Neurotoxicity of Dietary Supplements from Annonaceae Species

Abstract

Dietary supplements containing plant materials of Annonaceae species (Annona muricata L., A. squamosa L., A. mucosa JACQ., A. squamosa × cherimola Mabb.) were extracted by hot, pressurized ethyl acetate and analyzed for their effect in vitro on Lund human mesencephalic neurons. Cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell death was determined by lactate dehydrogenase levels. Three supplements strongly decreased the cell viability at extract concentrations of 1 µg/mL, of which 1 decreased cell viability at 0.1 µg/µL. Also, strong neuronal toxicities of these supplements were found. Cell death was observed at concentrations of 10 µg/mL. The degree of toxicity was comparable to the ones found in Annonaceous fruit extracts. Two fruit pulps of Annonaceae (A. muricata and A. squamosa) showed a reduction in cell viability at lower concentrations. The fruit pulp extract of A. muricata revealed the strongest neurotoxic effect, with 67% cell death at a concentration of 1 µg/mL. A high reduction in cell viability coupled with pronounced cell death was found at 0.1 µg/mL for an Annonaceous seed extract. These results demonstrate that the intake of dietary supplements containing plant material from Annonaceae may be hazardous to health in terms of neurotoxicity.

1H qNMR Quantification of Annonaceous Acetogenins in Crude Extracts of Annona muricata L. Fruit Pulp

“…The AAGs contents varied greatly between the samples, from 14 to 226 μmol per 100 g of fresh pulp (sample C – Mauritius Island and sample G – New Caledonia, respectively, yielding 0.14 to 1.3 mmoles per fruit; Table ). These results are in accordance with the order of magnitude proposed in previous estimations for annonacin (Champy et al, ; Hölleraghe et al , ). Interestingly, fruits obtained from the same location at a one year interval had similar content in AAGs of sub‐types 1a and 1b (samples A and B), while others from close areas and dates of harvest showed a 1.7‐fold difference (samples C and D).…”

“…The NMR profiles of the extracts evidenced a steady ratio between AAGs of sub‐types 1b (~72%) and 1a (~28%), except for sample C (~90%/10%). It is known that annonacin ( 1 ) (sub‐type 1b) is the main AAG in Annona muricata fruits (Champy et al, ; Höllerhage et al, ), but investigation of a soursop nectar by HPLC‐ESI‐LTQ‐Orbitrap® had previously evidenced the presence of sub‐type 1a AAGs in important proportions (Le Ven et al, ).…”

“…AAGs were identified in fruits of several cultivated Annonaceae, which are largely consumed worldwide (e.g. custard apple -Annona squamosa L.; pawpaw -Asimina triloba (L.) Dunal; soursop -Annona muricata, L.) (Champy et al, 2005;Höllerhage et al, 2015;Levine et al, 2015;Potts et al, 2012). These species might be responsible for sporadic Parkinsonism/dementia syndromes in tropical communities, as evidenced in New Caledonia (Angibaud et al, 2004) and in the French West Indies, where Guadeloupean Parkinsonism, an endemic tauopathy, was linked to Annona muricata (Lannuzel et al, 2007).…”

The safety and tolerability of Annona muricata leaf extract: a systematic review

“…[16,18,[25][26][27][28][29][30][31] Among the studies investigating hepatic effects, eight studies demonstrated a hepatoprotective effect of A. muricata leaf extracts [16,18,[25][26][27][28]30,31] while one study demonstrated a hepatotoxic effect with no substantial differences in the dose, formulation or route of administration. [29] Three in-vitro and one animal study identified neurotoxic effects (n = 4), [32][33][34][35] with the animal study using annonacin at a dose of 3.8-7.6 mg/kg per day when administrated intravenously to rats for 28 days. One animal study utilised ethanolic leaf extract at a dose of 25-100 mg/kg demonstrated sedative, anxiolytic and anticonvulsant-like effect.…”

Transcriptome Analysis and Identification of Genes Associated with Floral Transition and Flower Development in Sugar Apple (Annona squamosa L.)

“…Sugar apple ( Annona squamosa L.) is an important member of the Annonaceae family, which consists of ~166 genera and more than 2000 species (Höllerhage et al, 2015). As a commercially important fruit tree, sugar apple orchards are wide spread and well adapted to the edaphoclimatic conditions of tropical and subtropical zones.…”