The atypical antipsychotic agent, clozapine, protects against corticosterone-induced death of PC12 cells by regulating the Akt/FoxO3a signaling pathway

Zeng, Zhiwen, Wang, Xue, Bhardwaj, Sanjeev K., Zhou, Xuanhe, Little, Peter J., Quirion, Remi, Srivastava, Lalit K. and Zheng, Wenhua (2016) The atypical antipsychotic agent, clozapine, protects against corticosterone-induced death of PC12 cells by regulating the Akt/FoxO3a signaling pathway. Molecular Neurobiology, 1-12. doi:10.1007/s12035-016-9904-4


Author Zeng, Zhiwen
Wang, Xue
Bhardwaj, Sanjeev K.
Zhou, Xuanhe
Little, Peter J.
Quirion, Remi
Srivastava, Lalit K.
Zheng, Wenhua
Title The atypical antipsychotic agent, clozapine, protects against corticosterone-induced death of PC12 cells by regulating the Akt/FoxO3a signaling pathway
Journal name Molecular Neurobiology   Check publisher's open access policy
ISSN 1559-1182
0893-7648
Publication date 2016-05-13
Year available 2016
Sub-type Article (original research)
DOI 10.1007/s12035-016-9904-4
Open Access Status Not Open Access
Start page 1
End page 12
Total pages 12
Place of publication Heidelberg, Germany
Publisher Springer
Collection year 2017
Formatted 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.
Keyword Clozapine
Corticosterone
Neuroprotection
PI3K/Akt/FoxO3a
Schizophrenia
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Pharmacy Publications
 
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