Phytochemistry and Pharmacology of Anamirta cocculus Willd.

 

U. S. Jijith1,2*, C. R. Sudhakaran Nair1, K. C. Ajithkumar2, K. Pramod1,2

1College of Pharmaceutical Sciences, Govt. Medical College, Thiruvananthapuram – 695011, Kerala, India.

2College of Pharmaceutical Sciences, Govt. Medical College, Kozhikode – 673008, Kerala, India.

*Corresponding Author E-mail: jijithus@gmail.com

 

ABSTRACT:

Anamirta cocculus is a woody climber of Menispermaceae family remains popular folk remedy in Asia and adjacent regions. It crude drug is officially listed in many Pharmacopoeias. The fruits, especially the seed contain picrotoxin, a very strong poison that was toxic to all vertebrates affecting the CNS, stimulating the respiratory and vagus centres in the medulla and acting on the heart and lungs with diminished pulse. The toxicity results in vomiting, purging, profuse sweating, dimness of vision, unconsciousness and clonic convulsions. Death occurs rapidly due to respiration failure, or slowly from gastro-intestinal symptoms, particularly the medulla oblongata and respiratory centre. In South-East Asia the fruit of Anamirta cocculus is used mainly as a fish poison and as an insecticide. The plant was large-stemmed and, stem and roots contains quaternary alkaloids, such as beriberine, palmatine, magnoflorine, columbamine, oxypalmine, stepharine and the major tertiary alkaloid as 1-8-oxotetrahydropalmatine. The alkaloids of Anamirta cocculus have antibacterial, antimicrobial, sympatholytical (acetylcholine), and antifertility activities and the isolated alkaloids were confirmed and characterized by UV-spectrophotometry, Mass spectroscopy, H1-NMR and C13-NMR spectroscopy.

 

KEYWORDS: Anamirta cocculus; Picrotoxin; Quaternary alkaloids; Tertiary alkaloids; Mass spectroscopy

 

 

INTRODUCTION:

Anamirta cocculus Wild are large woody climbing plant of Menispermaceae family widely distributed in South-East Asia and in India mainly the deep forest of Kadappa, Mysoor, Malabar etc1. The plant was large stemmed (Up to 10cm in diameter) and the bark was “cokygray” with white wood. A poisonous alkaloid named picrotoxin was present in its fruit, Cocculus indicus have good stimulant properties. It has small yellowish-white, sweet scented flowers and drupe fruits. The fruits, also called as Levant berry have a diameter of about 1cm when it was dry.

 

Medicinal properties and uses:

Levant berry is a popular folk remedy in Asia and adjacent regions, but not widely used in Europe. In Philippines, the infusion of the roots of Anamirta cocculus is used to treat fevers, dyspepsia and menstrual problems, extract of the stem is added to native wine and is drunk to make the blood strong and the leaves used as a poultice for headache, stomachache or delayed menstruation. In Laos, the fruit was used in very small doses to treat eruptive fevers and the powdered fruit was used to treat acute barbiturate poisoning. In India, the fruits and seeds are made into an ointment for external application to treat skin diseases. The seeds are also externally applied to kill head lice. The jungle tribes of the Malay Peninsula use the plant to poison their arrows and their Kriss. The fresh leaves of Anamirta cocculus are used for the treatment of quotidian ague in Bengal. In Ceylon the bruised fresh bark is useful for the snake  bite2. An ointment containing 80 grains of finely powdered seed to one ounce of Vaseline was used as external application in ring worm2 and the fruits juice is useful for ulcers and scabies. Fruits of Anamirta cocculus are officially listed in the Pharmacopoeias of various countries. The fruit and especially the seed contain picrotoxin, a very strong poison. Picrotoxin has been used intravenously as an antidote against poisoning by barbiturates and morphine3. However, the safe therapeutic dose range is very narrow. Very minute doses of Picrotoxin were used as a nerve tonic in schizophrenia, epilepsy and similar afflictions. In more recent time, it has been used in the treatment of peripheral and vestibular nystagmus, and in both long and short-term therapy for peripherally based dizziness and travel sickness. In homeopathic medicine the drug is used for nervous exhaustion, attacks of dizziness, cramps, paralysis, dysmenorrhoeal and occipital headaches3. According to the Unani system of medicine, the fruit is slightly bitter, good expectorant removes gas from the intestine, good for rheumatism and as an application for inflammations4. It is used in morphine and chlorine poisonings. In South-East Asia the fruit of Anamirta cocculus is used mainly as a fish poison 5 and as an insecticide.  For fish poison fresh or dry semi-ripe fruits with or without the fruit pulp is ground with shell-fish, shrimp or small crabs.  The resulting paste is made into pellets used as fish bait. Upon ingestion of these pills the fish become stupefied and will float to the surface, after which the fish must be swiftly eviscerated. This is done in order to reuse the bait and avoid contamination of the fish with the poison6. In the Indian Medicine leaves are used as a contracting agent for the womb after birth.  In the Philippines fruits are heated or roasted, crushed and powdered. The resulting powder is simply thrown in the water to stupefy the fish. In the past the fruit was sometimes used fraudulently in the United Kingdom to flavour beers with its bitterness. The bast-fibres are used for basketry rope and belt making. The traditional healers of southern Chhattisgarh use its seeds externally in form of herbal oil. The seeds are boiled in base oil and continue boiling until all watery contents were evaporated, then the special oil is kept for future use for different purpose4. It is massaged gently on painful parts along with mustard oil. It is also considered useful in treatment of rheumatic pain and used to dress the wounds. Plant used in treatment of skeletal fractures7. Seeds and berries used as piscicide8. The traditional healers of Chhattisgarh specialized in the different types of cancer treatment using its seeds internally as well as externally. It is also used in combination therapy to nullify the toxic effects and the exact mechanism of this plant is traditional secret so that the healers do not want to disclose. They have acquired this unique knowledge from their ancestors4.

 

Phytochemistry of Anamirta cocculus:

The seed contains about 1.5% of a bitter, crystalline, highly toxic substance, picrotoxin. This consists of equimolecular proportions of picrotoxinin, C15H16O7. Picrotoxinine is a highly oxygenated sequiterpene derivative9. The pericarp of Cocculus indicus contains two isomeric, tasteless, crystallisable alkaloids, termed menispermine (C18H24O2N) and paramenispermine (C18H24C2N), combined with an acid called hypopicrotoxic acid1. The tasteless moieties anamirtin and cocculin were also present along with fixed oil (11% to 24% of the seed). The seed was also rich in fatty acids9. The stem and roots of Anamirta cocculus contains quaternary alkaloids, such as beriberine, palmatine, magnoflorine and columbamine3, 10 and the major tertiary alkaloid as 1-8-oxotetrahydropalmatine10.  The structure (figure 2) of the new alkaloids further confirmed by Ultraviolet spectroscopy, Mass spectroscopy, 1H NMR and 13C NMR. The study also reported the chemical conversion in to 1-tetrahydropalmatine. Roy et al[11] isolated stearic acid from seeds and fumaric acid from the flowers. Lalith et al 12 has isolated one new triterpenoid and two new triterpenoid glycosides from the stem of Anamirta cocculus. The major compounds isolated were already known -arjunolic acid and its 28-O-β-D-glucopyranoside. None of the isolated compounds showed any molluscicidal or antifungal activity. Agarwal et al13 isolated picrotoxin, picrotoxinine, methyl picrotoxate and two new sesquiterpene lactones, dihydroxypicrotoxnin and picrotoxic acid whose structure were determined by spectroscopic method. Chemical structures of some major alkaloids of Anamirta cocculus are shown in Figure 1.

 

 

Figure 1: Structure of isolated alkaloids from Anamirta cocculus

 

Pharmacology of Anamirta cocculus:

Picrotoxin had been used to manage epilepsy at a dose of 0.3-0.6 mg and slightly higher dose to manage night sweating14. The effect of drug was due to the picrotoxic content. Picrotoxin paralyzes presynaptic blocking mechanism and like strychnine, has an analeptic effect in low doses. The central ends of the parasympathetic nerve are stimulated, as the medulla oblongata. Breathing frequency was initially increased and subsequently decreased. The pulse slows due to the stimulation of the vagus and increases in blood pressure.  Central Nervous system stimulated vomiting along with an increase in perspiration3. Dhar et al reported the anticancer activity of Anamirta cocculus 15.

 

Fruits of Anamirta cocculus contain about 1.5% picrotoxin, which was also known as cocculin. Picrotoxin was a crystalline equimolar mixture of 2 sesquiterpene dilactones, i.e. picrotoxinin and picrotin. In which only picrotoxinin was pharmacologically active. When taken internally, the seed was toxic to vertebrates affecting the central nervous system, stimulating the motor and inhibitory centers (especially the respiratory and vagus centres) in the medulla and acting on the heart and lungs with periodic stopping of motions of the diaphragm and diminished pulse. The poisoning causes vomiting, purging, profuse sweating, intoxication, dimness of vision and unconsciousness. Breathing and the pulse become weak. The poisoning also results in clonic convulsions; during spasms and intervals of relaxations, the pupils correspondingly contract or dilate. Death occurs rapidly due to respiration failure, or slowly from gastro-intestinal symptoms, particularly the medulla oblongata and respiratory centre. Furthermore, the fruits contain the isoquinoline alkaloids menispermine, paramenispermine, magnoflorine, stephorine, berberine, palmatine and l, 8-oxotetrahydropalmatine. In addition, the stem and roots contain only small amounts (about 0.1%) of the alkaloids berberine, palmatine, magnoflorine, columbamine and l, 8-oxotetrahydropalmatine. The stem also contains oxypalmine and stepharine. In general, the alkaloids isolated from Anamirta cocculus have antibacterial-, antimicrobial-, sympatholytical- (acetylcholine), and antifertility activities12.

 

CONCLUSION:

Anamirta cocculus remains a popular folk remedy in Asia and adjacent regions, contain a powerful poison picrotoxin was a crystalline equimolar mixture of two sesquiterpene dilactones, i.e. picrotoxinin and picrotin. The poisoning affects the CNS of vertebrates causes vomiting, purging, profuse sweating, dimness of vision, unconsciousness, intoxication and clonic convulsions. The fruits stem and roots contain varieties of alkaloids have antibacterial, antimicrobial, sympatholytica (acetylcholine), and antifertility activities. The alkaloids include menispermine, paramenispermine, magnoflorine, columbamine, stepharine, berberine, palmatine, oxypalmine and l, 8-oxotetrahydropalmatine. Although the use of the plant had been abandoned in US and Europe due to safety concerns, it is still uses for research and as popular folk remedy in Asia and adjacent regions.

 

CONFLICT OF INTEREST:

None

 

REFERENCES:

1.     Lyle EC and James ES. Herbs, Spices and Medicinal Plants, Recent Advances in Botany. Horticulture and Pharmacology, CBS publishers. Vol-4:192.

2.     Basu BD, Kirtikar KR and Basu K. Indian Medicinal Plants, Bishen Singh Mahendra Pal Singh. 2nd Ed; 1991: 80-83

3.     Thomson PDR Staff. PDR for herbal Medicines, Thomson PDR. 2nd Ed; 2000: 312–313.

4.     Grieve M. A modern Herbal [online]. Available from: http://botanical.com/botanical/mgmh/comindxc.html. [Accessed: 18 Jan 2012]. 

5.     Trease GE and Evan WC. Text book of Pharmacognosy, Bailliere Tindall. 15th Ed; 2003: 320.

6.     Duman ML and Sen DMD. Toxic Effects of Fish-seed (Anamirta cocculus) on Carp (Cyprinus carpio). Journal of Biological Sciences. 1 (11); 2001: 1093-1094.

7.     Fr. Raphael Tharayil. Sri Lanka For 1980, 14, 145, in Oushadha Sasyangal, 2; 1998: 818-819.

8.     Fr. Raphael Tharayil. Econ.Bot.1970, 24, 134 in Oushadha Sasyangal. 2; 1998: 818-819

9.     Agarwal M. Medicinal Plants. RBSA Publishers, Jaipur. 2002: 1-8.

10.   Verporate R, Swon J, Ticken M and Svendsen AB. Studies on Indonesian medicinal plants V; The Alkaloids of Anamirta cocculus. Journal of Natural products. 44 (2); 1981: 221-224.

11.   Roy R, Pathak NKR, Biswas M and Pandey VB. Phytochemical investigation of Anamirta cocculus Linn. Journal of Indian chemical Society. 74(1); 1997: 61.

12.   Lalith JG, Wannigama P and Macleod JK. Triterpenoids from Anamirta cocculus, Photochemistry. 34(4); 1993: 1111-1116.

13.   Agarwal SK, Singh SS, Verma S, Kumar S. Two picrotoxin derivatives from Anamirta cocculus, Phytochemistry. 50(8); 1999: 1365-1368.

14.   Berry L and Marderosian AD. The review of natural products. West Port Plaza: Facts & comparison. 3rd Ed. 1996: 451

15.   Dhar M, Dhawan BN, Prasad CR, Rastogi RP, Singh KK and Tandon. Screening of Indian plants for Biological Activity: Part V. Indian Journal of Experimental Biology. 12; 1974: 512-523.

 

 

 

 

Received on 04.01.2016       Modified on 10.04.2016

Accepted on 27.01.2016      ©A&V Publications All right reserved

Res.  J. Pharmacognosy and Phytochem. 2016; 8(2): 90-92

DOI: 10.5958/0975-4385.2016.00017.0