The mitochondrial complex i inhibitor annonacin is toxic to mesencephalic dopaminergic neurons by impairment of energy metabolism
Section snippets
Mesencephalic cell cultures
Animals were treated in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council 1996), the European Communities Council Directive 86/609/EEC, and the guidelines of the local institutional committee. All efforts were made to minimize the number of animals used and their suffering. The embryos were removed at embryonic day 15.5 from pregnant Wistar rats (Elevage Janvier, Le Genest St Isle, France) that had been anesthetized then decapitated. The ventral
Annonacin specifically inhibits complex i activity
We first verified that annonacin acted as a specific inhibitor of the complex I of the mitochondrial respiratory chain using homogenates of adult rat brain cortex. The residual complex I activity in the presence of 100 nM annonacin was 21% of control values while even concentrations up to 1000 nM had no significant effect on complex IV activity (Fig. 1B). The concentration causing a 50% reduction of complex I activity was estimated to be 30 nM.
Annonacin is toxic to dopaminergic neurons
When mesencephalic cultures were treated with
Discussion
Our study demonstrates that low concentrations of the mitochondrial complex I inhibitor annonacin promote the death of dopaminergic neurons in mesencephalic cultures. Annonacin was approximately as effective as rotenone but 50-fold more potent than the prototypical dopaminergic neurotoxin MPP+. Unlike MPP+, but similar to rotenone, the effects of annonacin were not restricted to the dopaminergic neurons. Restoring glycolysis by treatment with glucose or mannose prevented neurodegeneration
Acknowledgements
This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Contrat de Recherche et d'Etude Stratégique (CeRS 4CR07F) to A.L., Secrétariat d'Etat à l'Outre-Mer (SEOM) and Délégation à la Recherche Clinique, University Hospital Antilles-Guyane (Pointe-à-Pitre, Guadeloupe, France). P.P.M. was supported by Centre de Recherche Pierre Fabre (Castres, France) and G.H. by the Deutsche Forschungsgemeinschaft (DFG).
References (50)
- et al.
Structure and function of mammalian facilitative sugar transporters
J Biol Chem
(1993) - et al.
Possible relation of atypical parkinsonism in the French West Indies with consumption of tropical plantsa case-control study
Lancet
(1999) - et al.
Immunohistochemical localization and quantification of glucose transporters in the mouse brain
Neuroscience
(2002) - et al.
Studies of mannose metabolism and effects of long-term mannose ingestion in the mouse
Biochim Biophys Acta
(2001) Inhibitors of NADH-Ubiquinone reductase: an overview
Biochim Biophys Acta
(1998)- et al.
Molecular characterization of the dopamine transporter
Trends Pharmacol Sci
(1993) - et al.
Cryopreservation of primary neurons for tissue culture
Brain Res
(1986) - et al.
The parkinsonism-inducing drug 1-methyl-4-phenylpyridinium triggers intracellular dopamine oxidationa novel mechanism of toxicity
J Biol Chem
(2000) - et al.
The glutamate antagonist, MK-801, does not prevent dopaminergic cell death induced by the 1-methyl-4-phenylpyridinium ion (MPP+) in rat dissociated mesencephalic cultures
Brain Res
(1992) - et al.
Essential structural factors of acetogenins, potent inhibitors of mitochondrial complex I
Bioorg Med Chem Lett
(2002)
Expression of the hexose transporters GLUT1 and GLUT2 during the early development of the human brain
Brain Res
Mitochondrial involvement in Parkinson's disease
Neurochem Int
Localisation in liposomal membranes of the THF ring moieties of Annonaceous acetogeninsannonacin and sylvaticin as determined by 1H RMN spectroscopy
Pharmacol Res
Epidemiology of Parkinson's disease
Neurol Clin
Specific interactions of monotetrahydrofuranic annonaceous acetogenins as inhibitors of mitochondrial complex I
Chem Biol Interact
Unlike MPP+, apoptosis induced by 6-OHDA in PC12 cells is independent of mitochondrial inhibition
Neurosci Lett
Annonaceous acetogeninsrecent progress
J Nat Prod
1-methyl-4-(2′-ethylphenyl)-1,2,3,6-tetrahydropyridine-induced toxicity in PC12 cells is enhanced by preventing glycolysis
J Neurochem
Chronic systemic pesticide exposure reproduces features of Parkinson's disease
Nat Neurosci
Guadeloupean parkinsonisma cluster of progressive supranuclear palsy-like tauopathy
Brain
Acetogenins from Annonaceae
Annonacin, the major acetogenin of Annona muricata induces basal-ganglia and mesencephalon degeneration in rats
FENS Abstr
Atypical parkinsonism in Afro-Caribbean and Indian origin immigrants to the U
K. Mov Disord
Neuroprotection of cultured foetal rat hippocampal cells against glucose deprivationare GABAergic neurons less vulnerable or more sensitive to TCP protection?
Eur J Neurosci
Ionic dependence of glutamate neurotoxicity
J Neurosci
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2022, PharmaNutritionCitation Excerpt :In vitro and in vivo studies (see Table 1) have indicated that anonacin can cause the development of signs related to taupathies, such as tau protein hyperphosphorylation, retrograde transport of mitochondria, redistribution of tau from the axon to the neuron body, in addition to neuronal cell death [16,25,27,28], as shown in Fig. 3. Champy et al. [18], Escobar-khondiker et al. [28], Rottscholl et al. [25], Lannuzel et al. [29], Potts et al. [30] all suggest that anonacin (mono-tetrahydrofuran) causes a reduction of ATP in neurons, through the inhibition of mitochondrial complex I (Fig. 2). Champy et al. [18] reported that chronic exposure to anonacin has an inhibitory capacity equivalent to that of rotenone, a highly neurotoxic insecticide.
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