Probenecid potentiates MPTP/MPP+ toxicity by interference with cellular energy metabolism

• Published in: Journal of neurochemistry 2013-12, Vol.127 (6), p.782-792
• Main Authors: Alvarez‐Fischer, 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
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - metabolism; 1-Methyl-4-phenylpyridinium - metabolism; Animals; ATP; Cellular biology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - pathology; Disease Models, Animal; Dopamine Agents - toxicity; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Drug Synergism; Electron Transport Complex I - antagonists & inhibitors; Energy Metabolism; Life Sciences; Metabolism; Mice; mitochondria; MPP; MPTP; Neurotoxins - toxicity; Parkinson Disease - etiology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; probenecid; Probenecid - toxicity; Rotenone - toxicity; Toxicity; Uricosuric Agents - toxicity
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12343

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. We showed in the present study that probenecid lowers the intra‐cellular ATP production by interfering with the cellular metabolism (black and green arrows). We excluded an altered MPP+ uptake via dopamine transporter (DAT) (blue arrow) or a disturbed glycolysis pathway as cause of the potentiated MPP+ toxicity and showed an indirect reduction in the Complex I activity. We therefore hypothesize (red dotted lines) that probenecid acts either by altering substrate oxidation downstream of pyruvate or by influencing the citric acid cycle. We showed that deleterious effects of probenecid can be reversed by extra‐cellular ATP (red arrows).