Annonacin, a lipophilic inhibitor of mitochondrial complex I, induces nigral and striatal neurodegeneration in rats: possible relevance for atypical parkinsonism in Guadeloupe.

摘要: In Guadeloupe, epidemiological data have linked atypical parkinsonism with fruit and herbal teas from plants of the Annonaceae family, particularly Annona muricata. These contain a class powerful, lipophilic complex I inhibitors, annonaceous acetogenins. To determine neurotoxic potential these substances, we administered annonacin, major acetogenin A. muricata, to rats intravenously Azlet osmotic minipumps (3.8 7.6 mg per kg day for 28 days). Annonacin inhibited in brain homogenates concentration-dependent manner, and, when systemically, entered parenchyma, where it was detected by matrix-associated laser desorption ionization-time flight mass spectrometry, decreased ATP levels 44%. absence evident systemic toxicity, observed neuropathological abnormalities basal ganglia brainstem nuclei. Stereological cell counts showed significant loss dopaminergic neurones substantia nigra (-31.7%), cholinergic (-37.9%) dopamine cyclic AMP-regulated phosphoprotein (DARPP-32)-immunoreactive GABAergic (-39.3%) striatum, accompanied increase number astrocytes (35.4%) microglial cells (73.4%). The distribution lesions similar that patients parkinsonism. are compatible theory acetogenins, such as might be implicated aetiology Guadeloupean support hypothesis some forms induced environmental toxins.