Clozapine protects adult neural stem cells from ketamine-induced cell death in correlation with decreased apoptosis and autophagy

Autor: Ingrid Agartz, Shiva Mansouri, Hannes Bohman, Sven-Ove Ögren, Sophie Curbo, Mathias Lundberg, Cesare Patrone
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Cell- och molekylärbiologi
Apoptosis
Pharmacology
Biochemistry
Molecular Bases of Health & Disease
haloperidol
0302 clinical medicine
Neural Stem Cells
Lateral Ventricles
Haloperidol
Clozapine
Research Articles
Cells
Cultured
reproductive and urinary physiology
Chemistry
Caspase 3
Stem Cells
Neurogenesis
Neural stem cell
Adult Stem Cells
medicine.anatomical_structure
Neuroprotective Agents
Proto-Oncogene Proteins c-bcl-2
neuroprotection
biological phenomena
cell phenomena
and immunity
Microtubule-Associated Proteins
medicine.drug
Signal Transduction
Programmed cell death
Cell Homeostasis & Autophagy
autophagy
ketamine
Biophysics
Subventricular zone
03 medical and health sciences
medicine
Animals
Viability assay
Molecular Biology
Dentate gyrus
fluoxetine
Cell Biology
Mice
Inbred C57BL
030104 developmental biology
nervous system
Excitatory Amino Acid Antagonists
Cell and Molecular Biology
030217 neurology & neurosurgery
Neuroscience
Zdroj: Bioscience Reports
ISSN: 0144-8463
Popis: Adult neurogenesis, the production of newborn neurons from neural stem cells (NSCs) has been suggested to be decreased in patients with schizophrenia. A similar finding was observed in an animal model of schizophrenia, as indicated by decreased bromodeoxyuridine (BrdU) labelling cells in response to a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist. The antipsychotic drug clozapine was shown to counteract the observed decrease in BrdU-labelled cells in hippocampal dentate gyrus (DG). However, phenotypic determination by immunohistochemistry analysis could not reveal whether BrdU-positive cells were indeed NSCs. Using a previously established cell model for analysing NSC protection in vitro, we investigated a protective effect of clozapine on NSCs. Primary NSCs were isolated from the mouse subventricular zone (SVZ), we show that clozapine had a NSC protective activity alone, as evident by employing an ATP cell viability assay. In contrast, haloperidol did not show any NSC protective properties. Subsequently, cells were exposed to the non-competitive NMDA-receptor antagonist ketamine. Clozapine, but not haloperidol, had a NSC protective/anti-apoptotic activity against ketamine-induced cytotoxicity. The observed NSC protective activity of clozapine was associated with increased expression of the anti-apoptotic marker Bcl-2, decreased expression of the pro-apoptotic cleaved form of caspase-3 and associated with decreased expression of the autophagosome marker 1A/1B-light chain 3 (LC3-II). Collectively, our findings suggest that clozapine may have a protective/anti-apoptotic effect on NSCs, supporting previous in vivo observations, indicating a neurogenesis-promoting activity for clozapine. If the data are further confirmed in vivo, the results may encourage an expanded use of clozapine to restore impaired neurogenesis in schizophrenia.
Databáze: OpenAIRE
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