What is soursop

Soursop also known as Annona muricata, graviola, sirsak and guanabana, is an evergreen plant that is mostly distributed in tropical and subtropical regions of the world ¹. Soursop is a member of the Annonaceae family comprising approximately 130 genera and 2300 species ², ³. Annona muricata is a fruit tree with a long history of traditional use. The soursop fruits are extensively used to prepare syrups, candies, beverages, ice creams and shakes.

Soursop is native to the warmest tropical areas in South and North America and is now widely distributed throughout tropical and subtropical parts of the world, including India, Malaysia and Nigeria ⁴. Annona muricata is an evergreen, terrestrial, erect tree reaching 5–8 m in height and features an open, roundish canopy with large, glossy, dark green leaves. Soursop, the edible fruits of the Annona muricata tree are large, heart-shaped and green in color, and the diameter varies between 15 and 20 cm (Figure 1) ⁵.

Figure 1. Soursop fruit

Figure 2. Soursop tree (Annona muricata), leaves, flowers and fruits

Soursop health benefits

Traditional Medicinal Uses

All portions of the Annona muricata tree, similar to other Annona species, including Annona squamosa and Annona reticulata are extensively used as traditional medicines against an array of human ailments and diseases, especially cancer and parasitic infections ¹. The fruit is used as natural medicine for ¹:

• arthritic pain,
• neuralgia,
• arthritis,
• diarrhea,
• dysentery,
• fever,
• malaria,
• parasites,
• rheumatism,
• skin rashes and
• worms.

And soursop is also eaten to elevate a mother’s milk after childbirth ¹.

Traditionally, the soursop leaves are used for headaches, insomnia, cystitis, liver problems, diabetes, hypertension and as an anti-inflammatory, antispasmodic and antidysenteric ⁶, ⁷. The decoction of the soursop leaves have parasiticide, anti-rheumatic and anti-neuralgic effects when used internally, while the cooked leaves, applied topically, fight rheumatism and abscesses ⁸, ², ⁴, ⁹.

The chemical constituents annomuricins A and B, gigantetrocin A, annonacin-10-one, muricatetrocins A and B, annonacin, goniothalamicin ¹⁰, muricatocins A and B, annonacin A, (2,4-trans)-isoannonacin, (2,4-cis)-isoannonacin ¹¹, annomuricin C, muricatocin C, gigantetronenin ¹², annomutacin, (2,4-trans)-10R-annonacin-A-one, (2,4-cis)-10R-annonacin-A-one ¹³, annopentocins A, B and C, cis- and trans-annomuricin-D-ones ¹⁴, annomuricine, muricapentocin ¹⁵, muricoreacin and murihexocin C ¹⁶ and annocatacin A and B ¹⁷ were identified in the soursop leaves. These acetogenins have cytotoxic properties against tumor cell lines ¹⁷ and molluscicidal activity ¹⁸. In addition, A. muricata leaf extracts have antioxidant ¹⁹ and molluscicidal properties ²⁰.

The crushed soursop seeds are believed to have anthelmintic activities against external and internal worms and parasites. In tropical Africa, the plant is used as an astringent, insecticide and piscicide agent and to treat coughs, pain and skin diseases. In India, the fruit and flower are employed as remedies against catarrh, while the root-bark and leaves are believed to have antiphlogistic and anthelmintic activities ²¹, ²². In Malaysia, the crushed leaf mixture of soursop together with A. squamosa and Hibiscus rosa-sinensis is used as a juice on the head to protect against fainting ²³. In South America and tropical Africa, including Nigeria, soursop leaves are deployed as an ethnomedicine against tumors and cancer ²¹. In addition, the anti-inflammatory, hypoglycemic, sedative, smooth muscle relaxant, hypotensive and antispasmodic effects are also attributed to the leaves, barks and roots of A. muricata ², ⁴. In addition to traditional medicinal uses, the soursop fruits are widely employed for the preparation of beverages, candy, ice creams, shakes and syrups ²⁴, ²⁵.

Soursop Plant Chemical Compositions

Extensive phytochemical evaluations on different parts of the soursop plant have shown the presence of various phytoconstituents and compounds, including alkaloids (reticulin, coreximine, coclarine and anomurine) ²⁶, ²⁷, megastigmanes ²⁸, flavonol triglycosides ²⁹, phenolics ³⁰, cyclopeptides and essential oils (β-caryophyllene, δ-cadinene, epi-α-cadinol and α-cadinol) ³¹, ³². In addition, Annona species, including soursop, have been shown to be a generally rich source of annonaceous acetogenin compounds ³³. The presence of different major minerals such as K, Ca, Na, Cu, Fe and Mg suggest that regular consumption of the soursop fruit can help provide essential nutrients and elements to the human body ³⁴.

Table 1. Chemical compounds isolated from soursop plant

Plant Part	Compound	Class	Biological Activity
Fruits	annonaine	ALK	anti-depressive
Fruits	nornuciferine	ALK	anti-depressive
Fruits	asimilobine	ALK	anti-depressive
Fruits	epomusenin-A	AGE	–
Fruits	epomusenin-B	AGE	–
Fruits	epomurinin-A	AGE	–
Fruits	epomurinin-B	AGE	–
Fruits	cis-annoreticuin	AGE	–
Fruits	muricin J	AGE	toxicity against prostate PC-3 cancer cells
Fruits	muricin K	AGE	toxicity against prostate PC-3 cancer cells
Fruits	muricin L	AGE	toxicity against prostate PC-3 cancer cells
Fruits	cinnamic acid derivative	PL	–
Fruits	coumaric acid hexose	PL	–
Fruits	5-caffeoylquinic acid	PL	–
Fruits	dihydrokaempferol-hexoside	PL	–
Fruits	p-coumaric acid	PL	–
Fruits	caffeic acid derivative	PL	–
Fruits	dicaffeoylquinic acid	PL	–
Fruits	feruloylglycoside	PL	–
Fruits	4-feruloyl-5-caffeoylquinic acid	PL	–
Fruits	p-coumaric acid methyl ester	PL	–
Leaves, Pericarp	annomuricin A	AGE	toxicity against brine shrimp, lung A549, breast MCF-7 and colon HT-29 cancer cells
Leaves	annomuricin B	AGE	toxicity against brine shrimp, lung A549, breast MCF-7 and colon HT-29 cancer cells
Leaves	annomuricin C	AGE	toxicity against brine shrimp, lung A549, breast MCF-7 and colon HT-29 cancer cells
Leaves	annomuricin E	AGE	toxicity against pancreatic MIA PaCa-2 and colon HT-29 cancer cells
Leaves	annomutacin	AGE	toxicity against lung A549 cancer cells
Leaves	(2,4-cis)-10R-annonacin-A-one	AGE	toxicity against lung A549 cancer cells
Leaves	(2,4-trans)-10R-annonacin-A-one	AGE	toxicity against lung A549 cancer cells
Leaves	annohexocin	AGE	toxicity against brine shrimp and different cancer cells
Leaves	muricapentocin	AGE	toxicity against pancreatic MIA PaCa-2 and colon HT-29 cancer cells
Leaves	(2,4-cis)-isoannonacin	AGE	–
Leaves, Seeds	(2,4-trans)-isoannonacin	AGE	–
Leaves	muricatocin A	AGE	toxicity against lung A549 cancer cells
Leaves	muricatocin B	AGE	toxicity against lung A549 cancer cells
Leaves	muricatocin C	AGE	toxicity against brine shrimp, lung A549, breast MCF-7 and colon HT-29 cancer cells
Leaves, Seeds	gigantetronenin	AGE	–
Leaves, Seeds, Pericarp	annonacin A	AGE	–
Leaves	annopentocin A	AGE	toxicity against pancreatic MIA PaCa-2 cancer cells
Leaves	annopentocin B	AGE	toxicity against lung A549 cancer cells
Leaves	annopentocin C	AGE	toxicity against lung A549 cancer cells
Leaves	cis-annomuricin-D-one	AGE	toxicity against lung A549, colon HT-29 and pancreatic MIA PaCa-2 cancer cells
Leaves	trans-annomuricin-D-one	AGE	toxicity against lung A549, colon HT-29 and pancreatic MIA PaCa-2 cancer cells
Leaves	murihexocin A	AGE	toxicity against different cancer cells
Leaves	murihexocin B	AGE	toxicity against different cancer cells
Leaves	murihexocin C	AGE	toxicity against different cancer cells
Leaves	muricoreacin	AGE	toxicity against different cancer cells
Leaves	cis-corossolone	AGE	toxicity against human hepatoma cells
Leaves	annocatalin	AGE	toxicity against human hepatoma cells
Leaves	annocatacin B	AGE	toxicity against human hepatoma cells
Leaves	anonaine	ALK	neurotoxic
Leaves	isolaureline	ALK	–
Leaves	xylopine	ALK	–
Leaves	Quercetin 3-O-α-rhamnosyl-(1→6)-β-sophoroside	FTG	–
Leaves	gallic acid	FTG	–
Leaves	epicatechine	FTG	–
Leaves	quercetin 3-O-rutinosid	FTG	–
Leaves	quercetin 3-O-neohispredoside	FTG	–
Leaves	quercetin 3-O-robinoside	FTG	–
Leaves	catechine	FTG	–
Leaves	chlorogenic acid	FTG	–
Leaves	argentinine (1-N,N-dimethylethanyl-4,6-dimethoxy-3,8-dihydroxy-phenanthrene)	FTG	–
Leaves	kaempferol 3-O-rutinoside	FTG	–
Leaves	quercetin 3-O-glucoside	FTG	–
Leaves	quercetin	FTG	–
Leaves	kaempferol	FTG	–
Leaves	annonamine	ALK	–
Leaves	(S)-norcorydine	ALK	–
Leaves	(R)-4′-O-methylcoclaurine	ALK	–
Leaves	(R)-O,O-dimethylcoclaurine	ALK	–
Leaves	annoionol A	MG	–
Leaves	annoionol B	MG	–
Leaves	annoionol C	MG	–
Leaves	annoionoside	MG	–
Leaves	vomifoliol	MG	–
Leaves	roseoside	MG	–
Leaves	turpinionoside A	MG	–
Leaves	citroside A	MG	–
Leaves	blumenol C	MG	–
Leaves	(+)-epiloliolide	MG	–
Leaves	loliolide	MG	–
Leaves	(1S,2S,4R)-trans-2-hydroxy-1,8-cineole β-d-glucopyranoside	MG	–
Leaves	(Z)-3-hexenyl β-d-glucopyranoside	MG	–
Leaves	rutin	MG	–
Leaves	kaempferol 3-O-rutinoside	MG	–
Leaves	kaempferol 3-O-robinobioside	MG	–
Leaves	kaempferol 3-O-β-d-(2′′-O-β-d-glucopyranosyl,6′′-O-α-l-rhamnopyranosyl)glucopyranoside	MG	–
Roots	montecristin	AGE	–
Roots	cohibin A	AGE	–
Roots	cohibin B	AGE	–
Roots	cis-solamin	AGE	–
Roots	cis-panatellin	AGE	–
Roots	cis-uvariamicin IV	AGE	–
Roots	cis-uvariamicin I	AGE	–
Roots	cis-reticulatacin	AGE	–
Roots	cis-reticulatacin-10-one	AGE	–
Roots	chatenaytrienin 1	AGE	–
Roots	chatenaytrienin 2	AGE	–
Roots	chatenaytrienin 3	AGE	–
Roots	muridienin 3	AGE	–
Roots	muridienin 4	AGE	–
Roots	muricadienin	AGE	–
Roots	coronin	AGE	–
Roots, Fruits	sabadelin	AGE	–
Seeds	murisolin	AGE	–
Seeds	muricatacin	AGE	toxicity against lung A549, breast MCF7, colon HT-29 cancer cells
Seeds, Leaves, Pericarp	annonacin	AGE	neurotoxic, molluscicidal, inhibitor of mitochondrial complex I
Seeds, Leaves	corossolone	AGE	toxicity against oral KB cancer cells and brine shrimp larva, antileishmanial
Seeds	corossolin	AGE	toxicity against oral KB cancer cells and brine shrimp larva
Seeds, Roots, Leaves	solamin	AGE	toxicity against oral KB cancer and normal kidney VERO cells
Seeds	corepoxylone	AGE	–
Seeds, Leaves	annonacin-10-one	AGE	–
Seeds	isoannonacin	AGE	molluscicidal, anticancer
Seeds	isoannonacin-10-one	AGE	–
Seeds, Leaves	goniothalamicin	AGE	molluscicidal
Seeds	gigantetrocin	AGE	–
Seeds, Leaves	gigantetrocin A	AGE	toxicity against colon HT-29 cancer cells
Seeds	gigantetrocin B	AGE	toxicity against colon HT-29 cancer cells
Seeds, Leaves	muricatetrocin A	AGE	toxicity against colon HT-29 cancer cells
Seeds, Leaves	muricatetrocin B	AGE	toxicity against colon HT-29 cancer cells
Seeds, Leaves	epomuricenin A	AGE	–
Seeds, Leaves	epomuricenin B	AGE	–
Seeds	annomuricatin A	CP	–
Seeds	annocatacin A	AGE	toxicity against human hepatoma cells
Seeds	annomuricatin C	CP	–
Seeds	cis-annonacin	AGE	crown gall tumor inhibition, toxicity against brine shrimp, lung A549, breast MCF-7 and colon HT-29 cancer cells
Seeds	cis-annonacin-10-one	AGE	crown gall tumor inhibition, toxicity against brine shrimp, lung A549, breast MCF-7 and colon HT-29 cancer cells
Seeds	cis-goniothalamicin	AGE	crown gall tumor inhibition, toxicity against brine shrimp, lung A549, breast MCF-7 and colon HT-29 cancer cells
Seeds	arianacin	AGE	crown gall tumor inhibition, toxicity against brine shrimp, lung A549, breast MCF-7 and colon HT-29 cancer cells
Seeds	javoricin	AGE	crown gall tumor inhibition, toxicity against brine shrimp, A549, breast MCF-7 and colon HT-29 cancer cells
Seeds	murihexol	AGE	–
Seeds	donhexocin	AGE	–
Seeds	cohibin C	AGE	–
Seeds	cohibin D	AGE	–
Seeds	muricatenol	AGE	–
Seeds	2,4-cis-gigantetrocinone	AGE	–
Seeds	2,4-trans-gigantetrocinone	AGE	–
Seeds	2,4-trans-isoannonacin-10-one	AGE	–
Seeds	annomontacin	AGE	–
Seeds	longifolicin	AGE	toxicity against human hepatoma cells
Seeds	muricin A	AGE	toxicity against human hepatoma cells
Seeds	muricin B	AGE	toxicity against human hepatoma cells
Seeds	muricin C	AGE	toxicity against human hepatoma cells
Seeds	muricin D	AGE	toxicity against human hepatoma cells
Seeds	muricin E	AGE	toxicity against human hepatoma cells
Seeds	muricin F	AGE	toxicity against human hepatoma cells
Seeds	muricin G	AGE	toxicity against human hepatoma cells
Seeds	muricin H	AGE	toxicity against human hepatoma cells
Seeds	muricin I	AGE	toxicity against human hepatoma cells
Seeds	cis-annomontacin	AGE	toxicity against human hepatoma cells
Seeds, Leaves	annonacinone	AGE	–
Seeds	xylomaticin	AGE	–
Seeds	N-fatty acyl tryptamines	ALK	–
Seeds	annoreticuin-9-one	AGE	–
Stem barks	epoxymurin A	AGE	–
Stem barks	epoxymurin B	AGE	–
Leaves, Roots, Stems, Barks	reticuline	ALK	–
Leaves, Roots, Stems, Barks	coclaurine	ALK	–
Leaves, Roots, Stems, Barks	coreximine	ALK	–
Leaves, Roots, Stems, Barks	atherosperminine	ALK	–
Leaves, Roots, Stems, Barks	stepharine	ALK	–
Leaves, Roots, Stems, Barks	anomurine	ALK	–
Leaves, Roots, Stems, Barks	anomuricine	ALK	–

Note: ALK: alkaloid; AGE: annonaceous acetogenin; MG: megastigmane; FTG: flavonol triglycoside; PL: phenolic; CP: cyclopeptide.

[Source ¹]

Biological Activities of Soursop

Anti-Arthritic Activity

A. muricata is among the ethnomedicines employed to treat arthritic pain. An in vivo study on different doses (3, 10, 30 and 100 mg/kg) of ethanolic extract from soursop leaves has investigated the anti-arthritic activity in complete Freund’s adjuvant (CFA)-induced arthritis in rats. According to the results, oral administration of the extract reduced the edema in a dose-dependent manner after two weeks of injection. Because the extract at higher doses significantly suppressed TNF-α and IL-1β expression in local tissue, the anti-arthritic activity of A. muricata leaves contributed to the suppression of pro-inflammatory cytokines ³⁵. Hence, the anti-arthritic potential of A. muricata was substantiated by the findings of this in vivo study.

Anticancer Activity

Plenty of studies report the significant antiproliferative effects of different extracts of the plant and isolated AGEs towards various cancer cell lines ³⁶; however, few of these studies have illustrated the underlying mechanism of action. Recent in vitro studies were performed by our research group to determine the mechanism of action of ethyl acetate extract of A. muricata leaves against colon cancer cells (HT-29 and HCT-116) and lung cancer cells (A549). The leaf extract was able to induce apoptosis in colon and lung cancer cells through the mitochondrial-mediated pathway. This antiproliferative effect was associated with cell cycle arrest in the G1 phase ³⁷. In addition, the migration and invasion of colon cancer cells were significantly inhibited by the leaf extract. The activation of caspase 3 by the ethanolic extract of the leaves also demonstrated an apoptosis-inducing effect in myelogenous leukemic K562 cells, which was confirmed with a TUNEL assay ³⁸.

Recent in vitro and in vivo studies were performed on the water extract of the soursop leaves against the benign prostatic hyperplasia (BPH-1) cell line and rats’ prostates. The results showed a suppressive effect on BPH-1 cells with an IC50 value of 1.36 mg/mL after 72 h associated with an up-regulation of Bax and a down-regulation of Bcl-2 at the mRNA level. After two months of treatment with the extract (30 and 300 mg/mL doses), the size of the rats’ prostates were decreased, which was suggested to occur through apoptosis induction ³⁹. This promising antitumor effect also reported in an in vivo study on 7,12-dimethylbenzene anthracene (DMBA)-induced cell proliferation in the breast tissues of mice. The protective effect against DNA damage induced by DMBA showed that oral administration of the A. muricata leaves may have protective effects towards the development of breast carcinogenesis ⁴⁰. The leaves, even at the low dose of 30 mg/kg suppressed the initiation and promotion stage of skin papillomagenesis in mice that was induced by DMBA and croton oil, respectively ⁴¹.

Moghadamtousi and colleagues ⁴² also examined the in vivo chemopreventive potential of the ethyl acetate extract of the A. muricata leaves against azoxymethane-induced colonic aberrant crypt foci (ACF) in rats. The oral administration of the extract at two doses (250 and 500 mg/kg) for 60 days significantly reduced ACF formation in rats, as assessed by methylene blue staining of colorectal specimens. The immunohistochemistry analysis showed that this activity was accompanied by the up-regulation of Bax and the down-regulation of Bcl-2. This significant reduction in ACF formation was also reported for the ethanolic extract of the leaves against 1,2-dimethyl hydrazine (DMH)-induced colon cancer ⁴³. Our study was followed by an in vitro bioassay-guided investigation against HT-29 cells, which led to the isolation of annomuricin E. This AGE showed mitochondrial-dependent apoptosis activity in colon cancer cells with an IC50 value of 1.62 ± 0.24 µg/mL after 48 h ⁴⁴.

Anticancer studies on sourssop were not only limited to in vitro and in vivo investigations. A case study of a 66-year old woman with a metastatic breast cancer reported that consumption of the leaves boiled in water and Xeloda resulted in stabilization of the disease ⁴⁵. These substantial anticancer and antitumor activities mentioned for A. muricata leaves led to tablet formulations of the ethyl acetate-soluble fraction of the leaves, which contains AGEs that can be used as a cancer adjuvant therapy ⁴⁶

Anticonvulsant Activity

In African countries, the decoction of the A. muricata leaves is traditionally used to control fever and convulsive seizures ⁴⁶. To substantiate the anticonvulsant activity of the leaves in ethnomedicine, Gouemo and colleagues ⁴⁷ investigated the effect of the ethanolic extract of the leaves against pentylenetetrazol-induced tonic-clonic seizures in mice. The result showed that the plant extract at 100 and 300 mg/kg doses significantly decreased the incidence and the mortality rate of tonic seizures. Administration of the extract to mice also lengthened the onset of clonic seizures. This study showed that a subsequent bioassay-guided investigation may lead to the isolation of a bioactive compound that can be used as an anticonvulsant drug.

Antidiabetic and Hypolipidemic Activity

The chronic disease of diabetes mellitus afflicts a large proportion of people all around the world. Therefore, an effective natural adjuvant therapy would be blindingly beneficial to diminish diabetic complications and augment the quality of life for diabetic patients. Due to the traditional application of A. muricata against diabetes, several studies have investigated this potential in vivo. Adeyemi and colleagues ⁴⁸ reported that daily intraperitoneal injection of streptozotocin-induced diabetic Wistar rats with the methanol extract of A. muricata leaves (100 mg/kg) for two weeks significantly reduced their blood glucose concentration from 21.64 to 4.22 mmol/L ⁴⁸. In addition, the extract at the same dose significantly decreased the serum total cholesterol, low-density lipoprotein, triglyceride and very low-density lipoprotein cholesterol ⁴⁸.

Based on the ethnopharmacological application of soursop leaves against diabetes in Cameroon, another similar study examined the aqueous extract of the leaves against streptozotocin-induced diabetes in rats and reported the same promising antidiabetic activities. This activity was explained by its antioxidant and hypolipidemic potentials and protective effects against pancreatic β-cells ⁴⁹. Histopathological examination showed that the leaf extract caused the regeneration of β-cells in the pancreas islets ⁵⁰. The stem bark ethanolic extract also demonstrated promising antidiabetic and hypolipidemic activities against alloxan- induced diabetic rats. Treatment with the extract (150 and 300 mg/kg) to rats for 14 days lowered the increased blood glucose and was associated with a reduction in cholesterol and triglyceride levels ⁵¹.

Anti-Inflammatory and Anti-Nociceptive Activities

Oral treatment in rats with A. muricata ethanolic leaf extracts (10, 30, 100 and 300 mg/kg) significantly reduced carrageenan-induced edema in rat paws by 79% in a dose-dependent manner, exhibiting its anti-inflammatory activities ⁵². This anti-inflammatory effect was accompanied by reductions in the leukocyte migration and exudate volume ⁹. Oral administration in mice with the same extract showed significant suppression of abdominal contortions induced with acetic acid (0.6% v/v), exhibiting a powerful anti-nociceptive activity ⁵³. In addition, the formalin test and paw licking and hot-plate responses also corroborated the marked analgesic effect of the A. muricata leaves ⁵³. The protective effect of the soursop leaves against Complete Freund’s adjuvant (CFA)-induced arthritis in rats and xylene-induced ear edema in mice was associated with an attenuation in the TNF-α and IL-1β protein expression, demonstrating that the leaves could be used against both acute and chronic inflammation ⁵³. The same assays showed the anti-inflammatory and analgesic activities for the soursop fruits, which were shown to be induced through the suppression of inflammatory mediators and interactions with the opioidergic pathway, respectively ⁵⁴. These findings demonstrated the anti-nociceptive and anti-inflammatory effects of A. muricata and substantiated its traditional consumption as pain killer.

Antioxidant Activity

Immoderate generation of intracellular reactive oxygen species (ROS) is a precursor of oxidative stress which subsequently catalyzes metabolic deficiency and cellular death through biochemical and physiological lesions. The identification of antioxidants from natural products has become a matter of great interest in recent studies for their noteworthy role in nullifying the destructive effects of ROS. DRSA, FRAP and HRSA tests on aqueous and methanolic leaf extracts of soursop revealed the marked antioxidative activities of both extracts accompanied with DNA protective effects against H2O2-induced toxicity ⁵⁵. The antioxidant activity of the A. muricata leaves was found to be stronger than A. squamosa and A. reticulata species as shown through different in vitro models, such as ABTS, nitric oxide and hydroxyl radicals ⁵⁶. The seeds and leaves of the plant are reported to possess enzymatic antioxidants, including catalase and superoxide dismutase, and non-enzymatic antioxidants, including vitamin C and E ⁵⁷. Padma and colleagues showed that the ethanolic extract of the A. muricata stem bark caused a reduction in lipid peroxidation induced by cold immobilization stress in the brain and liver of rats, indicating the adaptogenic potential of this plant. The stem bark extract (200 mg/kg) also showed protective effects against oxidative stress induced by carbon tetrachloride in rats and significantly increased the oxidant levels and serum enzyme activities to near normal. The DPPH test showed the antioxidant activity of the stem bark ⁵⁸. These findings strongly suggest the potential use of A. muricata as a natural source of antioxidants.

Antihypertensive Activity

To evaluate the antihypertensive properties of soursop leaves, aqueous leaf extract (9.17–48.5 mg/kg) was administered to normotensive Sprague–Dawley rats. The results demonstrated that treatments of rats with the leaf extract significantly decreased blood pressure in a dose-dependent manner without affecting heart rates. This effect was suggested to be induced through peripheral mechanisms involving the antagonism of Ca2+ ³⁵.

Antiparasitic Activity

Protozoal infections cause debilitating diseases, such as leishmaniasis and trypanosomiasis, which have both afflicted a noteworthy proportion of the world population. The development of resistance to empirically discovered drugs represents a major hindrance to treatment of protozoal diseases. Moreover, in case of long-term usage, toxicity and several side effects have made the available treatments more unsatisfactory. As a natural agent, A. muricata has been subjected to various pathogenic parasites to determine its cytotoxic effects. The ethyl acetate leaf extract of soursop was assayed against three Leishmania species (PH8, M2903 and PP75) and Trypanosoma cruzi. Promising activity was reported with IC50 values lower than 25 µg/mL ⁵⁹. The same promising antileishmanial effect was reported against L. braziliensis and L. panamensis species with a toxicity effect higher than Glucantime, which was used as a positive control. A bioassay-guided investigation on the A. muricata seeds against three Leishmania species, namely donovani, mexicana and major, led to the isolation of two AGEs as the bioactive compounds. Isolated annonacinone and corossolone elicited an EC50 dose of 6.72–8.00 and 16.14–18.73 µg/mL against the tested species, respectively ⁶⁰. A bioassay-guided investigation on the seeds of A. muricata against two forms of L. chagasi, promastigote and amastigote, also led to the isolation of the same bioactive AGE compounds, annonacinone and corossolone ⁶¹. In addition, the methanolic extract of A. muricata seeds showed significant antiparasitic activity against the infective larvae of Molinema dessetae, and this activity was contributed to its isolated AGEs ⁶². A recent in vitro investigation on A. muricata aqueous leaf extract was performed against Haemonchus contortus, a gastrointestinal parasite. The result showed 89.08% and 84.91% toxicity against larvae and eggs as assessed by larval motility and egg hatch tests. The immobilization of adult worms within 6 to 8 h of exposure to different doses of the extract revealed a promising anthelmintic activity in the leaves ⁶³.

Antiplasmodial Activity

Malaria, one of the most debilitating diseases, afflicts a substantial population in tropical and subtropical zones. The available antimalarial drugs demonstrate varying degrees of failure due to rapid spread of parasite resistance. Therefore, research into new antiplasmodial agents against the pathogenic parasites is definitely warranted. The pentane leaf extract of A. muricata was assayed against two strains of Plasmodium falciparum: the Nigerian chloroquine-sensitive strain and FcM29-Cameroon (chloroquine-resistant strain); a promising antiplasmodial effect was obtained with an IC50 value of 16 and 8 µg/mL after 72 h, respectively ⁶⁴. The leaf extract, also at 20 µg/mL, showed a 67% inhibition against an asynchronous F32 strain of P. falciparum ⁶⁵. Another study on different extracts of A. muricata leaves and stems also confirmed the reported cytotoxic effects against the chloroquine-sensitive (F32) and -resistant (W2) P. falciparum ⁶⁶. These findings substantiated the traditional use of A. muricata as an antimalarial agent.

Hepatoprotective and Bilirubin-Lowering Activity

A. muricata is traditionally employed to treat jaundice in Ghana. A study was conducted to determine the in vivo bilirubin-lowering potential of the aqueous extract of soursop leaves. This study was performed on phenylhydrazine-induced jaundice in adult rats, and the levels of direct and total bilirubin were measured in rats orally treated with 50 and 400 mg/kg of the extract. The extract at both doses caused a significant reduction to hyperbilirubinemia, which was close to normal levels. In addition, the hepatoprotective effect was also reported for the aqueous extract of the leaves against carbon tetrachloride and acetaminophen-induced liver damage. Pretreatment with different concentrations of the extract (50, 100, 200, and 400 mg/kg) for 7 days prior to liver damage restored liver function toward normal hemostasis, which was shown by biochemical and histological analyses. Therefore, these findings substantiated the traditional use of soursop against jaundice and showed the potential hepatoprotective activity.

Insecticidal Activity

Botanical insecticides can have a pivotal role in different agriculture programs, especially in small farming. Due to the presence of AGEs, plants from the Annonaceae family such as A. mucosa and A. sylvatica have shown to be promising biopesticides among tropical plants. An investigation on different Annona species showed the growth inhibition effect of A. muricata seeds and contact toxicity by topical administration to Trichoplusia ni larvae. In another study, different extracts of A. muricata seeds were examined against Sitophilus zeamais, a detrimental pest for stored grains, using ingestion and topical assays. Promising activity was obtained from the ingestion application of hexane and ethyl acetate extracts, and this activity was contributed to the presence of AGEs in the less polar fractions. By dipping and surface-protectant methods, the seed extracts revealed weevil mortality of 70% and 100% against S. zeamais at 20% (v/v) and 0.4% (v/w) concentrations, respectively.

Mosquito-controlling activity of both the aqueous and oil extracts of A. muricata seeds against the larvae and adults of Aedes albopictus and Culex quinquefasciatus demonstrated promising bioactivity with lethal concentration 50 (LC50) values ranging from 0.5% to 1% for larvae and 1% to 5% for adults ⁶⁷. In another study, this activity for the ethanolic extract of the leaves against C. quinquefasciatus was also reported with an LC50 value of 20.87 µg/mL after 24 h ⁶⁸. In addition, the larvae of the Aedes aegypti mosquito, the transmitters of dengue fever, elicited high susceptibility to the ethanolic extract of the seeds with the LC50 of 224.27 ppm ⁶⁹. A. muricata seeds showed more than five times synergistic larvicidal activity when combined with Piper nigrum fruit ethanolic extracts (A. muricata 90:10 P. nigrum) ⁷⁰. The fractionation analysis of the extract showed that n-hexane is the most active fraction with an LC50 of 73.77 ppm. The leaf extract of A. muricata also showed a time-dependent toxicity against the larvae of Anastrepha ludens (Mexican fruit fly) with a mortality rate of 63% to 74% ⁷⁰. Leatemia et al. ⁷¹ investigated the growth inhibition potential of the ethanolic seed extracts of A. muricata isolated from different locations against polyphagous lepidopteran Spodoptera litura. The surprising result showed significant differences for the growth inhibition based on the isolated locations ranging from 18% to 96% compared with the control (ethanol). The ethanolic leaf extract (1.0 g/L) showed 40%, 80% and 98% mortality against Callosobruchus maculatus (Fabricius) after 24, 48 and 72 h post-treatment, respectively. At the same concentration, the extract significantly decreased the oviposition of C. maculatus and appeared to be a promising protectant against the respective insect in stored cowpea. This growing body of experimental evidence supports the idea that A. muricata exhibits insecticidal activity against assorted types of insects.

Gastroprotective Activity

Gastroprotective activity of A. muricata leaves was examined against ethanol-induced gastric injury. The results of the oral administration of the ethyl acetate extract (200 and 400 mg/kg) showed significant antiulcer potential, which was mediated through protective effects against gastric wall mucosal damages ⁷². Immunohistochemical staining demonstrated that the leaf extract decreased the Bax protein expression and elevated the Hsp70 protein expression. The effect of the extract on the gastric tissues was accompanied with augmentation in the activity of enzymatic antioxidants and suppression of lipid peroxidation, representing the preservative effect against gastric wall mucus ⁷³. These findings strongly suggested the gastroprotective potential of the soursop leaves.

Molluscicidal Activity

To establish plant-derived molluscicides for the vector control of schistosomiasis, different parts of the Annona species were tested against Biomphalaria glabrata, both in egg masses and adult forms. Santos and colleagues, in 2001, demonstrated that the leaves of A. muricata possess significant toxicity against adult worms with an LD90 value of 8.75 ppm. Additional toxicity of the A. muricata leaves against snail egg masses was markedly noted among different Annona species ⁷⁴. A bioassay-guided investigation on the cytotoxicity of the ethanolic extract of A. muricata leaves against the larvae of the brine shrimp Artemia salina and the snail B. glabrata showed the potent molluscicidal activity of this plant. This study led to the isolation of three bioactive compounds of annonacin, goniothalamicin and isoannonacin ⁷⁵.

Wound Healing Activity

Moghadamtousi and colleagues ⁷⁶ investigated the wound healing activity of the ethyl acetate extract of A. muricata leaves (5% w/w and 10% w/w) against excisional wound healing in rats. Topical administration of the extract for 15 days demonstrated significant wound healing potential assessed by macroscopic and microscopic analyses. The anti-inflammatory effects of the extract were demonstrated during the healing process as shown by the up-regulation of Hsp70, as assessed by immunohistochemical evaluation. The antioxidant defense also fortified the wound healing activity of A. muricata leaves. The same experiment using the alcoholic extract of the stem bark also showed a significant reduction in the wound area from the 4th day after injury onwards ⁷⁷. These studies showed that AGEs from A. muricata may have potential wound healing activity against excisional wounds.

Soursop toxicity and side effects

In 1999, a study published in the Lancet Journal discussed the possible relationship between the consumption of tropical fruits and the incidence of atypical Parkinsonism in the French West Indies ⁷⁸. In addition, the cause of a neurodegenerative disease in Guadeloupe Island revealed a close correlation between AGE (Annonaceous Acetogenins) consumption and the endemic of this disease ⁷⁹. Hence, AGEs are suggested to be environmental neurotoxins responsible for neurodegenerative disorders, including Guadeloupean atypical Parkinsonism.

AGEs are a unique class of C-35/C37 secondary metabolites derived from long chain (C-32/C34) fatty acids in the polyketide pathway. They are usually characterized by a combination of fatty acids with a 2-propanol unit at C-2 that forms a methyl-substituted α,β-unsaturated γ-lactone ⁸⁰. Phytochemical investigations and biological studies on different parts of the soursop plant resulted in the identification of a wide array of AGE compounds. There are over 100 AGEs have been identified in soursop plant.

A recent study showed that the soursop fruit of A. muricata with annonacin as a major AGE may be a potential risk factor for neurodegeneration due to being a major source of exposure to AGEs ⁸¹. In rat striatal neurons, annonacin depleted the ATP supply and interrupted the transportation of mitochondria to the cell soma, which caused cellular perturbations in the protein tau and led to a number of similar characteristics as neurodegenerative diseases ⁷⁹. It is projected that if someone consumes one soursop fruit or its nectar daily, after one year, the total amount of annonacin which was ingested is sufficient to induce brain lesions in rats through intravenous infusion ⁸². Hence, excessive consumption of products from Annonaceae species should be precisely considered to prevent any neurotoxic damages.

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