Haloperidol causes cytoskeletal collapse in N1E-115 cells through tau hyperphosphorylation induced by oxidative stress: Implications for neurodevelopment

Benítez‐King, Gloria; Ortíz-López, Leonardo; Jiménez-Rubio, Graciela; Ramírez-Rodríguez, Gerardo

doi:10.1016/j.ejphar.2010.06.057

Cited by 22 publications

(12 citation statements)

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“…Antipsychotics such as olanzapine, quetiapine, and clozapine have been shown to enhance growth factor induced neurite outgrowth in PC12 cells, at concentrations of 10–40 μM (Lu and Dwyer, 2005). In neuroblastoma cells, high (100 μM) concentrations of haloperidol had the opposite effect, disrupting neuritic cytoskeletal organization (Benitez-King et al, 2010). Interestingly, clozapine, and to some extent fluphenazine, were able to increase axon lengths from mechanosensory neurons in C. elegans , when made available to larvae at high (160 μM) concentrations (Donohoe et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates

Johnstone

Reierson

Smith

et al. 2012

Molecular and Cellular Neuroscience

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Injury to the central nervous system (CNS) can result in lifelong loss of function due in part to the regenerative failure of CNS neurons. Inhibitory proteins derived from myelin and the astroglial scar are major barriers for the successful regeneration of injured CNS neurons. Previously, we described the identification of a novel compound, F05, which promotes neurite growth from neurons challenged with inhibitory substrates in vitro, and promotes axonal regeneration in vivo (Usher et al., 2010). To identify additional regeneration-promoting compounds, we used F05-induced gene expression profiles to query the Broad Institute Connectivity Map, a gene expression database of cells treated with >1,300 compounds. Despite no shared chemical similarity, F05-induced changes in gene expression were remarkably similar to those seen with a group of piperazine phenothiazine antipsychotics (PhAPs). In contrast to antipsychotics of other structural classes, PhAPs promoted neurite growth of CNS neurons challenged with two different glial derived inhibitory substrates. Our pharmacological studies suggest a mechanism whereby PhAPs promote growth through antagonism of calmodulin signaling, independent of dopamine receptor antagonism. These findings shed light on mechanisms underlying neurite-inhibitory signaling, and suggest that clinically approved antipsychotic compounds may be repurposed for use in CNS injured patients.

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Section: Discussionmentioning

confidence: 99%

A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates

Johnstone

Reierson

Smith

et al. 2012

Molecular and Cellular Neuroscience

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“…En las células de neuroblastoma N1E-115 previamente incubadas con 50 nM de AO, 100 µM de peróxido de hidrógeno o 100 µM de haloperidol, la MEL (1 o 100 nM) disminuye en un 100% la cantidad relativa de tau fosforilada en la serina 404. 77,82 Además, en modelos animales de EA, como los ratones 3xTg-AD, también se ha demostrado que la MEL disminuye los niveles de tau hiperfosforilada así como los síntomas conductuales similares a los de la demencia tales como la ansiedad y la pérdida de la conducta exploratoria. 83 De manera análoga se ha descrito que en animales pinealectomizados hay un incremento en los niveles de tau hiperfosforilada asociados con un detrimento de la cognición.…”

Section: La Melatonina Reduce Los Niveles De Tau Fosforiladaunclassified

La melatonina como un factor promotor de la diferenciación neuronal: implicaciones en el tratamiento de las demencias

et al. 2013

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SUMMARYDementias are progressive and neurodegenerative neuropsychiatric disorders, with a high worldwide prevalence. These disorders affect memory and behavior, causing impairment in the performance of daily activities and general disability in the elders. Cognitive impairment in these patients is related to anatomical and structural alterations at cellular and sub-cellular levels in the Central Nervous System. In particular, amyloid plaques and neurofibrillar tangles have been defined as histopathological hallmarks of Alzheimer's disease. Likewise, oxidative stress and neuroinflammation are implicated in the etiology and progression of the disease.Neuronal precursors from human olfactory neuroepithelium have been recently characterized as an experimental model to identify neuropsychiatric disease biomarkers. Moreover, this model not only allows the study of neuropsychiatric physiopathology, but also the process of neurodevelopment at cellular, molecular and pharmacological levels.This review gathers the evidence to support the potential therapeutic use of melatonin for dementias, based on its antioxidant properties, its anti-inflammatory effect in the brain, and its ability to inhibit both tau hyper-phosphorylation and amyloid plaque formation. Furthermore, since melatonin stimulates neurogenesis, and promotes neuronal differentiation by inducing the early stages of neuritogenesis and dendrite formation, it has been suggested that melatonin could be useful to counteract the cognitive impairment in dementia patients.Key words: Melatonin, dementia, biomarkers, neuroepithelium, neuritogenesis. RESUMENLas demencias son enfermedades neuropsiquiátricas, progresivas, neurodegenerativas y con una alta prevalencia a nivel mundial. Ocupan uno de los primeros lugares como enfermedades que causan incapacidad en los adultos mayores. En estos pacientes el Sistema Nervioso Central presenta alteraciones anatómico-estructurales a nivel celular y subcelular que se asocian con deficiencias cognitivas. En particular, en la enfermedad de Alzheimer se han caracterizado marcadores histopatológicos como las placas amiloides y las marañas neurofibrilares. Se sabe que el estrés oxidativo y la neuroinflamación participan en la etiología y el desarrollo de la enfermedad. Recientemente se caracterizó a los precursores neuronales del neuroepitelio olfatorio humano como un modelo experimental adecuado para identificar biomarcadores de rasgo y para estudiar la fisiopatología de diversas enfermedades neuropsiquiátricas, así como el proceso del neurodesarrollo, a nivel celular, molecular y farmacológico. En este trabajo se presenta la evidencia que sustenta que la melatonina puede ser útil en el tratamiento de las demencias, por su capacidad antioxidante, por su efecto anti-inflamatorio, así como por el efecto inhibidor de la hiperfosforilación de la proteina tau y de la formación de placas amiloides. Además, al estimular la formación de nuevas neuronas, la neuritogénesis en sus etapas tempranas y la formación de dendritas, la melatonina podría...

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“…The pathophysiology of these adverse reactions has been attributed to neuronal cell damage from free radicals induced by APs. Haloperidol, a typical AP, has been related to elevated lipid peroxidation in cell cultures [6][7][8] and in peripheral tissues of psychotic patients [9,10], and to the enhancement of vacuous chewing movements in animal models [11]. Regarding atypical APs, there is increased concern about the serious metabolic side effects they induce.…”

Section: Fundamental and Clinicalmentioning

confidence: 99%

Sulforaphane protects SK‐N‐SH cells against antipsychotic‐induced oxidative stress

Mas¹,

Gassó²,

Trias³

et al. 2011

Fundamemntal Clinical Pharma

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Adverse reactions to antipsychotic drugs (APs) have been attributed to oxidative stress. Sulforaphane (SF) is a potent antioxidant that protects against dopaminergic cell death. We examined the protective properties of SF against AP-induced oxidative stress in dopaminergic neuroblastoma cells. Human neuroblastoma SK-N-SH cells were treated with SF (0.5-5 μM), and 24 h later, haloperidol, risperidone or paliperidone (100 μM) was administered, either alone or in combination with dopamine (100 μM). To determine the antioxidant properties of SF, quinone oxidoreductase (NQO1) activity, glutathione S-transferase activity, and glutathione (GSH) levels were determined. Oxidative stress was measured by the increase in thiobarbituric acid reactive substances (TBARS) and in protein-bound quinones. Cell viability was also assessed. SF treatment increased GSH levels and induced NQO1 activity in SK-N-SH cells. Haloperidol was the only AP that increased TBARS when administered alone. When cells were cocultured with a drug in combination with dopamine, all three APs increased TBARS and protein-bound quinones and also induced neurotoxicity. In all the experimental conditions, 5 μM SF attenuated the accumulation of TBARS and protein-bound quinones and increased cell survival rates. Our results indicate that SF increases GSH levels and induces NQO1 activity and the removal of electrophilic quinones and radical oxygen species. Furthermore, SF could provide protective effects against AP-induced toxicity in dopaminergic cells.

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Haloperidol causes cytoskeletal collapse in N1E-115 cells through tau hyperphosphorylation induced by oxidative stress: Implications for neurodevelopment

Cited by 22 publications

References 58 publications

A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates

A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates

La melatonina como un factor promotor de la diferenciación neuronal: implicaciones en el tratamiento de las demencias

Sulforaphane protects SK‐N‐SH cells against antipsychotic‐induced oxidative stress

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