khayarhat, Alaipur, and Bagha beside the Padma River, Rajshahi district, Bangladesh.32 About 10 g of root juice is drunk for snakebite to minimize the rapid circulation of poison in the blood by the people of Nawalparasi district, Central Nepal.33 The tribes of Chhatarpur district, Madhya Pradesh, India use R. serpentina against snake bites.34 It is also recorded that R. serpentina has long been used by local people of the Himalayan mountains for snakebite.35
These three studies are worth mentioning. Rajashree et al. reported antivenom activity of the ethanolic extract of the whole plant of R. serpentina by neutralizing the toxic effect of Naja naja venom (Indian cobra). The plant extract significantly reduced the lethal effect of the Naja naja venom. About 0.14 mg of R. serpentina plant extract was able to completely neutralize the lethal activity of 2LD50 of the cobra’s venom.36
James et al. demonstrated the venom neutralizing potential of an aqueous R. serpentina extract in mice. In this study, the venom lethality dose of LD of D. russelli venom was found to be 0.628 µg/g which was effectively neutralized by 10.99 mg/3LD of R. serpentina plant extract. The LD of R. serpentina plant extract was >2000 mg/kg. These findings confirmed that R. serpentina plant extract possesses some compounds which inhibit the toxins present in D. russelli (Russell’s viper) venom. 37
In another study, Sivaraman et al. demonstrated an R. serpentina extract to be an effective antidote for Indian cobra. They concluded, “In the present study aqueous extract of Rauvolfia serpentina root was checked for the antidote properties against Naja naja venom by in vitro and in vivo methods. Various in vitro neutralization tests like Acetylcholinesterase, Protease, and ATPase activity of Naja naja venom were carried out and the root extract neutralized all the toxic effects induced by the venom. The in vivo assessment of venom lethality (LD50) of Naja naja venom was found to be 0.301 µg. The aqueous root extract effectively neutralized the venom lethality and the effective dose (ED50) was found to be 12.88 mg/ 3LD50 of Naja naja venom. LC-MS analysis from the root extract of Rauvolfia serpentina was done for confirmation of the bioactive compounds.”38
Dosage and Form:
For hypertension, an average adult dosage is one gram of powdered root taken once or twice a day under the direction of a knowledgeable health practitioner.
For many years now, and particularly after the isolation of the alkaloid reserpine, a strong controversy has been raging between opposing schools of thought about the relative merits or superiority of the one form of R. serpentina preparation over the other. Most practitioners of Ayurvedic medicine believe in the use of the whole herb because of its apparent benefits over the extract. The whole herb has many components that can:
(1) Help in biotransformation into pharmacologically active forms,
(2) Enhance bioavailability,
(3) Reduce the possible side effects,
(4) Help in smooth excretion, and
(5) Prevent the development of possible drug resistance.
An extensive literature survey has revealed that R. serpentina has been used since the pre-Vedic period to treat various ailments including snakebites, insomnia, psychological disorders, gastric disorders, epilepsy, wounds, and fever. Recent studies also suggest it is highly effective for hypertension. More research is needed on its wide array of pharmacological and therapeutic properties.
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