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Protein thiol oxidation by haloperidol results in inhibition of mitochondrial complex I in brain regions: comparison with atypical antipsychotics

  1. Author:
    Balijepalli, S.
    Kenchappa, R. S.
    Boyd, M. R.
    Ravindranath, V.

  2. Author Address

    Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Hosur Rd, Bangalore 560029, Karnataka, India. Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Bangalore 560029, Karnataka, India. NCI, Frederick Canc Res & Dev Ctr, Dev Therapeut Program, Lab Drug Discovery Res & Dev, Frederick, MD 21702 USA. Natl Brain Res Ctr, New Delhi 110067, India. Ravindranath V Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Hosur Rd, Bangalore 560029, Karnataka, India.
    1. Year: 2001
  2. Journal: Neurochemistry International
    1. 38
    2. 5
    3. Pages: 425-435
  4. Type of Article: Article
  1. Abstract:

    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, alpha -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. (C) 2001 Elsevier Science Ltd. All rights reserved.

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