Probenecid potentiates MPTP/MPP+ toxicity by interference with cellular energy metabolism.
Identifieur interne : 000C53 ( Main/Exploration ); précédent : 000C52; suivant : 000C54Probenecid potentiates MPTP/MPP+ toxicity by interference with cellular energy metabolism.
Auteurs : Daniel Alvarez-Fischer [Allemagne] ; Carmen Noelker ; Anne Grünewald ; Franca Vulinovi ; Serge Guerreiro ; Julia Fuchs ; Lixia Lu ; Anne Lombès ; Etienne C. Hirsch ; Wolfgang H. Oertel ; Patrick P. Michel ; Andreas HartmannSource :
- Journal of neurochemistry [ 1471-4159 ] ; 2013.
English descriptors
- KwdEn :
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (metabolism), 1-Methyl-4-phenylpyridinium (metabolism), Animals, 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, Mice, Neurotoxins (toxicity), Parkinson Disease (etiology), Parkinson Disease (metabolism), Parkinson Disease (pathology), Probenecid (toxicity), Rotenone (toxicity), Uricosuric Agents (toxicity).
- MESH :
- chemical , antagonists & inhibitors : Electron Transport Complex I.
- chemical , metabolism : 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-Methyl-4-phenylpyridinium.
- drug effects : Corpus Striatum, Dopaminergic Neurons.
- etiology : Parkinson Disease.
- metabolism : Corpus Striatum, Dopaminergic Neurons, Parkinson Disease.
- pathology : Corpus Striatum, Dopaminergic Neurons, Parkinson Disease.
- chemical , toxicity : Dopamine Agents, Neurotoxins, Probenecid, Rotenone, Uricosuric Agents.
- Animals, Disease Models, Animal, Drug Synergism, Energy Metabolism, Mice.
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.
DOI: 10.1111/jnc.12343
PubMed: 23802648
Affiliations:
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Hirsch</name></author><author><name sortKey="Oertel, Wolfgang H" sort="Oertel, Wolfgang H" uniqKey="Oertel W" first="Wolfgang H" last="Oertel">Wolfgang H. Oertel</name></author><author><name sortKey="Michel, Patrick P" sort="Michel, Patrick P" uniqKey="Michel P" first="Patrick P" last="Michel">Patrick P. Michel</name></author><author><name sortKey="Hartmann, Andreas" sort="Hartmann, Andreas" uniqKey="Hartmann A" first="Andreas" last="Hartmann">Andreas Hartmann</name></author></analytic><series><title level="j">Journal of neurochemistry</title><idno type="eISSN">1471-4159</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (metabolism)</term><term>1-Methyl-4-phenylpyridinium (metabolism)</term><term>Animals</term><term>Corpus Striatum (drug effects)</term><term>Corpus Striatum (metabolism)</term><term>Corpus Striatum (pathology)</term><term>Disease Models, Animal</term><term>Dopamine Agents (toxicity)</term><term>Dopaminergic Neurons (drug effects)</term><term>Dopaminergic Neurons (metabolism)</term><term>Dopaminergic Neurons (pathology)</term><term>Drug Synergism</term><term>Electron Transport Complex I (antagonists & inhibitors)</term><term>Energy Metabolism</term><term>Mice</term><term>Neurotoxins (toxicity)</term><term>Parkinson Disease (etiology)</term><term>Parkinson Disease (metabolism)</term><term>Parkinson Disease (pathology)</term><term>Probenecid (toxicity)</term><term>Rotenone (toxicity)</term><term>Uricosuric Agents (toxicity)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Electron Transport Complex I</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</term><term>1-Methyl-4-phenylpyridinium</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Corpus Striatum</term><term>Dopaminergic Neurons</term></keywords><keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Corpus Striatum</term><term>Dopaminergic Neurons</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Corpus Striatum</term><term>Dopaminergic Neurons</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Dopamine Agents</term><term>Neurotoxins</term><term>Probenecid</term><term>Rotenone</term><term>Uricosuric Agents</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Drug Synergism</term><term>Energy Metabolism</term><term>Mice</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="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.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country></list><tree><noCountry><name sortKey="Fuchs, Julia" sort="Fuchs, Julia" uniqKey="Fuchs J" first="Julia" last="Fuchs">Julia Fuchs</name><name sortKey="Grunewald, Anne" sort="Grunewald, Anne" uniqKey="Grunewald A" first="Anne" last="Grünewald">Anne Grünewald</name><name sortKey="Guerreiro, Serge" sort="Guerreiro, Serge" uniqKey="Guerreiro S" first="Serge" last="Guerreiro">Serge Guerreiro</name><name sortKey="Hartmann, Andreas" sort="Hartmann, Andreas" uniqKey="Hartmann A" first="Andreas" last="Hartmann">Andreas Hartmann</name><name sortKey="Hirsch, Etienne C" sort="Hirsch, Etienne C" uniqKey="Hirsch E" first="Etienne C" last="Hirsch">Etienne C. Hirsch</name><name sortKey="Lombes, Anne" sort="Lombes, Anne" uniqKey="Lombes A" first="Anne" last="Lombès">Anne Lombès</name><name sortKey="Lu, Lixia" sort="Lu, Lixia" uniqKey="Lu L" first="Lixia" last="Lu">Lixia Lu</name><name sortKey="Michel, Patrick P" sort="Michel, Patrick P" uniqKey="Michel P" first="Patrick P" last="Michel">Patrick P. Michel</name><name sortKey="Noelker, Carmen" sort="Noelker, Carmen" uniqKey="Noelker C" first="Carmen" last="Noelker">Carmen Noelker</name><name sortKey="Oertel, Wolfgang H" sort="Oertel, Wolfgang H" uniqKey="Oertel W" first="Wolfgang H" last="Oertel">Wolfgang H. Oertel</name><name sortKey="Vulinovi, Franca" sort="Vulinovi, Franca" uniqKey="Vulinovi F" first="Franca" last="Vulinovi">Franca Vulinovi</name></noCountry><country name="Allemagne"><noRegion><name sortKey="Alvarez Fischer, Daniel" sort="Alvarez Fischer, Daniel" uniqKey="Alvarez Fischer D" first="Daniel" last="Alvarez-Fischer">Daniel Alvarez-Fischer</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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