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Titolo:
Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation
Autore:
Balijepalli, S; Boyd, MR; Ravindranath, V;
Indirizzi:
Natlka,st Mental Hlth & Neurosci, Dept Neurochem, Bangalore 560029, Karnata Natl Inst Mental Hlth & Neurosci Bangalore Karnataka India 560029 Karnata NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, FCRDC, Frederick, NCI Frederick MD USA 21702 Dev, Dev Therapeut Program, FCRDC, Frederick,
Titolo Testata:
NEUROPHARMACOLOGY
fascicolo: 4, volume: 38, anno: 1999,
pagine: 567 - 577
SICI:
0028-3908(199904)38:4<567:IOMCIB>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
NEUROTOXIC PYRIDINIUM METABOLITE; ELECTRON-TRANSPORT CHAIN; PARKINSONS-DISEASE; ANTIPSYCHOTIC-DRUGS; BRAIN-SLICES; DOPAMINE; STRESS; GLUTATHIONE; CLOZAPINE; BINDING;
Keywords:
haloperidol; complex I; brain; glutathione; protein thiol; neuroleptic;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
36
Recensione:
Indirizzi per estratti:
Indirizzo: Ravindranath, V Natl9,nst Mental Hlth & Neurosci, Dept Neurochem, Hosur Rd, Bangalore 56002 Natl Inst Mental Hlth & Neurosci Hosur Rd Bangalore Karnataka India 560029
Citazione:
S. Balijepalli et al., "Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation", NEUROPHARM, 38(4), 1999, pp. 567-577

Abstract

We have examined the: effects of a variety of classical and atypical neuroleptic drugs on mitochondrial NADH ubiquinone oxido-reductase (complex I) activity. Sagittal slices of mouse brain incubated in vitro with haloperidol(10 nM) showed time- and concentration-dependent inhibition of complex I. Similar concentrations of the pyridinium metabolite of haloperidol (HPP+) failed to inhibit complex I activity in this model; indeed, comparable inhibition was obtained only at a 10 000-fold higher concentration of HPP+ (100 mu M). Treatment of brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and alpha-lipoic acidabolished haloperidol-induced loss of complex I activity. Incubation of mitochondria from haloperidol treated brain slices with the thiol reductant, dithiothreitol, completely regenerated complex I activity demonstrating thiol oxidation as a feasible mechanism of inhibition. In a comparison of different neuroleptic drugs, haloperidol was the most potent inhibitor of complex I, followed by chlorpromazine, fluphenazine and risperidone while the atypical neuroleptic, clozapine (100 mu M) did not inhibit complex I activityin mouse brain slices. The present studies support the view that classicalneuroleptics such as haloperidol inhibit mitochondrial complex I through oxidative modification of the enzyme complex. (C) 1999 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/01/20 alle ore 10:24:20