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

• Published in: Journal of neurochemistry Vol. 88; no. 1; pp. 63 - 69
• Main Authors: Champy, Pierre, Höglinger, Günter U., Féger, Jean, Gleye, Christophe, Hocquemiller, Reynald, Laurens, Alain, Guérineau, Vincent, Laprévote, Olivier, Medja, Fadia, Lombès, Anne, Michel, Patrick P., Lannuzel, Annie, Hirsch, Etienne C., Ruberg, Merle
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.01.2004; Blackwell
• Subjects: acetogenin; Adenosine Triphosphate - metabolism; Animals; Annona muricata; annonacin; atypical Parkinson syndrome; Behavior, Animal - drug effects; Biological and medical sciences; Cell Count; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Electron Transport Complex I - antagonists & inhibitors; Furans - administration & dosage; Furans - toxicity; Gliosis - chemically induced; Gliosis - pathology; Guadeloupe; Infusions, Intravenous; Lactones - administration & dosage; Lactones - toxicity; Male; Medical sciences; Mitochondria - enzymology; mitochondrial complex I; Neurodegenerative Diseases - chemically induced; Neurodegenerative Diseases - enzymology; Neurodegenerative Diseases - pathology; Neurology; Neurons - drug effects; Neurons - pathology; Parkinsonian Disorders - etiology; Plant Extracts - administration & dosage; Plant Extracts - toxicity; Rats; Rats, Inbred Lew; rotenone; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Substantia Nigra - pathology; Central America; Guadeloupe; America; West Indies; Rat; Toxicity; annonacin; acetogenin; Phosphoproteins; Dicotyledones; Guadeloupe; Angiospermae; Degenerative disease; Degeneration; Annonaceae; Dopamine; Rodentia; Cyclic AMP; Enzyme inhibitor; rotenone; Mitochondrial complex I; Basal ganglion; Corpus striatum; Cerebral disorder; Parkinsonism; Vertebrata; Mammalia; Locus niger; Cell death; Animal; Central nervous system disease; DARPP-32 protein; Dopaminergic neuron; Spermatophyta; atypical Parkinson syndrome
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2003.02138.x

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