Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation

Balijepalli, Sadguna ; Boyd, Michael R. ; Ravindranath, Vijayalakshmi (1999) Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation Neuropharmacology, 38 (4). pp. 567-577. ISSN 0028-3908

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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 a10 000-fold higher concentration of HPP+ (100 μM). Treatment of brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and α-lipoic acid abolished 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 μM) did not inhibit complex I activity in mouse brain slices. The present studies support the view that classical neuroleptics such as haloperidol inhibit mitochondrial complex I through oxidative modification of the enzyme complex.

Item Type:Article
Source:Copyright of this article belongs to Elsevier Science.
Keywords:Haloperidol; Complex I; Brain; Glutathione; Protein Thiol; Neuroleptic
ID Code:40648
Deposited On:24 May 2011 13:49
Last Modified:24 May 2011 13:49

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