TY - JOUR
T1 - Protein thiol oxidation by haloperidol results in inhibition of mitochondrial complex I in brain regions
T2 - Comparison with atypical antipsychotics
AU - Balijepalli, Sadguna
AU - Kenchappa, Rajappa S.
AU - Boyd, Michael R.
AU - Ravindranath, Vijayalakshmi
N1 - Funding Information:
We are grateful to Eisai Pharmaceutical (Japan) and F. Hoffman La Roche (Basel, Switzerland) for providing ubiquinone 1. S. Balijepalli thanks the Council for Scientific and Industrial Research (India) for award of Senior Research Fellowship. This research was funded by a grant from the Theodore and Vada Stanley Research Foundation.
PY - 2001
Y1 - 2001
N2 - Usage of 'typical' but not 'atypical' antipsychotic drugs is associated with severe side effects involving extrapyramidal tract (EPT). Single dose of haloperidol caused selective inhibition of complex I in frontal cortex, striatum and midbrain (41 and 26%, respectively) which was abolished by pretreatment of mice with thiol antioxidants, α-lipoic acid and glutathione isopropyl ester, and reversed, in vitro, by disulfide reductant, dithiothreitol. Prolonged administration of haloperidol to mice resulted in complex I loss in frontal cortex, hippocampus, striatum and midbrain, while chronic dosing with clozapine affected only hippocampus and frontal cortex. Risperidone caused complex I loss in frontal cortex, hippocampus and striatum but not in midbrain from which extrapyramidal tract emanates. Inhibition of the electron transport chain component, complex I by haloperidol is mediated through oxidation of essential thiol groups to disulfides, in vivo. Further, loss of complex I in extrapyramidal brain regions by anti-psychotics correlated with their known propensity to generate side-effects involving extra-pyramidal tract.
AB - Usage of 'typical' but not 'atypical' antipsychotic drugs is associated with severe side effects involving extrapyramidal tract (EPT). Single dose of haloperidol caused selective inhibition of complex I in frontal cortex, striatum and midbrain (41 and 26%, respectively) which was abolished by pretreatment of mice with thiol antioxidants, α-lipoic acid and glutathione isopropyl ester, and reversed, in vitro, by disulfide reductant, dithiothreitol. Prolonged administration of haloperidol to mice resulted in complex I loss in frontal cortex, hippocampus, striatum and midbrain, while chronic dosing with clozapine affected only hippocampus and frontal cortex. Risperidone caused complex I loss in frontal cortex, hippocampus and striatum but not in midbrain from which extrapyramidal tract emanates. Inhibition of the electron transport chain component, complex I by haloperidol is mediated through oxidation of essential thiol groups to disulfides, in vivo. Further, loss of complex I in extrapyramidal brain regions by anti-psychotics correlated with their known propensity to generate side-effects involving extra-pyramidal tract.
KW - Antipsychotic
KW - Brain
KW - Complex I
KW - Haloperidol
KW - Mitochondria
KW - Oxidative stress
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U2 - 10.1016/S0197-0186(00)00108-X
DO - 10.1016/S0197-0186(00)00108-X
M3 - Article
C2 - 11222923
AN - SCOPUS:0035108147
SN - 0197-0186
VL - 38
SP - 425
EP - 435
JO - Neurochemistry International
JF - Neurochemistry International
IS - 5
ER -