[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

The Atypical Antipsychotic Agent, Clozapine, Protects Against Corticosterone-Induced Death of PC12 Cells by Regulating the Akt/FoxO3a Signaling Pathway

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

Akt:

Protein kinase B

BSA:

Bovine serum albumin

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

ERK1/2:

Extracellular regulated protein kinases 1/2

FBS:

Fetal bovine serum

FoxO3a:

Forkhead box O3a

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GSK-3β:

Glycogen synthase kinase-3β

HPA:

Hypothalamic–pituitary–adrenal

IGF-1:

Insulin-like growth factor-1

MAPK:

Mitogen-activated protein kinase

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

OD:

Optical density

PBS:

Phosphate-buffered saline

PC12:

Pheochromocytoma cells

PI3K:

Phosphatidylinositol 3-kinase

ShRNA:

Short hairpin RNA

References

  1. Myles-Worsley M, Coon H, Tiobech J, Collier J, Dale P, Wender P, Reimherr F, Polloi A et al (1999) Genetic epidemiological study of schizophrenia in Palau, Micronesia: prevalence and familiality. Am J Med Genet 88:4–10

    Article  CAS  PubMed  Google Scholar 

  2. Zheng W, Wang H, Zeng Z, Lin J, Little PJ, Srivastava LK, Quirion R (2012) The possible role of the Akt signaling pathway in schizophrenia. Brain Res 1470:145–158

    Article  CAS  PubMed  Google Scholar 

  3. Kempton MJ, Stahl D, Williams SC, DeLisi LE (2010) Progressive lateral ventricular enlargement in schizophrenia: a meta-analysis of longitudinal MRI studies. Schizophr Res 120:54–62

    Article  PubMed  Google Scholar 

  4. Smieskova R, Fusar-Poli P, Allen P, Bendfeldt K, Stieglitz RD, Drewe J, Radue EW, McGuire PK et al (2010) Neuroimaging predictors of transition to psychosis—a systematic review and meta-analysis. Neurosci Biobehav Rev 34:1207–1222

    Article  CAS  PubMed  Google Scholar 

  5. Yu K, Cheung C, Leung M, Li Q, Chua S, McAlonan G (2010) Are bipolar disorder and schizophrenia neuroanatomically distinct? An anatomical likelihood meta-analysis. Front Hum Neurosci 4:189

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lindenmayer JP, Khan A, Iskander A, Abad MT, Parker B (2007) A randomized controlled trial of olanzapine versus haloperidol in the treatment of primary negative symptoms and neurocognitive deficits in schizophrenia. J Clin Psychiatry 68:368–379

    Article  CAS  PubMed  Google Scholar 

  7. Kim NR, Park SW, Lee JG, Kim YH (2008) Protective effects of olanzapine and haloperidol on serum withdrawal-induced apoptosis in SH-SY5Y cells. Prog Neuro-Psychopharmacol Biol Psychiatry 32:633–642

    Article  CAS  Google Scholar 

  8. Kurosawa S, Hashimoto E, Ukai W, Toki S, Saito S, Saito T (2007) Olanzapine potentiates neuronal survival and neural stem cell differentiation: regulation of endoplasmic reticulum stress response proteins. J Neural Transm 114:1121–1128

    Article  CAS  PubMed  Google Scholar 

  9. Lieberman JA, Bymaster FP, Meltzer HY, Deutch AY, Duncan GE, Marx CE, Aprille JR, Dwyer DS et al (2008) Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection. Pharmacol Rev 60:358–403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Peng L, Zhang X, Cui X, Zhu D, Wu J, Sun D, Yue Q, Li Z et al (2014) Paliperidone protects SK-N-SH cells against glutamate toxicity via Akt1/GSK3beta signaling pathway. Schizophr Res 157:120–127

    Article  PubMed  Google Scholar 

  11. Qing H, Xu H, Wei Z, Gibson K, Li XM (2003) The ability of atypical antipsychotic drugs vs. haloperidol to protect PC12 cells against MPP+-induced apoptosis. Eur J Neurosci 17:1563–1570

    Article  PubMed  Google Scholar 

  12. Wang H, Xu H, Dyck LE, Li XM (2005) Olanzapine and quetiapine protect PC12 cells from beta-amyloid peptide(25-35)-induced oxidative stress and the ensuing apoptosis. J Neurosci Res 81:572–580

    Article  CAS  PubMed  Google Scholar 

  13. Kane JM, Honigfeld G, Singer J, Meltzer H (1988) Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull 24:62–67

    CAS  PubMed  Google Scholar 

  14. Wahlbeck K, Cheine M, Essali MA (2000) Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev CD000059

  15. Magliaro BC, Saldanha CJ (2009) Clozapine protects PC-12 cells from death due to oxidative stress induced by hydrogen peroxide via a cell-type specific mechanism involving inhibition of extracellular signal-regulated kinase phosphorylation. Brain Res 1283:14–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Freyberg Z, Ferrando SJ, Javitch JA (2010) Roles of the Akt/GSK-3 and Wnt signaling pathways in schizophrenia and antipsychotic drug action. Am J Psychiatry 167:388–396

    Article  PubMed  Google Scholar 

  17. Mao Z, Liu L, Zhang R, Li X (2007) Lithium reduces FoxO3a transcriptional activity by decreasing its intracellular content. Biol Psychiatry 62:1423–1430

    Article  CAS  PubMed  Google Scholar 

  18. Polter A, Yang S, Zmijewska AA, van Groen T, Paik JH, Depinho RA, Peng SL, Jope RS et al (2009) Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation. Biol Psychiatry 65:150–159

    Article  CAS  PubMed  Google Scholar 

  19. Zhou W, Chen L, Yang S, Li F, Li X (2012) Behavioral stress-induced activation of FoxO3a in the cerebral cortex of mice. Biol Psychiatry 71:583–592

    Article  CAS  PubMed  Google Scholar 

  20. Keowkase R, Aboukhatwa M, Luo Y (2010) Fluoxetine protects against amyloid-beta toxicity, in part via daf-16 mediated cell signaling pathway, in Caenorhabditis elegans. Neuropharmacology 59:358–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liang B, Moussaif M, Kuan CJ, Gargus JJ, Sze JY (2006) Serotonin targets the DAF-16/FOXO signaling pathway to modulate stress responses. Cell Metab 4:429–440

    Article  CAS  PubMed  Google Scholar 

  22. Weeks KR, Dwyer DS, Aamodt EJ (2011) Clozapine and lithium require Caenorhabditis elegans beta-arrestin and serum- and glucocorticoid-inducible kinase to affect Daf-16 (Foxo) localization. J Neurosci Res 89:1658–1665

    Article  CAS  PubMed  Google Scholar 

  23. Karmacharya R, Sliwoski GR, Lundy MY, Suckow RF, Cohen BM, Buttner EA (2009) Clozapine interaction with phosphatidyl inositol 3-kinase (PI3K)/insulin-signaling pathway in Caenorhabditis elegans. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol 34:1968–1978

    Article  CAS  Google Scholar 

  24. Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 73:2424–2428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bennett AOM (2008) Stress and anxiety in schizophrenia and depression: glucocorticoids, corticotropin-releasing hormone and synapse regression. Aust N Z J Psychiatry 42:995–1002

    Article  Google Scholar 

  26. Corcoran C, Walker E, Huot R, Mittal V, Tessner K, Kestler L, Malaspina D (2003) The stress cascade and schizophrenia: etiology and onset. Schizophr Bull 29:671–692

    Article  PubMed  Google Scholar 

  27. Herman JP, Seroogy K (2006) Hypothalamic-pituitary-adrenal axis, glucocorticoids, and neurologic disease. Neurol Clin 24(461-481):vi

    Google Scholar 

  28. Walker E, Mittal V, Tessner K (2008) Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia. Annu Rev Clin Psychol 4:189–216

    Article  PubMed  Google Scholar 

  29. Jiang Y, Li Z, Liu Y, Liu X, Chang Q, Liao Y, Pan R (2015) Neuroprotective effect of water extract of Panax ginseng on corticosterone-induced apoptosis in PC12 cells and its underlying molecule mechanisms. J Ethnopharmacol 159:102–112

    Article  CAS  PubMed  Google Scholar 

  30. Liu B, Zhang H, Xu C, Yang G, Tao J, Huang J, Wu J, Duan X et al (2011) Neuroprotective effects of icariin on corticosterone-induced apoptosis in primary cultured rat hippocampal neurons. Brain Res 1375:59–67

    Article  CAS  PubMed  Google Scholar 

  31. Moosavi M, Maghsoudi N, Zahedi-Asl S, Naghdi N, Yousefpour M, Trounce IA (2008) The role of PI3/Akt pathway in the protective effect of insulin against corticosterone cell death induction in hippocampal cell culture. Neuroendocrinology 88:293–298

    Article  CAS  PubMed  Google Scholar 

  32. Nitta A, Zheng WH, Quirion R (2004) Insulin-like growth factor 1 prevents neuronal cell death induced by corticosterone through activation of the PI3k/Akt pathway. J Neurosci Res 76:98–103

    Article  CAS  PubMed  Google Scholar 

  33. Wang H, Zhou X, Huang J, Mu N, Guo Z, Wen Q, Wang R, Chen S et al (2013) The role of Akt/FoxO3a in the protective effect of venlafaxine against corticosterone-induced cell death in PC12 cells. Psychopharmacology 228:129–141

    Article  CAS  PubMed  Google Scholar 

  34. Wang R, Yang J, Peng L, Zhao J, Mu N, Huang J, Lazarovici P, Chen H et al (2015) Gardenamide A attenuated cell apoptosis induced by serum deprivation insult via the ERK1/2 and PI3K/AKT signaling pathways. Neuroscience 286:242–250

    Article  CAS  PubMed  Google Scholar 

  35. Zheng WH, Quirion R (2009) Glutamate acting on N-methyl-D-aspartate receptors attenuates insulin-like growth factor-1 receptor tyrosine phosphorylation and its survival signaling properties in rat hippocampal neurons. J Biol Chem 284:855–861

    Article  CAS  PubMed  Google Scholar 

  36. Zhang X, Tang N, Hadden TJ, Rishi AK (2011) Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 1813:1978–1986

    Article  CAS  PubMed  Google Scholar 

  37. Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA (2012) Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry 17:1206–1227

    Article  CAS  PubMed  Google Scholar 

  38. Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA (2004) Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 36:131–137

    Article  CAS  PubMed  Google Scholar 

  39. Beaulieu JM, Gainetdinov RR, Caron MG (2009) Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 49:327–347

    Article  CAS  PubMed  Google Scholar 

  40. Ernst CL, Goldberg JF (2004) Antisuicide properties of psychotropic drugs: a critical review. Harv Rev Psychiatry 12:14–41

    PubMed  Google Scholar 

  41. Sharma V (2003) Atypical antipsychotics and suicide in mood and anxiety disorders. Bipolar Disord 5(Suppl 2):48–52

    Article  CAS  PubMed  Google Scholar 

  42. Brar JS, Chengappa KN, Parepally H, Sandman AR, Kreinbrook SB, Sheth SA, Ganguli R (1997) The effects of clozapine on negative symptoms in patients with schizophrenia with minimal positive symptoms. Ann Clin Psychiatry: Off J Am Acad Clin Psychiatrists 9:227–234

    Article  CAS  Google Scholar 

  43. Lindenmayer JP, Iskander A, Park M, Apergi FS, Czobor P, Smith R, Allen D (1998) Clinical and neurocognitive effects of clozapine and risperidone in treatment-refractory schizophrenic patients: a prospective study. J Clin Psychiatry 59:521–527

    Article  CAS  PubMed  Google Scholar 

  44. Meltzer HY, McGurk SR (1999) The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 25:233–255

    Article  CAS  PubMed  Google Scholar 

  45. Pereira A, Fink G, Sundram S (2009) Clozapine-induced ERK1 and ERK2 signaling in prefrontal cortex is mediated by the EGF receptor. J Mol Neurosci : MN 39:185–198

    Article  CAS  PubMed  Google Scholar 

  46. Pereira A, Sugiharto-Winarno A, Zhang B, Malcolm P, Fink G, Sundram S (2012) Clozapine induction of ERK1/2 cell signalling via the EGF receptor in mouse prefrontal cortex and striatum is distinct from other antipsychotic drugs. Int J Neuropsychopharmacol / Off Sci J Collegium Int Neuropsychopharmacol 15:1149–1160

    CAS  Google Scholar 

  47. Kang UG, Seo MS, Roh MS, Kim Y, Yoon SC, Kim YS (2004) The effects of clozapine on the GSK-3-mediated signaling pathway. FEBS Lett 560:115–119

    Article  CAS  PubMed  Google Scholar 

  48. Weeks KR, Dwyer DS, Aamodt EJ (2010) Antipsychotic drugs activate the C. elegans akt pathway via the DAF-2 insulin/IGF-1 receptor. ACS Chem Neurosci 1:463–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Maiese K, Chong ZZ, Shang YC (2007) “Sly as a FOXO”: new paths with Forkhead signaling in the brain. Curr Neurovasc Res 4:295–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zheng WH, Kar S, Quirion R (2000) Insulin-like growth factor-1-induced phosphorylation of the forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells. J Biol Chem 275:39152–39158

    Article  CAS  PubMed  Google Scholar 

  51. Zheng WH, Kar S, Quirion R (2002) Insulin-like growth factor-1-induced phosphorylation of transcription factor FKHRL1 is mediated by phosphatidylinositol 3-kinase/Akt kinase and role of this pathway in insulin-like growth factor-1-induced survival of cultured hippocampal neurons. Mol Pharmacol 62:225–233

    Article  CAS  PubMed  Google Scholar 

  52. Shi GX, Cai W, Andres DA (2013) Rit subfamily small GTPases: regulators in neuronal differentiation and survival. Cell Signal 25:2060–2068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang H, Duan X, Ren Y, Liu Y, Huang M, Liu P, Wang R, Gao G et al (2013) FoxO3a negatively regulates nerve growth factor-induced neuronal differentiation through inhibiting the expression of neurochondrin in PC12 cells. Mol Neurobiol 47:24–36

    Article  CAS  PubMed  Google Scholar 

  54. Qin W, Pan J, Qin Y, Lee DN, Bauman WA, Cardozo C (2014) Identification of functional glucocorticoid response elements in the mouse FoxO1 promoter. Biochem Biophys Res Commun 450:979–983

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by National Natural Science Fund of China (No. 31371088) and the Science and Technology Development Fund (FDCT) of Macao (FDCT 021/2015/A1), Funding from Guangdong Science and Technology Department (No. 2011B050200005), SRG2015-00004-FHS and MYRG2016-00052-FHS from University of Macau.

Author information

Author notes

    Authors and Affiliations

    1. Faculty of Health Sciences, University of Macau, Taipa, Macau, China

      Zhiwen Zeng, Xue Wang, Xuanhe Zhou & Wenhua Zheng

    2. The School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China

      Zhiwen Zeng, Xue Wang, Xuanhe Zhou & Wenhua Zheng

    3. Douglas Hospital Research Center, McGill University, Montreal, Canada

      Sanjeev K. Bhardwaj, Remi Quirion & Lalit K. Srivastava

    4. School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, 20 Cornwall St, Woolloongabba, QLD, 4102, Australia

      Peter J Little

    Authors
    1. Zhiwen Zeng
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Xue Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Sanjeev K. Bhardwaj
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Xuanhe Zhou
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Peter J Little
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Remi Quirion
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Lalit K. Srivastava
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Wenhua Zheng
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Wenhua Zheng.

    Additional information

    Zhiwen Zeng and Xue Wang contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Zeng, Z., Wang, X., Bhardwaj, S.K. et al. The Atypical Antipsychotic Agent, Clozapine, Protects Against Corticosterone-Induced Death of PC12 Cells by Regulating the Akt/FoxO3a Signaling Pathway. Mol Neurobiol 54, 3395–3406 (2017). https://doi.org/10.1007/s12035-016-9904-4

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12035-016-9904-4

    Keywords

    Search

    Navigation