Probenecid potentiates MPTP/MPP+ toxicity by interference with cellular energy metabolism
- 27 June 2013
- journal article
- research article
- Published by Wiley in Journal of Neurochemistry
- Vol. 127 (6), 782-792
- https://doi.org/10.1111/jnc.12343
Abstract
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.Keywords
This publication has 40 references indexed in Scilit:
- Purinergic signalling in the nervous system: an overviewTrends in Neurosciences, 2009
- Membrane compartments and purinergic signalling: P2X receptors in neurodegenerative and neuroinflammatory eventsThe FEBS Journal, 2008
- Modelling Parkinson‐like neurodegeneration via osmotic minipump delivery of MPTP and probenecidJournal of Neurochemistry, 2008
- All-trans retinoic acid arrests neuroblastoma cells in a dormant state. Subsequent nerve growth factor/brain-derived neurotrophic factor treatment adds modest benefitJournal of Pediatric Surgery, 2008
- Quantitative [123I]FP-CIT pinhole SPECT imaging predicts striatal dopamine levels, but not number of nigral neurons in different mouse models of Parkinson's diseaseNeuroImage, 2007
- Annonacin, a Natural Mitochondrial Complex I Inhibitor, Causes Tau Pathology in Cultured NeuronsJournal of Neuroscience, 2007
- Multidrug Resistance-Associated Proteins: Expression and Function in the Central Nervous SystemPharmacological Reviews, 2006
- Molecular Physiology of Urate TransportPhysiology, 2005
- ATP Released From Astrocytes During Swelling Activates Chloride ChannelsJournal of Neurophysiology, 2003
- Effect of Probenecid on Tetraethyl Ammonium TEA Transport Across Basolateral Membrane of Rabbit Proximal TubuleThe Korean Journal of Internal Medicine, 1992