Haloperidol induces neurotoxicity by the NMDA receptor downstream signaling pathway, alternative from glutamate excitotoxicity

• Published in: Neurochemistry international Vol. 50; no. 7; pp. 976 - 982
• Main Authors: Zhuravliova, E., Barbakadze, T., Natsvlishvili, N., Mikeladze, D.G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-06-2007
• Subjects: Animals; Animals, Newborn; Cell Survival - drug effects; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Dizocilpine Maleate - pharmacology; Glutamic Acid - toxicity; Haloperidol; Haloperidol - pharmacokinetics; Haloperidol - toxicity; L-Lactate Dehydrogenase - analysis; Neuroglia - drug effects; Neuroglia - physiology; Neurons - drug effects; Neurons - physiology; Neurotoxicity; Nitric Oxide Synthase Type I - metabolism; NMDA receptor; Ras-GRF; ras-GRF1 - metabolism; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - physiology; Signal Transduction - drug effects; Neurotoxicity; Haloperidol; NMDA receptor; Ras-GRF
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2006.09.015

The NMDA receptor is believed to be important in a wide range of nervous system functions including neuronal migration, synapse formation, learning and memory. In addition, it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders. Besides of agonist/coagonist sites, other modulator sites, including butyrophenone site may regulate the
N-methyl-
d-aspartate receptor. It has been shown that haloperidol, an antipsychotic neuroleptic drug, interacts with the NR2B subunit of NMDA receptor and inhibits NMDA response in neuronal cells. We found that NMDA receptor was co-immunoprecipitated by anti-Ras antibody and this complex, beside NR2 subunit of NMDA receptor contained haloperidol-binding proteins, nNOS and Ras-GRF. Furthermore, we have shown that haloperidol induces neurotoxicity of neuronal cells via NMDA receptor complex, accompanied by dissociation of Ras-GRF from membranes and activation of c-Jun-kinase. Inclusion of insulin prevented relocalization of Ras-GRF and subsequent neuronal death. Haloperidol-induced dissociation of Ras-GRF leads to inhibition of membrane-bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way. Our results suggest that haloperidol induces neuronal cell death by the interaction with NMDA receptor, but through the alternative from glutamate excitotoxicity signaling pathway.