Mutagenic effect, antioxidant and anticancer activities of six medicinal plants from Burkina Faso.

The antiproliferative activities of six medicinal plant extracts from Burkina Faso were evaluated in order to justify their traditional use for the treatment of cancer. The SOS chromotest method was used in vitro on Escherichia coli PQ37 to evaluate the mutagenic effect of the plant extracts. The DPPH method was used to evaluate the antioxidant activity of each plant. The antiproliferative activity was evaluated by MTS method on normal cells (Vero and MCR5) and cancer cells (KB) in contact with the extracts for 72 h. The results showed that the studied plants are not genotoxic. Lantana ukambensis and Acacia macrostachya induced a very significant antiproliferative effect against cancer cells with 94% and 95%, respectively. They also developed a strong antioxidant activity. The IC50 values were 5.96 ± 0.40 µg mL⁻¹ for L. ukambensis and 4.30 ± 0.26 µg mL⁻¹ for A. macrostachya. These two plants are therefore potential sources for isolating new antioxidant and anticancer molecules.

Kaurenoic acid from pulp of Annona cherimolia in regard to Annonaceae-induced Parkinsonism.

Guadeloupean Parkinsonism has been linked epidemiologically to the consumption of Annonaceae fruits. These were proposed to be etiological agents for sporadic atypical Parkinsonism worldwide, because of their content of neurotoxins such as isoquinolinic alkaloids and Annonaceous acetogenins. The pulp of Annona cherimolia Mill. from Spain was screened for these toxic molecules using Matrix-Assisted Laser Desorption Ionisation - Time of Flight mass spectrometry (MALDI-TOF MS) and it was found not to be a source of exposure. However, kaurenoic acid, a diterpene considered to be cytotoxic, was detected in high amounts (66 mg/fresh fruit). Treatment of rat embryonic striatal primary cultures, up to a high concentration (50 µM), did not cause neuronal death nor astrogliosis, suggesting that this molecule is not at risk of implication in human neurodegenerative diseases.

A novel 1-indanone isolated from Uvaria afzelii roots.

Bioactivity-guided fractionations of chloromethylenic extract of the roots of U. afzelii (Annonaceae), using Leishmania donovani and Trypanosoma brucei brucei bioassay, resulted in the isolation of the two known compounds, emorydone (1) and demethoxymatteucinol (2), previously isolated from the stems, which were characterised from this source. In addition, the novel 1-indanone, afzeliindanone (3), was also isolated. The structure determination of afzeliindanone (3) was elucidated on the basis of spectral data as 4-[4-hydroxy-3-methoxyphenyl]-indan-1-one. This compound is the first 1-indanone derivative isolated from plants.

Is atypical parkinsonism in the Caribbean caused by the consumption of Annonacae?

An abnormally frequent atypical levodopa-unresponsive, akinetic-rigid syndrome with some similarity to PSP was identified in the Caribbean island Guadeloupe, and was associated with the consumption of plants of the Annonacea family, especially Annona muricata (corossol, soursop) suggesting a possible toxic etiology. Annonaceae contain two groups of potential toxins, alkaloids and acetogenins. Both alkaloids and annonacin, the most abundant acetogenin, were toxic in vitro to dopaminergic and other neurons. However we have focused our work on annonacin for two reasons: (1) annonacin was toxic in nanomolar concentrations, whereas micromolar concentrations of the alkaloids were needed, (2) acetogenins are potent mitochondrial poisons, like other parkinsonism-inducing compounds. We have also shown that high concentrations of annonacin are present in the fruit or aqueous extracts of the leaves of A. muricata, can cross the blood brain barrier since it was detected in brain parenchyma of rats treated chronically with the molecule, and induced neurodegeneration of basal ganglia in these animals, similar to that observed in atypical parkinsonism. These studies reinforce the concept that consumption of Annonaceae may contribute to the pathogenesis of atypical parkinsonism in Guadeloupe.

The mitochondrial complex I inhibitor annonacin is toxic to mesencephalic dopaminergic neurons by impairment of energy metabolism.

The death of dopaminergic neurons induced by systemic administration of mitochondrial respiratory chain complex I inhibitors such as 1-methyl-4-phenylpyridinium (MPP(+); given as the prodrug 1-methyl-1,2,3,6-tetrahydropyridine) or the pesticide rotenone have raised the question as to whether this family of compounds are the cause of some forms of Parkinsonism. We have examined the neurotoxic potential of another complex I inhibitor, annonacin, the major acetogenin of Annona muricata (soursop), a tropical plant suspected to be the cause of an atypical form of Parkinson disease in the French West Indies (Guadeloupe). When added to mesencephalic cultures for 24 h, annonacin was much more potent than MPP(+) (effective concentration [EC(50)]=0.018 versus 1.9 microM) and as effective as rotenone (EC(50)=0.034 microM) in killing dopaminergic neurons. The uptake of [(3)H]-dopamine used as an index of dopaminergic cell function was similarly reduced. Toxic effects were seen at lower concentrations when the incubation time was extended by several days whereas withdrawal of the toxin after a short-term exposure (<6 h) arrested cell demise. Unlike MPP(+) but similar to rotenone, the acetogenin also reduced the survival of non-dopaminergic neurons. Neuronal cell death was not excitotoxic and occurred independently of free radical production. Raising the concentrations of either glucose or mannose in the presence of annonacin restored to a large extent intracellular ATP synthesis and prevented neuronal cell demise. Deoxyglucose reversed the effects of both glucose and mannose. Other hexoses such as galactose and fructose were not protective. Attempts to restore oxidative phosphorylation with lactate or pyruvate failed to provide protection to dopaminergic neurons whereas idoacetate, an inhibitor of glycolysis, inhibited the survival promoting effects of glucose and mannose indicating that these two hexoses acted independently of mitochondria by stimulating glycolysis. In conclusion, our study demonstrates that annonacin promotes dopaminergic neuronal death by impairment of energy production. It also underlines the need to address its possible role in the etiology of some atypical forms of Parkinsonism in Guadeloupe.