Haloperidol causes cytoskeletal collapse in N1E-115 cells through tau hyperphosphorylation induced by oxidative stress: Implications for neurodevelopment.
Haloperidol a typical antipsychotic commonly used in the treatment of schizophrenia causes neuronal damage and extrapiramidal symptoms after several years of treatment. These symptoms have been associated with increased levels of oxidative stress. Reactive oxygen species produce cytoskeletal collapse and an excessive phosphorylation of tau, a microtubule-associated protein that plays a key role in microtubule stabilization, and in growth cone and neurite formation, which are cytoskeletal phenotypes that participate in neurodevelopment. Thus, we hypothesized that haloperidol produces neurocytoskeletal disorganization by increasing free radicals and tau hyperphosphorylation, and consequently, the loss of neurodevelopmental cytoskeletal phenotypes, neurites and growth cones. The purpose of this work was the characterization of neuronal cytoskeletal changes caused by haloperidol in neuroblastoma N1E-115 cells. We also studied the mechanisms by which haloperidol causes cytoskeletal changes. The results showed that haloperidol at 100microM caused a complete cytoskeleton collapse in the majority of the cells. Melatonin, a free radical scavenger, blocks tau hyperphosphorylation, and microtubule disorganization caused by haloperidol in a dose-response mode. Additionally, the indole blocks lipoperoxide formation in haloperidol treated cells. The results indicate that free radicals and tau hyperphosphorylation produced by haloperidol caused a cytoskeletal collapse and the lost of growth cones and neurites. These effects were blocked by melatonin. Data suggest that extrapiramidal symptoms in schizophrenic patients can be produced by cytoskeletal disorganization during adult brain neurodevelopment after prolonged haloperidol treatment that can be prevented by melatonin.
Benítez-King
Gloria
G
Departamento de Neurofarmacología, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, México, D.F., México. bekin@imp.edu.mx
Ortíz-López
Leonardo
L
Jiménez-Rubio
Graciela
G
Ramírez-Rodríguez
Gerardo
G
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000633:toxicity*; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals / Q000378:metabolism; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000008:administration & dosage / Q000633:toxicity*; D008550:Melatonin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism
D000975:Antioxidants; D014150:Antipsychotic Agents; D005609:Free Radicals; D016875:tau Proteins; D006220:Haloperidol; D008550:Melatonin