title: The Atypical Antipsychotic Agent, Clozapine, Protects Against Corticosterone-Induced Death of PC12 Cells by Regulating the Akt/FoxO3a Signaling Pathway.
abstract: Schizophrenia is one of the most severe psychiatric disorders. Increasing evidence implicates that neurodegeneration is a component of schizophrenia pathology and some atypical antipsychotics are neuroprotective and successful in slowing the progressive morphological brain changes. As an antipsychotic agent, clozapine has superior and unique effects, but the intracellular signaling pathways that mediate clozapine action remain to be elucidated. The phosphatidylinositol-3-kinase/protein kinase B/Forkhead box O3 (PI3K/Akt/FoxO3a) pathway is crucial for neuronal survival. However, little information is available regarding this pathway with clozapine. In the present study, we investigated the protective effect of clozapine on the PC12 cells against corticosterone toxicity. Our results showed that corticosterone decreases the phosphorylation of Akt and FoxO3a, leading to the nuclear localization of FoxO3a and the apoptosis of PC12 cells, while clozapine concentration dependently protected PC12 cells against corticosterone insult. Pathway inhibitors studies displayed that the protective effect of clozapine was reversed by LY294002 and wortmannin, two PI3K inhibitors, or Akt inhibitor VIII although several other inhibitors had no effect. The shRNA knockdown results displayed that downregulated Akt1 or FoxO3a attenuated the protective effect of clozapine. Western blot analyses revealed that clozapine induced the phosphorylation of Akt and FoxO3a by the PI3K/Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a and the nuclear translocation of FoxO3a evoked by corticosterone. Together, our data indicates that clozapine protects PC12 cells against corticosterone-induced cell death by modulating activity of the PI3K/Akt/FoxO3a pathway.
authors.affiliation: Faculty of Health Sciences, University of Macau, Taipa, Macau, China.|The School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Faculty of Health Sciences, University of Macau, Taipa, Macau, China.|The School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Douglas Hospital Research Center, McGill University, Montreal, Canada.
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Bhardwaj
authors.affiliation: Faculty of Health Sciences, University of Macau, Taipa, Macau, China.|The School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xuanhe
authors.initials: X
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, 20 Cornwall St, Woolloongabba, QLD, 4102, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Little
authors.affiliation: Douglas Hospital Research Center, McGill University, Montreal, Canada.
authors.forename: Remi
authors.initials: R
authors.lastname: Quirion
authors.affiliation: Douglas Hospital Research Center, McGill University, Montreal, Canada.
authors.forename: Lalit K
authors.initials: LK
authors.lastname: Srivastava
authors.affiliation: Faculty of Health Sciences, University of Macau, Taipa, Macau, China. wenhuazheng@umac.mo.|The School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China. wenhuazheng@umac.mo.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D003345:Corticosterone / Q000009:adverse effects*; D019610:Cytoprotection / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D009025:Morpholines / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D014150:Antipsychotic Agents; D002867:Chromones; D003024:Clozapine; D003345:Corticosterone; D005419:Flavonoids; D000071316:Forkhead Box Protein O3; D009025:Morpholines; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; C499515:FOXO3 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Clozapine; Corticosterone; Neuroprotection; PI3K/Akt/FoxO3a; Schizophrenia