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The Journal of Neuroscience, August 6, 2008, 28(32):8040-8052; doi:10.1523/JNEUROSCI.1947-08.2008
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Neurobiology of Disease
Electrophysiology and Pharmacology of Striatal Neuronal Dysfunction Induced by Mitochondrial Complex I Inhibition
Cinzia Costa,1,2 Vincenzo Belcastro,1,2 Alessandro Tozzi,1,2 Massimiliano Di Filippo,1,2 Michela Tantucci,1,2 Sabrina Siliquini,1,2 Alessia Autuori,1,2 Barbara Picconi,1,2 Maria Grazia Spillantini,3 Ernesto Fedele,4 Anna Pittaluga,4 Maurizio Raiteri,4 andPaolo Calabresi1,2 1Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, 06156 Perugia, Italy, 2Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, 00143 Rome, Italy, 3Centre for Brain Repair and Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 1TN, United Kingdom, and 4Dipartimento di Medicina Sperimentale, Sezione di Farmacologia e Tossicologia, Università degli Studi di Genova, 16148 Genoa, Italy
Correspondence should be addressed to Prof. Paolo Calabresi, Clinica Neurologica, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, 06156 Perugia, Italy. Email: calabre{at}unipg.it
Reduced activity of the mitochondrial respiratory chain and in particular of complex I is implicated not only in the etiology of Parkinson's disease but also in other forms of parkinsonism in which striatal neurodegeneration occurs, such as progressive supranuclear palsy.
The pesticide rotenone inhibits mitochondrial complex I and reproduces features of these basal ganglia neurological disorders in animal models. We have characterized the electrophysiological effects of rotenone in the striatum as well as potential neuroprotective strategies to counteract the detrimental effects of this neurotoxin. We found that rotenone causes a dose-dependent and irreversible loss of the corticostriatal field potential amplitude, which was related to the development of a membrane depolarization/inward current in striatal spiny neurons, coupled to an increased release of both excitatory amino acids and dopamine (DA).
In particular, we have investigated whether glutamate, DA, and GABA systems might represent possible targets for neuroprotection against rotenone-induced striatal neuronal dysfunction. Interestingly, whereas modulation of glutamatergic transmission was not neuroprotective, blockade of D2-like but not D1-like DA receptors significantly reduced the rotenone-induced effects via a GABA-mediated mechanism. In addition, because antiepileptic drugs (AEDs) modulate multiple transmitter systems, we have analyzed the possible neuroprotective effects of some AEDs against rotenone. We found that carbamazepine, unlike other tested AEDs, exerts a potent neuroprotective action against rotenone-induced striatal neuronal dysfunction. This neuroprotection was observed at therapeutically relevant concentrations requiring endogenous GABA. Differential targeting of GABAergic transmission may represent a possible therapeutic strategy against basal ganglia neurodegenerative disorders involving mitochondrial complex I dysfunction.
Key words: antiepileptic drugs; dopamine; GABA; Parkinson's disease; rotenone; striatum
Received Feb. 27, 2008; revised June 12, 2008; accepted June 18, 2008.
Correspondence should be addressed to Prof. Paolo Calabresi, Clinica Neurologica, Facoltà di Medicina e Chirurgia, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, 06156 Perugia, Italy. Email: calabre{at}unipg.it
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