Neuroleptic medications inhibit complex I of the electron transport chain

Abstract

Neuroleptic medications are prescribed to millions of patients, but their use is limited by potentially irreversible extrapyramidal side effects. Haloperidol shows striking structural similarities to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces parkinsonism apparently through inhibition of NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial electron transport chain. We now report that haloperidol, chlorpromazine, and thiothixene inhibit complex I in vitro in rat brain mitochondria. Clozapine, an atypical antipsychotic reported to have little or no extrapyramidal toxicity, also inhibits complex I, but at a significantly higher concentration. Neuroleptic treated patients have significant depression of platelet complex I activity similar to that seen in idiopathic Parkinson's disease. Complex I inhibition may be associated with the extrapyramidal side effects of these drugs.

Superoxide, neuroleptics and the ubiquinone and cytochrome b5 reductases in brain and lymphocytes from normals and schizophrenic patients

“…The related enzyme NADHubiquinone reductase which contains both mitochondrially and nuclear coded subunits is known to be decreased by neuroleptics, 23,24 and is also decreased in Parkinson's disease. 25 The decrease in cytochrome b 5 reductase has been shown at the mRNA level in rats by in situ hybridisation (Table 5) and at the enzymic level also in rat brain (Table 6).…”

Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood–brain barrier

“…These effects need not be secondary to that of phospholipidosis; since, CPZ, HAL, RIS and CLZ are known to affect mitochondrial function by an inhibition of Complex I of the electron transport chain, with IC50's of ~35µM for CPZ and HAL, ~65 µM for RIS and >200µM for CLZ in isolated mitochondrial preparations (Burkhardt et al, 1993;Modica-Napolitano et al, 2003). CPZ can also impair succinate-cytochrome C reductase activity as well as acting as a mitochondrial uncoupler (Modica-Napolitano et al, 2003).…”

Effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells

“…However, recent research has revealed HAL, which is a typical AP to be less cytotoxic than CLZ metabolite (desmethyle CLZ), which is an atypical AP (Donard et al, 2003). Other studies however showed HAL to have a more potent neurotoxic due to its metabolite (Subramanyam et al, 1991;Burkhardt et al, 1993, Raudenska et al, 2013). …”

“…An in-vitro study by Burkhardt et al (1993) found that APs inhibited mitochondrial complex I. In addition, other studies found that injecting mice with different APs (HAL, CLZ and RIS) led to inhibition of complex I activity in different parts of the brain after a variable length of time ( Balijepalli et al, 2001;Karry et al,.…”

“…Several APs, such as haloperidol (HAL), chlorpromazine (CPZ), thiothixine and clozapine (CLZ), have been found to inhibit mitochondrial respiratory enzyme complexes, which have a crucial role in Oxidative phosphorylation cycle for the synthesis of adenosine triphosphates (ATP) (Burkhardt et al, 1993). Inhibited respiratory enzyme complexes have been found to induce damage to the mitochondria via the release of reactive oxygen species (ROS) (Wei et al, 1998and Harper et al, 2004, Guo et al, 2013.…”