Toxicity of Annonaceae for dopaminergic neurons: potential role in atypical parkinsonism in Guadeloupe.
In the French West Indies there is an abnormally high frequency of levodopa-resistant parkinsonism, suggested to be caused by consumption of fruit and infusions of tropical plants, especially Annona muricata (corossol, soursop). To determine whether toxic substances from this plant can cause the neuronal degeneration or dysfunction underlying the syndrome, we exposed mesencephalic dopaminergic neurons in culture to the total extract (totum) of alkaloids from Annona muricata root bark and to two of the most abundant subfractions, coreximine and reticuline. After 24 hours, 50% of dopaminergic neurons degenerated with 18 microg/ml totum, 4.3 microg/ml (13 microM) coreximine, or 100 microg/ml (304 microM) reticuline. The effects of the alkaloid totum were not restricted to the population of dopaminergic cells since GABAergic neurons were also affected by the treatment. Nuclei in dying neurons showed DNA condensation or fragmentation, suggesting that neuronal death occurred by apoptosis. Cell death was not excitotoxic and did not require toxin uptake by the dopamine transporter. Neurodegeneration was attenuated by increasing the concentration of glucose in the culture medium, which also reduced the effect of the dopaminergic neurotoxin MPP+, a mitochondrial respiratory chain inhibitor. Toxin withdrawal after short-term exposure arrested cell death. Acute treatment with totum, coreximine, or reticuline reversibly inhibited dopamine uptake by a mechanism that was distinct from that causing neuronal death. GABA uptake was not reduced under the same conditions. This study suggests that alkaloids from A. muricata can modulate the function and the survival of dopaminergic nerve cells in vitro. It is therefore conceivable that repeated consumption could cause the neuronal dysfunction and degeneration underlying the West Indian parkinsonian syndrome.
Lannuzel
Annie
A
Service de Neurologie, Centre hospitalier universitaire des Antilles et de la Guyane, Pointe-à-Pitre, Guadeloupe, France. lannuzel@ais.gp
Michel
Patrick P
PP
Caparros-Lefebvre
Dominique
D
Abaul
Jacqueline
J
Hocquemiller
Reynald
R
Ruberg
Merle
M
D029061:Annonaceae / Q000009:adverse effects*; D000978:Antiparkinson Agents / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D004351:Drug Resistance; D019430:Guadeloupe / Q000453:epidemiology; D006801:Humans; D007980:Levodopa / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000187:drug effects; D008636:Mesencephalon / Q000187:drug effects / Q000473:pathology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000453:epidemiology
D000978:Antiparkinson Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D007980:Levodopa; D004298:Dopamine