Annonacin, a lipophilic inhibitor of mitochondrial complex I, induces nigral and striatal neurodegeneration in rats: possible relevance for atypical parkinsonism in Guadeloupe.
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.
Champy
Pierre
P
Experimental Neurology and Therapeutics, INSERM U289, Hôpital de la Salpêtrière, Paris, France.
Höglinger
Günter U
GU
Féger
Jean
J
Gleye
Christophe
C
Hocquemiller
Reynald
R
Laurens
Alain
A
Guérineau
Vincent
V
Laprévote
Olivier
O
Medja
Fadia
F
Lombès
Anne
A
Michel
Patrick P
PP
Lannuzel
Annie
A
Hirsch
Etienne C
EC
Ruberg
Merle
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D005663:Furans / Q000008:administration & dosage / Q000633:toxicity*; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology; D019430:Guadeloupe; D007262:Infusions, Intravenous; D007783:Lactones / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D020734:Parkinsonian Disorders / Q000209:etiology; D010936:Plant Extracts / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011917:Rats, Inbred Lew; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D005663:Furans; D007783:Lactones; D010936:Plant Extracts; C053442:annonacin; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I