Neurotoxicity of Dietary Supplements from Annonaceae Species

Int J Toxicol. Nov-Dec 2015;34(6):543-50. doi: 10.1177/1091581815602252. Epub 2015 Sep 24.


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.

Keywords: annonaceae; dietary supplements; graviola; neurotoxicity; pawpaw.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annonaceae / toxicity*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Dietary Supplements / toxicity*
  • Fruit / chemistry
  • Fruit / toxicity
  • Humans
  • L-Lactate Dehydrogenase / analysis
  • L-Lactate Dehydrogenase / metabolism
  • Mesencephalon / cytology
  • Mesencephalon / drug effects
  • Neurons / drug effects
  • Neurotoxicity Syndromes / pathology*
  • Plant Extracts / toxicity
  • Seeds / chemistry
  • Seeds / toxicity
  • Tetrazolium Salts
  • Thiazoles


  • Plant Extracts
  • Tetrazolium Salts
  • Thiazoles
  • L-Lactate Dehydrogenase
  • thiazolyl blue