Annonacin, a lipophilic inhibitor of mitochondrial complex I, induces nigral and striatal neurodegeneration in rats: possible relevance for atypical parkinsonism in Guadeloupe.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and in vitro laboratory study
PubMed 14675150 · doi:10.1046/j.1471-4159.2003.02138.x
What was done
Researchers tested the neurotoxic potential of annonacin, a lipophilic mitochondrial complex I inhibitor and major acetogenin from Annona muricata, in rats. Annonacin was administered intravenously using osmotic minipumps at doses of 3.8 and 7.6 mg per kg per day for 28 days. The authors evaluated complex I inhibition in brain homogenates, verified parenchymal brain penetration using mass spectrometry, measured brain ATP levels, and performed stereological cell counts in the basal ganglia and brainstem.
What was found
Annonacin entered the brain parenchyma, inhibited complex I in a concentration-dependent manner, and reduced brain ATP levels by 44%. In the absence of evident systemic toxicity, it caused a 31.7% loss of substantia nigra dopaminergic neurons, a 37.9% loss of striatal cholinergic neurons, and a 39.3% loss of striatal DARPP-32-immunoreactive GABAergic neurons. Astrocytes increased by 35.4% and microglial cells increased by 73.4%.
Why it matters
These findings show that systemic exposure to a plant-derived complex I inhibitor can cross the blood-brain barrier and cause striatonigral neurodegeneration matching the pathological distribution of Guadeloupean atypical parkinsonism.
Limits
This is an animal study using continuous intravenous infusion, which does not capture oral ingestion kinetics, human metabolism, or dietary exposure duration. The abstract does not report the total sample size of rats or distinguish dose-specific outcomes between the two dose levels.
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