Skip to main content
SpringerLink
Log in

Characterization of temporal expressions of FOXO and pFOXO proteins in the hippocampus by kainic acid in mice: involvement of NMDA and non-NMDA receptors

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

In the present study, we characterized the expression and role of forkhead box O (FoxO3a) in kainic acid (KA)-induced hippocampal neuronal cell death. FoxO3a and pFoxO3a expression in the CA1, CA2, and dentate gyrus regions in the hippocampus increased 0.5 and 1 h after intracerebroventricular administration of KA. In addition, both FoxO3a and pFoxO3a expression in the hippocampal CA3 region increased significantly and equally for 1 h but decreased gradually for 24 h after KA administration. In particular, the KA-induced increases in FoxO3a and pFoxO3a expression in the hippocampal CA3 region were inhibited by pretreatment with the N-methyl-d-aspartate (NMDA) receptor antagonist (MK-801, dizocilpine, 1 µg/5 µl) or a non-NMDA receptor antagonist (CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione, 0.5 µg/5 µl). Furthermore, dizocilpine and CNQX produced a neuroprotective effect against KA-induced neuronal death in the CA3 region of the hippocampus. Our results suggest that FoxO3a and pFoxO3 expression is upregulated by KA. Both FoxO3a and pFoxO3a expression appear to be responsible for KA-induced neuronal death in the CA3 region of the hippocampus.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Arzimanoglou A, Hirsch E, Nehlig A, Castelnau P, Gressens P, Pereira de Vasconcelos A (2002) Epilepsy and neuroprotection: an illustrated review. Epileptic Disord 4:173–182

    PubMed  Google Scholar 

  • Bakker WJ, Harris IS, Mak TW (2007) FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Mol Cell 28:941–953

    Article  CAS  PubMed  Google Scholar 

  • Beal MF (1992) Mechanisms of excitotoxicity in neurologic diseases. FASEB J 6:3338–3344

    CAS  PubMed  Google Scholar 

  • Benveniste H, Drejer J, Schousboe A, Diemer NH (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369–1374

    Article  CAS  PubMed  Google Scholar 

  • Bleakman D, Lodge D (1998) Neuropharmacology of AMPA and kainate receptors. Neuropharmacology 37:1187–1204

    Article  CAS  PubMed  Google Scholar 

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 96:857–868

    Article  CAS  PubMed  Google Scholar 

  • Candelario-Jalil E, Al-Dalain SM, Castillo R, Martinez G, Fernandez OS (2001) Selective vulnerability to kainate-induced oxidative damage in different rat brain regions. J Appl Toxicol 21:403–407

    Article  CAS  PubMed  Google Scholar 

  • Chong ZZ, Li F, Maiese K (2005a) Activating Akt and the brain’s resources to drive cellular survival and prevent inflammatory injury. Histol Histopathol 20:299–315

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chong ZZ, Li F, Maiese K (2005b) Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol 75:207–246

    Article  CAS  PubMed  Google Scholar 

  • Chong ZZ, Li F, Maiese K (2006) Group I metabotropic receptor neuroprotection requires Akt and its substrates that govern FOXO3a, Bim, and beta-catenin during oxidative stress. Curr Neurovasc Res 3:107–117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Essers MA, Weijzen S, de Vries-Smits AM, Saarloos I, de Ruiter ND, Bos JL, Burgering BM (2004) FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J 23:4802–4812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haley TJ, McCormick WG (1957) Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. Br J Pharmacol Chemother 12:12–15

  • Hoekman MF, Jacobs FM, Smidt MP, Burbach JP (2006) Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain. Gene Expr Patterns 6:134–140

    Article  CAS  PubMed  Google Scholar 

  • Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP (2003) FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem 278:35959–35967

    Article  CAS  PubMed  Google Scholar 

  • Kaestner KH, Knochel W, Martinez DE (2000) Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev 14:142–146

    CAS  PubMed  Google Scholar 

  • Kaku DA, Goldberg MP, Choi DW (1991) Antagonism of non-NMDA receptors augments the neuroprotective effect of NMDA receptor blockade in cortical cultures subjected to prolonged deprivation of oxygen and glucose. Brain Res 554:344–347

    Article  CAS  PubMed  Google Scholar 

  • Kim CH, Park SH, Sim YB, Sharma N, Kim SS, Lim SM, Jung JS, Suh HW (2014) Effect of pertussis and cholera toxins administered supraspinally on CA3 hippocampal neuronal cell death and the blood glucose level induced by kainic acid in mice. Neurosci Res 89:31–36

  • Lee JK, Choi SS, Lee HK, Han KJ, Han EJ, Suh HW (2002) Effects of MK-801 and CNQX on various neurotoxic responses induced by kainic acid in mice. Mol Cells 14:339–347

    CAS  PubMed  Google Scholar 

  • Lehtinen MK, Yuan Z, Boag PR, Yang Y, Villen J, Becker EB, DiBacco S, de la Iglesia N, Gygi S, Blackwell TK, Bonni A (2006) A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125:987–1001

    Article  CAS  PubMed  Google Scholar 

  • Leong ML, Maiyar AC, Kim B, O’Keeffe BA, Firestone GL (2003) Expression of the serum- and glucocorticoid-inducible protein kinase, Sgk, is a cell survival response to multiple types of environmental stress stimuli in mammary epithelial cells. J Biol Chem 278:5871–5882

    Article  CAS  PubMed  Google Scholar 

  • Luo X, Puig O, Hyun J, Bohmann D, Jasper H (2007) Foxo and Fos regulate the decision between cell death and survival in response to UV irradiation. EMBO J 26:380–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maiese K, Hou J, Chong ZZ, Shang YC (2009) A fork in the path: developing therapeutic inroads with FoxO proteins. Oxid Med Cell Longev 2:119–129

    Article  PubMed  PubMed Central  Google Scholar 

  • Milatovic D, Gupta RC, Dettbarn WD (2002) Involvement of nitric oxide in kainic acid-induced excitotoxicity in rat brain. Brain Res 957:330–337

    Article  CAS  PubMed  Google Scholar 

  • Perry G, Taddeo MA, Nunomura A, Zhu X, Zenteno-Savin T, Drew KL, Shimohama S, Avila J, Castellani RJ, Smith MA (2002) Comparative biology and pathology of oxidative stress in Alzheimer and other neurodegenerative diseases: beyond damage and response. Comp Biochem Physiol C 133:507–513

    Google Scholar 

  • Rothman SM, Olney JW (1986) Glutamate and the pathophysiology of hypoxic–ischemic brain damage. Ann Neurol 19:105–111

    Article  CAS  PubMed  Google Scholar 

  • Salih DA, Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20:126–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sapolsky RM (2003) Neuroprotective gene therapy against acute neurological insults. Nat Rev Neurosci 4:61–69

    Article  CAS  PubMed  Google Scholar 

  • Shinoda S, Schindler CK, Meller R, So NK, Araki T, Yamamoto A, Lan JQ, Taki W, Simon RP, Henshall DC (2004) Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy. J Clin Invest 113:1059–1068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simon RP, Griffiths T, Evans MC, Swan JH, Meldrum BS (1984) Calcium overload in selectively vulnerable neurons of the hippocampus during and after ischemia: an electron microscopy study in the rat. J Cereb Blood Flow Metab 4:350–361

    Article  CAS  PubMed  Google Scholar 

  • Sperk G (1994) Kainic acid seizures in the rat. Prog Neurobiol 42:1–32

    Article  CAS  PubMed  Google Scholar 

  • Sun AY, Cheng Y, Sun GY (1992) Kainic acid-induced excitotoxicity in neurons and glial cells. Prog Brain Res 94:271–280

    Article  CAS  PubMed  Google Scholar 

  • van der Horst A, Burgering BM (2007) Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 8:440–450

    Article  PubMed  Google Scholar 

  • Wang Q, Yu S, Simonyi A, Rottinghaus G, Sun GY, Sun AY (2004) Resveratrol protects against neurotoxicity induced by kainic acid. Neurochem Res 29:2105–2112

    Article  CAS  PubMed  Google Scholar 

  • Wang MC, Bohmann D, Jasper H (2005) JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell 121:115–125

    Article  CAS  PubMed  Google Scholar 

  • Zagrean AM, Spataru A, Ceanga M, Zagrean L (2014) The single versus combinatorial effects of MK-801, CNQX, nifedipine and AP-3 on primary cultures of cerebellar granule cells in an oxygen-glucose deprivation model. Rom J Morphol Embryol 55:811–816

    PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by Priority Research Centers (NRF-2009-0094071 and NRF-2014R1A1A1006791) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology and Hallym University Specialization Fund (HRF-S-52).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, Okchun-Dong, Chuncheon, Kangwon-Do, 200-702, Republic of Korea

    Soo-Hyun Park, Yun-Beom Sim & Hong-Won Suh

  2. #81 Biotechnology Incubating Center, Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Seoul National University, Seoul, 151-742, Republic of Korea

    Yun-Beom Sim

  3. Department of Pharmacology, College of Medicine, Dankook University, Cheonan, 330-714, Republic of Korea

    Jin-Koo Lee

  4. Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, 200-702, Republic of Korea

    Jae-Yong Lee

Authors
  1. Soo-Hyun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun-Beom Sim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin-Koo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jae-Yong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hong-Won Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hong-Won Suh.

Ethics declarations

Conflict of interest

No potential conflicts of interest relevant to this article were reported.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, SH., Sim, YB., Lee, JK. et al. Characterization of temporal expressions of FOXO and pFOXO proteins in the hippocampus by kainic acid in mice: involvement of NMDA and non-NMDA receptors. Arch. Pharm. Res. 39, 660–667 (2016). https://doi.org/10.1007/s12272-016-0733-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-016-0733-9

Keywords

Search

Navigation