title: Aripiprazole protects cortical neurons from glutamate toxicity.
abstract: Neurodegeneration is thought to be a component of schizophrenia pathology, and some antipsychotics appear to slow degenerative changes in patients. Aripiprazole, the first partial dopamine D(2) receptor agonist approved for the treatment of schizophrenia, is suggested to be neuroprotective based on non-clinical studies using transformed cell lines and in vivo stress and lesion paradigms. However, aripiprazole-induced neuroprotection has not been studied in a neuronal glutamate toxicity assay, which may model aspects of neurodegeneration occurring in schizophrenia. This study examined whether therapeutically relevant concentrations of aripiprazole protect rat embryonic cortical neurons from glutamate toxicity in biochemical and high-content imaging assays. Aripiprazole inhibited glutamate-induced neurotoxicity by 40% in a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, in contrast to risperidone and olanzapine, which had little neuroprotective activity. This neuroprotective effect of aripiprazole was not mediated by the activation of serotonin 5-HT(1A) or dopamine D(2) receptors, Akt or glycogen-synthase kinase-3β signaling (GSK-3β), or through the inhibition of poly-ADP ribose polymerase (PARP). Further experiments are required to determine the biochemical nature of aripiprazole-induced neuroprotection and whether any such activity might have clinical relevance.
authors.affiliation: CNS Drug Discovery & Development, Otsuka Maryland Medicinal Laboratories, Inc., Rockville, MD 20850, USA. vukk@otsuka.com
authors.forename: Vuk
authors.initials: V
authors.lastname: Koprivica
authors.forename: Karen
authors.initials: K
authors.lastname: Regardie
authors.forename: Christina
authors.initials: C
authors.lastname: Wolff
authors.forename: Raymond
authors.initials: R
authors.lastname: Fernalld
authors.forename: Janelle Johnson
authors.initials: JJ
authors.lastname: Murphy
authors.forename: Junichi
authors.initials: J
authors.lastname: Kambayashi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Shaun
authors.initials: S
authors.lastname: Jordan
mesh_terms: D000818:Animals; D000068180:Aripiprazole; D001569:Benzodiazepines / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology*; D019610:Cytoprotection / Q000187:drug effects*; D065127:Dopamine D2 Receptor Antagonists; D018698:Glutamic Acid / Q000633:toxicity*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057054:Molecular Imaging; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000077152:Olanzapine; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D018696:Neuroprotective Agents; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015363:Quinolones; D058829:Serotonin 5-HT1 Receptor Antagonists; D013778:Tetrazolium Salts; D013844:Thiazoles; D044282:Receptor, Serotonin, 5-HT1A; D001569:Benzodiazepines; D018698:Glutamic Acid; D000068180:Aripiprazole; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C022616:thiazolyl blue; D018967:Risperidone; D000077152:Olanzapine