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Article (Scientific journals)
Probenecid potentiates MPTP/MPP+ toxicity by interference with cellular energy metabolism.
Alvarez-Fischer, Daniel; Noelker, Carmen; Grünewald, Anne et al.
2013In Journal of Neurochemistry, 127 (6), p. 782-92
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Keywords :
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/metabolism; 1-Methyl-4-phenylpyridinium/metabolism; Animals; Corpus Striatum/drug effects/metabolism/pathology; Disease Models, Animal; Dopamine Agents/toxicity; Dopaminergic Neurons/drug effects/metabolism/pathology; Drug Synergism; Electron Transport Complex I/antagonists & inhibitors; Energy Metabolism; Mice; Neurotoxins/toxicity; Parkinson Disease/etiology/metabolism/pathology; Probenecid/toxicity; Rotenone/toxicity; Uricosuric Agents/toxicity; ATP; MPP +; MPTP; Parkinson's disease; mitochondria; probenecid
Abstract :
[en] The uricosuric agent probenecid is co-administered with the dopaminergic neurotoxin MPTP to produce a chronic mouse model of Parkinson's disease. It has been proposed that probenecid serves to elevate concentrations of MPTP in the brain by reducing renal elimination of the toxin. However, this mechanism has never been formally demonstrated to date and is questioned by our previous data showing that intracerebral concentrations of MPP(+), the active metabolite of MPTP, are not modified by co-injection of probenecid. In this study, we investigated the potentiating effects of probenecid in vivo and in vitro arguing against the possibility of altered metabolism or impaired renal elimination of MPTP. We find that probenecid (i) is toxic in itself to several neuronal populations apart from dopaminergic neurons, and (ii) that it also potentiates the effects of other mitochondrial complex I inhibitors such as rotenone. On a mechanistic level, we show that probenecid is able to lower intracellular ATP concentrations and that its toxic action on neuronal cells can be reversed by extracellular ATP. Probenecid can potentiate the effect of mitochondrial toxins due to its impact on ATP metabolism and could therefore be useful to model atypical parkinsonian syndromes.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Alvarez-Fischer, Daniel
Noelker, Carmen
Grünewald, Anne  
Vulinovic, Franca
Guerreiro, Serge
Fuchs, Julia
Lu, Lixia
Lombes, Anne
Hirsch, Etienne C.
Oertel, Wolfgang H.
Michel, Patrick P.
Hartmann, Andreas
External co-authors :
yes
Language :
English
Title :
Probenecid potentiates MPTP/MPP+ toxicity by interference with cellular energy metabolism.
Publication date :
2013
Journal title :
Journal of Neurochemistry
ISSN :
1471-4159
Publisher :
Blackwell, Oxford, United Kingdom
Volume :
127
Issue :
6
Pages :
782-92
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
(c) 2013 International Society for Neurochemistry.
Available on ORBilu :
since 09 February 2016

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