Enhancement in Phospholipase D Activity as a New Proposed Molecular Mechanism of Haloperidol-Induced Neurotoxicity

Membrane phospholipase D (PLD) is associated with numerous neuronal functions, such as axonal growth, synaptogenesis, formation of secretory vesicles, neurodegeneration, and apoptosis. PLD acts mainly on phosphatidylcholine, from which phosphatidic acid (PA) and choline are formed. In turn, PA is a...

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Bibliographic Details
Published in:International journal of molecular sciences 2020-12, Vol.21 (23), p.9265
Main Authors: Krzystanek, Marek, Krzystanek, Ewa, Skałacka, Katarzyna, Pałasz, Artur
Format: Article
Language:English
Subjects:
Animals
Antipsychotics
Apoptosis
Brain research
Chlorpromazine
Chlorpromazine - adverse effects
Chlorpromazine - pharmacology
Choline
Communication
Cytotoxicity
Drug dosages
Drugs
Enzyme Activation - drug effects
Enzymes
Experiments
Fluphenazine
Haloperidol
Haloperidol - adverse effects
Kinases
Lecithin
Mammals
Medical research
Membranes
Neurodegeneration
Neurotoxicity
Neutrophils
Olanzapine
Phosphatidic acid
Phosphatidylcholine
Phospholipase
Phospholipase D
Phospholipase D - metabolism
Plasma
Proteins
Psychotropic drugs
Rats
Rodents
Secretory vesicles
Synaptogenesis
Variance analysis
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Summary:Membrane phospholipase D (PLD) is associated with numerous neuronal functions, such as axonal growth, synaptogenesis, formation of secretory vesicles, neurodegeneration, and apoptosis. PLD acts mainly on phosphatidylcholine, from which phosphatidic acid (PA) and choline are formed. In turn, PA is a key element of the PLD-dependent secondary messenger system. Changes in PLD activity are associated with the mechanism of action of olanzapine, an atypical antipsychotic. The aim of the present study was to assess the effect of short-term administration of the first-generation antipsychotic drugs haloperidol, chlorpromazine, and fluphenazine on membrane PLD activity in the rat brain. Animals were sacrificed for a time equal to the half-life of the antipsychotic drug in the brain, then the membranes in which PLD activity was determined were isolated from the tissue. The results indicate that only haloperidol in a higher dose increases the activity of phospholipase D. Such a mechanism of action of haloperidol has not been described previously. Induction of PLD activity by haloperidol may be related to its mechanism of cytotoxicity. The finding could justify the use of PLD inhibitors as protective drugs against the cytotoxicity of first-generation antipsychotic drugs like haloperidol.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms21239265