Neurotoxicity of Fruits, Seeds and Leaves of Plants in the Annonaceae Family

Research Article

Austin Neurol & Neurosci. 2016; 1(1): 1005.

Neurotoxicity of Fruits, Seeds and Leaves of Plants in the Annonaceae Family

Smith RE¹*, Tran K¹, Shejwalkar P¹ and Hara K²

¹U.S. Food and Drug Administration, Total Diet and Pesticide Research Center, Lenexa, USA

²School of Engineering, Tokyo University of Technology, Japan

*Corresponding author: Smith RE, U.S. Food and Drug Administration, Total Diet and Pesticide Research Center, Lenexa, USA

Received: April 07, 2016; Accepted: May 31, 2016; Published: June 07, 2016

Abstract

Fruits, seeds, twigs and leaves of several plants in the Annonaceae family contain neurotoxic compounds called acetogenins. Overconsumption of at least one of these fruits, graviola (Annona Muricata), caused an atypical form of Parkinson’s disease on the islands of Guadeloupe, Guam and New Caledonia. It does not respond to the standard treatment with L-Dihydroxyphenylalanine (L-DOPA). This type of atypical Parkinsonism is similar to progressive supranuclear palsy, but with important differences. It is characterized by L-DOPA-resistant Parkinsonism, tremor, subcortical dementia and abnormal eye movements suggestive of Progressive Supranuclear Palsy (PSP). Patients also have hallucinations and dysautonomia, which are not characteristic of PSP. Furthermore, the oculomotor abnormalities and the tremor, which is jerky, differ from what is observed in classical PSP patients. The neurotoxicity is caused by mitochondrial dysfunction. A class of compounds called Acetogenins (ACGs) inhibits the mitochondrial NADH: Ubiquinone Oxidoreductase (complex-I of the respiratory chain). These compounds are lipophilic polyketides that are found in plants in the Annonaceae family. They have two toxicophores: a γ-Butyrolactone and one or more Tetrahydrofuran (THF) or Tetrahydropyran (THP) rings. There is also a long chain alkyl group on the other end of the molecule. Even though it strongly affects the physical-chemical properties of ACGs, it is not a toxicophores. Over 400 ACGs have been found in different plants in the Annonaceae family. They can be identified by Nuclear Magnetic Resonance (NMR) and liquid chromatography coupled to mass spectrometry (LC-MS). They form adducts with Ca2+ and Mg2+, which helps to confirm their presence in samples.

Keywords: Parkinson’s disease; Acetogenins; NADH: Ubiquinone Oxidoreductase; Graviola; Annona Muricata

Introduction

Fruits, seeds, twigs and leaves of several plants in the Annonaceae family contain neurotoxic compounds called acetogenins [1-3]. Epidemiological studies showed a link between the overconsumption of graviola (Annona Muricata) fruit and aqueous infusions of leaves (tea), and an atypical form of Parkinson’s disease on the islands of Guadeloupe, Guam and New Caledonia, as well as the Afro- Caribbean and Indian population in London [4-15]. It does not respond to the standard treatment with L-Dihydroxyphenylalanine (L-DOPA) [4]. This atypical form of Parkinsonism is similar to progressive supranuclear palsy, but with important differences [4]. It is characterized by L-DOPA-resistant Parkinsonism, tremor, subcortical dementia and abnormal eye movements suggestive of Progressive Supranuclear Palsy (PSP) [11]. However, Patients also have hallucinations and dysautonomia, which are not characteristic of PSP. Furthermore, the oculomotor abnormalities and the tremor, which is jerky, differ from what is observed in classical PSP patients [11]. The neurotoxicity is caused (at least in part) by mitochondrial dysfunction [3,8,12-15]. Patients in Guadeloupe were separated into three different categories. Only one-third of them presented the classical features of idiopathic Parkinson disease. Another one-third had a syndrome resembling Progressive Supranuclear Palsy (PSP).

The others were unclassifiable, according to criteria existing in 2007 [8].

A class of compounds called Acetogenins (ACGs) inhibits the mitochondrial NADH: Ubiquinone Oxidoreductase (complex I of the respiratory chain), which decreases ATP levels. This leads to neuronal cell loss and gliosis in the brain stem and basal ganglia [18-20]. However, other mechanisms of toxicity may be involved. This includes modulating histone H3 phosphorylation [16], complexation with Ca2+ ions [17] and somatodendritic redistribution of phosphorylated tau protein [12]. NADH: Ubiquinone Oxidoreductase is a mitochondrial enzyme present in not just neurons, but also cancer cells. As a result, there is a substantial body of literature on the anti-cancer properties of graviola, the North American pawpaw (Asimina triloba), acetogenins and acetogenin mimetics [19,21-25]. One recent article told how drinking a tea made from graviola leaves helped cure a patient who had metastatic negative breast cancer [23]. However, data on single individuals seldom means much to most oncologists. Still, it is worth noting that the dose of the major acetogenin in tea made graviola leaves (annonacin) is only 0.213% of the dose that one would receive from consuming the entire leaves that are sold as a dietary supplement [26]. That is, there are dietary supplements made from different parts of plants in the Annonaceae family that are sold as cures for cancer, even though they may be neurotoxic [1]. For graviola, “The estimated amounts of annonacin ingested in a year by eating one fruit or can of nectar a day were comparable to the dose (3.8 mg/kg/day) that induced widespread neurodegeneration in the basal ganglia and mesencephalon when infused intravenously into rats for 28 days (106 mg/kg)” [27]. More recently, it has been shown that annonacin can cross the blood-brain barrier and its bioavailability was about 3.2% of the orally ingested dose in rats [28].

The goals of this report are to review the literature on the neurotoxicities of the fruits, seeds and leaves of plants in the Annonaceae family and the biochemical toxins that are in them (acetogenins), as well as use Mass Spectrometry (MS) to find as many acetogenins as possible in the fruits of the North American pawpaw (Asimina triloba).

Plants in the Annonaceae Family

Acetogenins (ACGs) have been isolated from the fruit pulp, seeds, twigs, roots, stems, leaves and bark of many plants in the Annonaceae family, which contains about 2400 species in 108 genera, based on the sequences of nucleotides on multiple plastid DNA loci [29]. This is better than previous classifications based mostly on morphology. The new classification consists of four major clades, which were given the taxonomic rank of subfamily [29]. Some of the genera in the Annonoideae subfamily have acetogenins. They include Annona, Anonidium, Asimina, Boutiquea, Dasymaschalon, Diclinanona, Disepalum, Goniothalamus, and Neostenanthera. Even though many previous articles used the name Asimina triloba for the North American pawpaw, it is more properly called Annona triloba [29]. A partial list of plants in the Annonaceae family that have been sources of purified acetogenins is shown in Table 1 [16,17,30- 32]. Note that some of them share the same common names. Also, many of them have uses in folk remedies and traditional medicine, including treating cancer. A book about the Annonaceae family was even published recently [33].