Annona muricata / Graviola / Zuurzak

Annona muricata (Annonaceae): A Review of Its Traditional Uses, Isolated Acetogenins and Biological Activities. Soheil Zorofchian Moghadamtousi,1 Mehran Fadaeinasab,2 Sonia Nikzad,1 Gokula Mohan,1 Hapipah Mohd Ali,2 and Habsah Abdul Kadir1,*aurizio Battino, Academic EditorM

Abstract
Annona muricata is a member of the Annonaceae family and is a fruit tree with a long history of traditional use. A. muricata, also known as soursop, graviola and guanabana, is an evergreen plant that is mostly distributed in tropical and subtropical regions of the world. The fruits of A. muricata are extensively used to prepare syrups, candies, beverages, ice creams and shakes. A wide array of ethnomedicinal activities is contributed to different parts of A. muricata, and indigenous communities in Africa and South America extensively use this plant in their folk medicine. Numerous investigations have substantiated these activities, including anticancer, anticonvulsant, anti-arthritic, antiparasitic, antimalarial, hepatoprotective and antidiabetic activities. Phytochemical studies reveal that annonaceous acetogenins are the major constituents of A. muricata. More than 100 annonaceous acetogenins have been isolated from leaves, barks, seeds, roots and fruits of A. muricata. In view of the immense studies on A. muricata, this review strives to unite available information regarding its phytochemistry, traditional uses and biological activities.

1. Introduction
Natural products, especially those derived from plants, have been used to help mankind sustain its health since the dawn of medicine. Over the past century, the phytochemicals in plants have been a pivotal pipeline for pharmaceutical discovery. The importance of the active ingredients of plants in agriculture and medicine has stimulated significant scientific interest in the biological activities of these substances [1]. Despite these studies, a restricted range of plant species has experienced detailed scientific inspection, and our knowledge is comparatively insufficient concerning their potential role in nature. Hence, the attainment of a reasonable perception of natural products necessitates comprehensive investigations on the biological activities of these plants and their key phytochemicals [2]. In a pharmaceutical landscape, plants with a long history of use in ethno medicine are a rich source of active phytoconstituents that provide medicinal or health benefits against various ailments and diseases. One such plant with extensive traditional use is Annona muricata. In this review, we describe the botany, distribution and ethnomedicinal uses of this plant, and we summarize the phytochemistry, biological activities and possible mechanisms of A. muricata bioactivities.

2. Botanical Description and Distribution
A. muricata L., commonly known as soursop, graviola, guanabana, paw-paw and sirsak, is a member of the Annonaceae family comprising approximately 130 genera and 2300 species [3,4]. A. muricata 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 [5]. A. 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. The edible fruits of the tree are large, heart-shaped and green in color, and the diameter varies between 15 and 20 cm (Figure 1) [6].

3. Ethnomedicinal Uses
All portions of the A. muricata tree, similar to other Annona species, including A. squamosa and A. reticulata are extensively used as traditional medicines against an array of human ailments and diseases, especially cancer and parasitic infections. The fruit is used as natural medicine for arthritic pain, neuralgia, arthritis, diarrhea, dysentery, fever, malaria, parasites, rheumatism, skin rushes and worms, and it is also eaten to elevate a mother’s milk after childbirth. The leaves are employed to treat cystitis, diabetes, headaches and insomnia. Moreover, internal administration of the leaf’s decoction is believed to exhibit anti-rheumatic and neuralgic effects, whereas the cooked leaves are topically used to treat abscesses and rheumatism [3,5,7]. The crushed 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 [8,9]. In Malaysia, the crushed leaf mixture of A. muricata together with A. squamosa and Hibiscus rosa-sinensis is used as a juice on the head to protect against fainting [10]. In South America and tropical Africa, including Nigeria, leaves of A. muricata are deployed as an ethnomedicine against tumors and cancer [8]. 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 [3,5]. In addition to ethnomedicinal uses, the fruits are widely employed for the preparation of beverages, candy, ice creams, shakes and syrups [11,12].

4. Phytochemistry
Extensive phytochemical evaluations on different parts of the A. muricata plant have shown the presence of various phytoconstituents and compounds, including alkaloids (ALKs) [4,13], megastigmanes (MGs) [14] flavonol triglycosides (FTGs) [15], phenolics (PLs) [16], cyclopeptides (CPs) and essential oils (Table 1, Figure 2) [17,18]. However, Annona species, including A. muricata, have been shown to be a generally rich source of annonaceous acetogenin compounds (AGEs) [19]. The presence of different major minerals such as K, Ca, Na, Cu, Fe and Mg suggest that regular consumption of the A. muricata fruit can help provide essential nutrients and elements to the human body [20].

4.1. Essential Oil

GC and GC-MS analyses on the leaf oil of A. muricata collected from Cameroon showed the presence of mostly sesquiterpenes, with the major compound present being β-caryophyllene [69]. Another study on A. muricata collected from Vietnam identified significant volatile oil constituents of β-pinene (20.6%), germacrene D (18.1%), ρ-mentha-2,4(8)-diene (9.8%), α-pinene (9.4%) and β-elemene (9.1%) from the leaf oil [70]. The compounds of δ-cadinene, epi-α-cadinol and α-cadinol are also other major compounds reportedly found in the leaf oil extracts [18]. The fruit pulp essential oil was found to have esters of aliphatic acids with major compounds of 2-hexenoic acid methyl ester and 2-hexenoic acid ethyl ester. However, high concentrations of mono- and sesquiterpenes, including β-caryophyllene, 1,8-cineole and linalool, were also isolated from the fruit pulp [71].

4.2. Annonaceous Acetogenins

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 [72]. Since the discovery of uvaricin from Uvaria accuminata in 1982, more than 500 AGEs have been identified from different parts of the plants in the Annonaceae family [73,74]. Due to the special structures and extensive biological activities, AGEs have attracted significant scientific interest in recent years. Various biological activities have been reported for AGEs, including antimalarial, antiparasitic and pesticidal activities [72,75]. However, the biological activities of AGEs are primarily characterized with toxicity against cancer cells and inhibitory effects against the mitochondrial complex I (mitochondrial NADH: ubiquinone oxidoreductase) [76,77]. Phytochemical investigations and biological studies on different parts of the A. muricata plant resulted in the identification of a wide array of AGE compounds, as summarized in Table 1. The chemical structures of the major acetogenins are shown in Figure 2. To the best of our knowledge, at the time of preparation (January 2015) of the present review over 100 AGEs have been identified in A. muricata.


5. Biological Activities
5.1. 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 A. muricata 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 [78]. Hence, the anti-arthritic potential of A. muricata was substantiated by the findings of this in vivo study.

5.2. Anticancer Activity

Plenty of studies report the significant antiproliferative effects of different extracts of the plant and isolated AGEs towards various cancer cell lines [26,79,80,81,82]; however, few of these studies have illustrated the underlying mechanism of action (Table 2). 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 [83,84]. 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 [85].

Recent in vitro and in vivo studies were performed on the water extract of the A. muricata 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 [86]. 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 [87]. 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 [88].

Moghadamtousi and colleagues [91] 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 [89]. 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 [91].

Anticancer studies on A. muricata 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 [90]. 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 [92].

5.3. Anticonvulsant Activity

In African countries, the decoction of the A. muricata leaves is traditionally used to control fever and convulsive seizures [93]. To substantiate the anticonvulsant activity of the leaves in ethnomedicine, Gouemo and colleagues [93] 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.

5.4. 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 [94] 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 [94]. In addition, the extract at the same dose significantly decreased the serum total cholesterol, low-density lipoprotein, triglyceride and very low-density lipoprotein cholesterol [95].

Based on the ethnopharmacological application of A. muricata 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 [96]. Histopathological examination showed that the leaf extract caused the regeneration of β-cells in the pancreas islets [5,97]. 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 [98].

5.5. 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 [99]. This anti-inflammatory effect was accompanied by reductions in the leukocyte migration and exudate volume [7]. 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 [99,100]. In addition, the formalin test and paw licking and hot-plate responses also corroborated the marked analgesic effect of the A. muricata leaves [7,99,100]. The protective effect of the A. muricata 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 [100]. The same assays showed the anti-inflammatory and analgesic activities for the A. muricata fruits, which were shown to be induced through the suppression of inflammatory mediators and interactions with the opioidergic pathway, respectively [101]. These findings demonstrated the anti-nociceptive and anti-inflammatory effects of A. muricata and substantiated its traditional consumption as pain killer.

5.6. 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 [102]. 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 [103,104]. DRSA, FRAP and HRSA tests on aqueous and methanolic leaf extracts of A. muricata revealed the marked antioxidative activities of both extracts accompanied with DNA protective effects against H2O2-induced toxicity [105]. 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 [106]. 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 [107]. 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 [108,109]. 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 [110]. These findings strongly suggest the potential use of A. muricata as a natural source of antioxidants.

5.7. Antihypertensive Activity

To evaluate the antihypertensive properties of A. muricata 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+ [111].

5.8. 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 (Table 3). The ethyl acetate leaf extract of A. muricata 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 [112]. 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 [26]. 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 [53]. 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 [54]. 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 [113]. 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 [114].

Antiplasmodial Activity

Malaria, one of the most debilitating diseases, afflicts a substantial population in tropical and subtropical zones [116]. The available antimalarial drugs demonstrate varying degrees of failure due to rapid spread of parasite resistance [117]. 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 [115]. The leaf extract, also at 20 µg/mL, showed a 67% inhibition against an asynchronous F32 strain of P. falciparum [118]. 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 [112]. These findings substantiated the traditional use of A. muricata as an antimalarial agent.

5.9. 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 A. muricata 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 [119]. 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 [120]. Therefore, these findings substantiated the traditional use of A. muricata against jaundice and showed the potential hepatoprotective activity.

5.10. Insecticidal Activity

Botanical insecticides can have a pivotal role in different agriculture programs, especially in small farming [121]. 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 [72,122]. 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 [122]. 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 [123]. 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 [124].

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 [125]. 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 [126]. 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 [127]. 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) [128]. 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% [129]. Leatemia et al. [130] 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) [130]. 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 [131]. This growing body of experimental evidence supports the idea that A. muricata exhibits insecticidal activity against assorted types of insects.

5.11. 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 [100]. 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 [132]. These findings strongly suggested the gastroprotective potential of the A. muricata leaves.

5.12. 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 [133]. 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 [49].

5.13. Wound Healing Activity

Moghadamtousi and colleagues [134] 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 [135]. These studies showed that AGEs from A. muricata may have potential wound healing activity against excisional wounds.

6. Toxicology
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 [136]. In addition, the etiology of a neurodegenerative disease in Guadeloupe Island revealed a close correlation between AGE consumption and the endemic of this disease [50]. Hence, AGEs are suggested to be environmental neurotoxins responsible for neurodegenerative disorders, including Guadeloupean atypical Parkinsonism. A recent study showed that the 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 [137]. 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 [50]. 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 [138]. Hence, excessive consumption of products from Annonaceae species should be precisely considered to prevent any neurotoxic damages.

7. Conclusions
A. muricata is a coveted tropical tree, and a wealth of phytochemical investigations have been conducted for this fruit plant. In addition to being an important source for the food industry and an indigenous medicinal plant, A. muricata is proven to possess a wide spectrum of biological activities. Among all former studies on this plant, the most promising activities are found to be its anticancer, antiparasitic and insecticidal activity. Because the majority of the previous studies were focused on the biological activities of the plant extract, further investigations on the biochemical and physiological functions of active compounds and the detailed mechanisms underlying these activities are completely pivotal for the development of pharmaceutical and agricultural products. In addition, clinical trials concerning the rich pharmaceutical potential of A. muricata have been markedly neglected in previous studies. Several reports on the neurodegenerative effects of A. muricata and its isolated AGEs are completely perplexing, and further research is crucial to distinguish all the compounds contributing to this effect and determine the threshold of these compounds at which this effect is caused. This review is hoped to be a source of enlightenment and motivation for researchers to further perform in vitro, in vivo and clinical investigations on the biological activities of A. muricata to gain insight into developing new agricultural and pharmaceutical agents.

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