A Comprehensive Review on the Miracle Nature of Annona muricata Linn

Introduction

Medicinal plants are rich sources of ingredients that form the basis for health preservation. Plant-derived herbal compounds have a long history of clinical use, better patient tolerance and acceptance, and can be called the wealth of the traditional medicine system. A. muricata is one such traditional fruit plant that has been trending in use since decades due to its potential therapeutic effects. This plant belongs to the Annonaceae family and attracts the attention of the population due to its tremendous evidence of medicinal uses.^1-3

A. muricata is also called Graviola or Soursop or Gunbanana. The name soursop represents the sour and sweet flavour of its large fruit. The plant is locally seen in tropical regions such as South and Central America and the Caribbean and is now widely cultivated in tropical areas worldwide, including southern Florida and Southeast Asia. Successful cultivation requires altitudes of around 1150 meters from sea level. This plant shows allelopathic effect by inhibiting the growth of other plants growing around it. The plant produces specific biomolecules known as secondary metabolites that can induce suffering or give benefit to other plant species around it, a phenomenon known as allelopathy. The pulp of the fruit can be eaten and used as a main ingredient of many foods and beverages.⁴

A. muricata contains more than 212 phytochemical varieties in the extract of fruits, seeds, bark, roots, and pericarp which are used to treat various ailments.⁵ Ancient reports mention that A. muricata has been used as an insecticide and parasiticide. The fruit juice as well as leaf and bark infusions have been used to treat fever, pain, respiratory illness, sedative, malaria, gastrointestinal problems, arthritis, liver and kidney problems. In recent years, studies have shown that A. muricata also has anti-diabetic and anti-tumor activity.

The toxicity of several bioactive compounds of the plant has been reported in recent years.^1,2

Vernacular names

English – Soursop, Portuguese – Graviola, Latin American Spanish – Guanábana, Uganda – Omusitafeli or Ekitafeli, Thailand - Thu-rian-khack^1,4, Hindi – Shoolramaphala, Kannada – Hanumaphala or Lakshmanaphala, Malayalam – Mullatha, Tamil – Pulippu Palam.

Taxonomy 

Origin and distribution

A. muricata belongs to the Annonaceae family which comprise of approximately 130 genera and 2300 species. A. muricata is plentiful in the West Indies and in northern parts of South America. In recent days, it has extensively spread within the West Indies and from southern Mexico to Peru and Argentina.⁶ A. muricata is also found in the warmest tropical areas in North and South America and throughout tropical and subtropical parts of the world at altitudes below 1,200 m above sea level with temperature ranging from 25 to 28°C, relative humidity between 60 and 80% and annual rainfall above 1500 mm.^3,7

Plant Description

A. muricata is an evergreen, terrestrial and erect tree.³ The tree is bushy, low-branching and slender. The tree can reach up to 25-30 ft (7.5-9 m). Young branchlets have a rusty-hairy appearance (Figure 1).

Flowers

The tree bears flowers which emerge anywhere on the trunk, branches, or twigs. The flowers are triangular or conical in shape with outer petals of yellowish green and inner petals of pale yellow (Figure 2).

Leaves

The upper surface of the leaves is smooth, glossy, and dark green with light green underneath. The leaves may be oblong, elliptic or narrow obovate and pointed at both the ends. Leaves are 2.5 to 8 in (6.25 to 20 cm) long and 1 to 2.5 in (2.5 to 6.25 cm) wide (Figure 3).

Fruits

 The seeding fruit can be classified into sweet, subacid, and acid based on the aroma and taste, and can be further sub-classified into round, heart shaped, oblong, or angular. The size of the fruit ranges from 4-12 in (10- 30 cm) long and up to 6 in (15 cm) in width. One fruit weighs around 10-15 lbs (4.5-6.8 kg). The fruit is tender, and skin of the fruit is bitter, having soft spines which can break easily when the fruit is ripe. The skin of the fruit is a darker green in the immature fruit and turns soft, slight yellow when it becomes mature. The inner surface of the fruit is cream colored and separates from the mass of snow white, fibrous, and juicy segment easily. In each fertile segment of the fruit, a single oval, smooth, hard, black seed, 1.25-2 cm long can be seen6 (Figure 4).

Cultivation

Climate

It can be found at an altitude of 1,150 m from sea level with temperature ranging from 25 to 28◦ C, relative humidity ranging 60-80% and the annual rainfall above 1500 mm.

Soil

The finest growth of the plant is seen in deep, welldrained semi-dry soil. The tree commonly requires sandy acid soil and grows well in porous, oolitic limestone.

Propagation

The seed must be sown in flats or containers and kept in moist and shaded places. Germination takes about 15-30 days.

Culture

At the beginning of the rainy season, the pants of height about 1 ft (30 cm) are planted, with placed 12-15 ft (3.65- 4.5 m) apart. The trees grow rapidly and begin to give fruits in 3 to 5 years. Relevant fertilizers must be added depending on the geographical location. The season for the flowers and fruits varies with the geographical location.

Harvesting

The fully grown, slightly yellow coloured fruit can be plucked.

Yield

The tree can offer 12-20 or sometimes 24 fruits per tree. The yield starts to decline as the tree grows old.^4,7

Traditional Uses

In different locations of the world, people use the decoction of fruits, leaves, roots, and bark of the plant for many purposes.⁸

Fruits of A. muricata are used internationally as antipyretic, germicidal, astringent, anti-diarrheal and to increase mother’s milk. The unripe fruit along with olive oil is used in neuralgia, rheumatism, and arthritic – pain.

The leaves are used traditionally to treat headache, hypertension, cough, and asthma. The leaves are also used as antispasmodic, sedative and as a nervine tonic for heart conditions.⁹

The seeds and roots are used as bio pesticides, bio insecticides and insect repellents in different parts of the world.^1,2

Phytoconstituents

The extract of the A. muricata contains more than 212 varieties of phytoconstituents in it.⁵ Acetogenins, alkaloids, phenols and flavonoids are the chemicals most present and contributing to bioactivity. Several researchers have highlighted the presence of flavonol triglycosides, alkaloids, phenolics, megastigmanes, cyclopeptides and essential oils in their studies. The body obtains minerals such as calcium, sodium, iron, potassium, copper and magnesium upon consumption.¹⁰

Acetogenins

The acetogenins are a unique class of compounds considered as the main bioactive compound of the Annonaceae family and are thus also called annonaceous acetogenins. More than 120 acetogenins are identified in the various parts of the plant such as leaves, stem, bark, seed, pulp, and fruit peel. The bioactivity of A. muricata depends on the structure of the acetogenins. Annonacin is an important acetogenin found in the fruit and leaf abundantly, and in smaller amounts in the seeds, roots, and peel. Some studies have shown that acetogenins are more cytotoxic than alkaloids.

Alkaloids

Reticuline and coreximine are two important alkaloids present in A. muricata. The alkaloids are present more in the leaves and to a lesser extent in the roots, stems, and fruits in that order. The most important alkaloids present include isoquinoline, apomorphine and protoberberine. The alkaloids extracted from A. muricata have affinity towards 5-HT1A receptors which participate in the synthesis of dopamine and are thus found to have antidepressant activity and cytotoxic effects in the body.

Phenolic compounds

Reports show that A. muricata contains up to 37 phenolic compounds. The most important among those are quercetin and gallic acid. The pulp of the fruit contains tocopherols and tocotrienols in large amounts. Studies show that most phenols are found to be soluble in aqueous extract. Phenolic compounds are reported to be possess antioxidant property.

Other compounds

Several studies have identified the presence of other compounds such as vitamins, carotenoids, amides and cyclopeptides in the leaves, seeds, and fruit pulp. The seeds contain amides called N-p-coumaroyl tyramine and cyclopeptides which show anti-inflammatory and anti-tumor effects. In the pulp of the fruit, around 37 volatile compounds have been identified and sesquiterpene derivatives have been found in the leaf.^1,2,8 The pulp of the soursop also contains enzymes such as pectinase, catalase, and peroxidase. The enzyme amylase is detected during ripening and its activity increases around 18-fold as fruit ethylene level increases.¹¹

Pharmacological Activities

Plenty of in vitro, in vivo and in silico studies have been conducted on A. muricata that have shown promising pharmacological activity for the betterment of mankind.

Anti-cancer activity

Significant antiproliferative effects on various cancer cell lines of different extracts of the plant and isolated annonaceous acetogenins have been reported.^12,13 Studies have shown that the various extracts of A. muricata give more toxic effects on cancer cells than normal cells.¹³ A. muricata leaf/stem extract showed antitumor effects throughout the regulation of the tumor cell cycle by inducing apoptotic signals in tumor xenograft mice.⁵ Crude extract samples of A. muricata leaves showed anti-cancerous effects by reducing tumor’s size and weight, showing anti-metastatic features and inducing apoptosis of the 4T1 cells in vitro and in vivo, thus reporting different levels of cytotoxicity towards breast cancer cell lines (MCF-7, MDA-MB-231, and 4 T1).¹⁴ The aerial parts of the plant are also known for their in vitro and in vivo pharmacological activities.¹³ It is reported that the ethanolic extract of the plant inhibit the growth of liver cancer cell HepG215 by its apoptogenic nature.¹⁶ The leaf extract of the plant, rich in flavanoid and acetogenin, show negative effect on prostate cancer proliferation. Another study on the plant extract also showed its effect against pancreatic cancer cells by inhibiting the pathways responsible for pancreatic cell growth. A. muricata extract showed apoptosis induction in lung cancer cells. A. muricata extract also showed anti-colon cancer effect on cell lines by inducing the G1 cell cycle arrest.¹⁷

Antiparasitic activity

Protozoal infection is a serious health problem across the world. The stem extract of A. muricata showed promising activity against Leishmania species and Trypanosoma cruzi.¹⁸ Ethyl acetate, methanol and hexane extracts of A. muricata pericarp showed activity against the L. Braziliensis and L. Panamensi, with ethyl acetate exhibiting more activity.¹⁹ It is also reported that methanol: water (80:20) extract of A. muricata seeds has leishmanicidal activity.²⁰ The pentane extract of A. muricata leaf showed toxicity against chloroquine sensitive and resistant strains.²¹

Antioxidant activity

Generation of intracellular reactive oxygen species (ROS) results in oxidative stress which subsequently catalyzes metabolic deficiency and cellular death through biochemical and physiological lesions.⁸ It is reported that antioxidant activity is found more in the leaves and seeds when compared to the fruit-skin of A. muricata. The higher antioxidant potential of leaves and seeds of A. muricata has been attributed to the presence of both enzymatic and non-enzymatic antioxidants, including catalase and superoxide dismutase as well as tocopherol and ascorbic acid.²² The extracts from the bark and stem of A. muricata are reported to reduce lipid peroxidation in the brain and liver of rats subjected to cold-immobilized stress, showing apoptogenic characteristics. Several other researchers have also reported that various plant parts of A. muricata such as leaves, pulp, stem, bark, and root have significantly reduced lipid peroxidation in vitro and in vivo.²³ Ethanolic extract of stem bark of A. muricata also shows protective effects against oxidative stress induced by carbon tetrachloride in rats and significantly increases the oxidant levels and serum enzyme activities to near normal.²⁴

Anti-Inflammatory and Anti-Nociceptive activities

Oral administration of ethanolic leaf extract of A. muricata shows protective effect against Complete Freund’s adjuvant (CFA)-induced arthritis in rats and xylene-induced ear edema in mice, associated with decrease in TNF-α and IL-1β protein expression, proving that the leaves could be used against both acute and chronic inflammation.²⁵ The fruit extract of A. muricata showed anti-inflammatory and analgesic activity. A. muricata increased the time threshold of mice on hot plate and decreased the paw circumference induced by carrageenan.⁹

Antihypertensive activity

The antihypertensive properties of A. muricata leaves were evaluated by taking the aqueous leaf extract and administering it to normotensive Sprague–Dawley rats. The results showed that treatment of rats with the leaf extract significantly decreased blood pressure without affecting heart rate, in a dose dependent manner. This effect was proposed to be induced through peripheral mechanisms involving the antagonism of Ca2+.²⁶

Hypoglycemic activity

The methanolic leaf extract of A. muricata was shown to bring about a decrease in blood sugar in the streptozotocin induced diabetic rat.²⁷ It is also reported that the administration of aqueous extract of A. muricata leaves orally to streptozotocin induced rats showed a decrease in blood sugar level. It is also reported that the aqueous extract has antioxidant, hypolipidemic and protective actions on pancreatic β-cells responsible for improving glucose metabolism.²⁸

Gastroprotective activity and Hepatoprotective activity

In vivo studies demonstrated that the ethyl acetate extract of A. muricata leaves showed promising effects against ethanol induced gastric mucosal injury, which were assumed to be through reactive oxygen species (ROS)- scavenging activity and the protective activity against gastric mucosal damage.²⁹ The aqueous leaf extract of A. muricata was reported to have hepatoprotective effect in carbon tetrachloride and acetaminophen – induced liver damage. Leakage of enzymes from cells due to altered permeability of the membrane occurs as a result of hepatic injury, and the ensuing disturbance in the transport function of the hepatocytes, which was reversed by the extract.³⁰

Anxiolytic activity

A study on aqueous leaf extract of A. muricata showed its anxiolytic effect in an in vivo anxiety model. It also showed that the extract causes minimum side effects on the microanatomy of the cerebrum.³¹

Wound healing activity

It is reported that the ethyl acetate extract of A. muricata leaves accelerate wound healing, including wound contraction, epithelization and collagen synthesis in rats. It was also found to decrease oxidative and inflammatory stresses in the wound area. The treated wounds were observed to generate organized collagen fibre with reduced number of inflammatory cells.³²

Contraindications

A. muricata was revealed as a uterine stimulant in an animal study (on rats) and should not be used during pregnancy. It is also demonstrated to have hypotensive, vasodilator, and cardio depressant activities in animal studies and therefore is contraindicated for people with low blood pressure. Taking anti-hypertensive drug(s) along with the A. muricata can also be a contraindication. A. muricata has been demonstrated to have significant in vitro antimicrobial properties, and chronic use of the plant may lead to a decrease in the friendly bacteria of the digestive tract. Therefore, supplementing with probiotics and digestive enzymes is suggested when the plant is used for more than 30 days.⁸

Toxicology

Annonacin present in A. muricata is found to be neurotoxic in the nanomolar concentration. Also, acetogenins present in the plant are potent mitochondrial poisons, and a potential compound causing parkinsonism. Aqueous extract of the fruit and leaf, with high concentration of annonacin, can cross the blood brain barrier easily and induce neurodegeneration of basal ganglia in test animals.³³ Mutagenic effect tested by Ames test, was not observed in the extract containing annonacin (1000 lg/plate).²

Conclusion

A. muricata is an evergreen plant and is distributed almost throughout the world. A. muricata extract contains more than 212 varieties of phytoconstituents. Annonaceous acetogenins are important chemical constituents present almost everywhere in the plant and contribute to human ailments. Alkaloids, flavanoids and phenols present in this plant show a large spectrum of activity. In different places of the world, people use the decoction of fruit, leaves, roots and bark of the plant for many purposes. Cytotoxic, antiparasitic, antiinflammatory and antioxidant activities of the plant are the most promising. Previous research has been mostly concerned with the biological activity of the plant extract. Further investigations on the biochemical and physiological functions of active compounds and the detailed mechanisms underlying these activities is required. Several reports suggest the neurotoxicological effect of the important constituent annonacin. A clear distinction of the chemical constituents with their dose and toxicity are crucial. Future research and clinical trials must concentrate on the compounds contributing toxicity and its dose and effect on the body. This article is hoped to be a source of enlightenment and motivation for researchers to study this plant further.

Conflicts of interest

None.