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Probenecid potentiates MPTP / MPP + toxicity by interference with cellular energy metabolism
Author(s) -
AlvarezFischer Daniel,
Noelker Carmen,
Grünewald Anne,
Vulinović Franca,
Guerreiro Serge,
Fuchs Julia,
Lu Lixia,
Lombès Anne,
Hirsch Etienne C.,
Oertel Wolfgang H.,
Michel Patrick P.,
Hartmann Andreas
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12343
Subject(s) - probenecid , mptp , pharmacology , neurotoxin , chemistry , dopaminergic , metabolite , biochemistry , dopamine , biology , neuroscience
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.