Skip to main content
Log in

Transient Cerebral Ischemia Alters GSK-3β and p-GSK-3β Immunoreactivity in Pyramidal Neurons and Induces p-GSK-3β Expression in Astrocytes in the Gerbil Hippocampal CA1 Area

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Glycogen synthase kinase 3β (GSK-3β) is a key downstream protein in the PI3K/Akt pathway. Phosphorylation of serine 9 of GSK-3β (GSK-3β activity inhibition) promotes cell survival. In this study, we examined changes in expressions of GSK-3β and phosphorylation of GSK-3β (p-GSK-3β) in the gerbil hippocampal CA1 area after 5 min of transient cerebral ischemia. GSK-3β immunoreactivity in the CA1 area was increased in pyramidal cells at 6 h after ischemia–reperfusion. It was decreased in CA1 pyramidal cells from 12 h after ischemia–reperfusion, and hardly detected in the CA1 pyramidal cells at 5 days after ischemia–reperfusion. p-GSK-3β immunoreactivity was slightly decreased in CA1 pyramidal cells at 6 and 12 h after ischemia–reperfusion. It was significantly increased in these cells at 1 and 2 days after ischemia–reperfusion. Five days after ischemia–reperfusion, p-GSK-3β immunoreactivity was hardly found in CA1 pyramidal cells. However, p-GSK-3β immunoreactivity was strongly expressed in astrocytes primarily distributed in strata oriens and radiatum. In conclusion, GSK-3β and p-GSK-3β were significantly changed in pyramidal cells and/or astrocytes in the gerbil hippocampal CA1 area following 5 min of transient cerebral ischemia. This finding indicates that GSK-3β and p-GSK-3β are closely related to delayed neuronal death.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Lee CH, Ahn JH, Won MH (2015) New expression of 5-HT1A receptor in astrocytes in the gerbil hippocampal CA1 region following transient global cerebral ischemia. Neurol Sci 36:383–389

    Article  PubMed  Google Scholar 

  2. Lee JC, Chen BH, Cho JH et al (2015) Changes in the expression of DNA-binding/differentiation protein inhibitors in neurons and glial cells of the gerbil hippocampus following transient global cerebral ischemia. Mol Med Rep 11:2477–2485

    CAS  PubMed  Google Scholar 

  3. Park OK, Lee CH, Hwang IK et al (2010) Effects of repeated restraint stress on platelet endothelial cell adhesion molecule-1 immunoreactivity and protein levels in the gerbil hippocampus after transient cerebral ischemia. Anat Cell Biol 43:54–63

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:57–69

    Article  CAS  PubMed  Google Scholar 

  5. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397

    Article  CAS  PubMed  Google Scholar 

  6. Radak D, Katsiki N, Resanovic I et al (2016) Apoptosis and acute brain ischemia in ischemic stroke. Curr Vasc Pharmacol

  7. Wang JK, Yu LN, Zhang FJ et al (2010) Postconditioning with sevoflurane protects against focal cerebral ischemia and reperfusion injury via PI3K/Akt pathway. Brain Res 1357:142–151

    Article  CAS  PubMed  Google Scholar 

  8. Abe E, Fujiki M, Nagai Y et al (2010) The phosphatidylinositol-3 kinase/Akt pathway mediates geranylgeranylacetone-induced neuroprotection against cerebral infarction in rats. Brain Res 1330:151–157

    Article  CAS  PubMed  Google Scholar 

  9. Xu X, Chua CC, Gao J et al (2008) Neuroprotective effect of humanin on cerebral ischemia/reperfusion injury is mediated by a PI3K/Akt pathway. Brain Res 1227:12–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pap M, Cooper GM (1998) Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J Biol Chem 273:19929–19932

    Article  CAS  PubMed  Google Scholar 

  11. Morioka M, Kawano T, Yano S et al (2006) Hyperphosphorylation at serine 199/202 of tau factor in the gerbil hippocampus after transient forebrain ischemia. Biochem Biophys Res Commun 347:273–278

    Article  CAS  PubMed  Google Scholar 

  12. Venna VR, Benashski SE, Chauhan A et al (2015) Inhibition of glycogen synthase kinase-3β enhances cognitive recovery after stroke: the role of TAK1. Learn Mem 22:336–343

    Article  PubMed  PubMed Central  Google Scholar 

  13. Xiong T, Tang J, Zhao J et al (2012) Involvement of the Akt/GSK-3β/CRMP-2 pathway in axonal injury after hypoxic–ischemic brain damage in neonatal rat. Neuroscience 216:123–132

    Article  CAS  PubMed  Google Scholar 

  14. Kim DH, Lee HE, Kwon KJ et al (2015) Early immature neuronal death initiates cerebral ischemia-induced neurogenesis in the dentate gyrus. Neuroscience 284:42–54

    Article  CAS  PubMed  Google Scholar 

  15. Endo H, Nito C, Kamada H et al (2006) Activation of the Akt/GSK3β signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats. J Cereb Blood Flow Metab 26:1479–1489

    Article  CAS  PubMed  Google Scholar 

  16. Radenovic L, Selakovic V, Olivan S et al (2014) Neuroprotective efficiency of tetanus toxin C fragment in model of global cerebral ischemia in Mongolian gerbils. Brain Res Bull 101:37–44

    Article  CAS  PubMed  Google Scholar 

  17. Shcherbak NS, Galagudza MM, Ovchinnikov DA et al (2013) Activity of succinate dehydrogenase in the neocortex and hippocampus of Mongolian gerbils with ischemic and reperfusion brain injury. Bull Exp Biol Med 155:14–17

    Article  CAS  PubMed  Google Scholar 

  18. Zhao XY, Wu CF, Yang J et al (2015) Effect of arginine vasopressin on the cortex edema in the ischemic stroke of Mongolian gerbils. Neuropeptides 51:55–62

    Article  CAS  PubMed  Google Scholar 

  19. Ahn JH, Choi JH, Park JH et al (2016) Long-term exercise improves memory deficits via restoration of myelin and microvessel damage, and enhancement of neurogenesis in the aged gerbil hippocampus after ischemic stroke. Neurorehabil Neural Repair 30:894–905

    Article  PubMed  Google Scholar 

  20. Yan BC, Park JH, Ahn JH et al (2012) Comparison of the immunoreactivity of Trx2/Prx3 redox system in the hippocampal CA1 region between the young and adult gerbil induced by transient cerebral ischemia. Neurochem Res 37:1019–1030

    Article  CAS  PubMed  Google Scholar 

  21. Chen BH, Park JH, Cho JH et al. (2016) Tanshinone I enhances neurogenesis in the mouse hippocampal dentate gyrus via increasing Wnt-3, phosphorylated glycogen synthase kinase-3beta and beta-catenin immunoreactivities. Neurochem Res 41:1958–1968

    Article  CAS  PubMed  Google Scholar 

  22. Seo JY, Yan BC, Park JH et al (2013) Comparison of the immunoreactivities of NMDA receptors between the young and adult hippocampal CA1 region induced by experimentally transient cerebral ischemia. J Neurol Sci 325:108–114

    Article  CAS  PubMed  Google Scholar 

  23. Yan BC, Kim SK, Park JH et al (2012) Comparison of inflammatory cytokines changes in the hippocampal CA1 region between the young and adult gerbil after transient cerebral ischemia. Brain Res 1461:64–75

    Article  CAS  PubMed  Google Scholar 

  24. Ko I-G, Shin M-S, Kim B-K et al (2009) Tadalafil improves short-term memory by suppressing ischemia-induced apoptosis of hippocampal neuronal cells in gerbils. Pharmacol Biochem Behav 91:629–635

    Article  CAS  PubMed  Google Scholar 

  25. Lee CH, Park JH, Cho JH et al (2014) Changes and expressions of Redd1 in neurons and glial cells in the gerbil hippocampus proper following transient global cerebral ischemia. J Neurol Sci 344:43–50

    Article  CAS  PubMed  Google Scholar 

  26. Peineau S, Bradley C, Taghibiglou C et al (2008) The role of GSK-3 in synaptic plasticity. Br J Pharmacol 153:S428–S437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Doble BW, Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116:1175–1186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kim WY, Snider WD (2011) Functions of GSK-3 signaling in development of the nervous system. Front Mol Neurosci 4:44

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kim WY, Zhou FQ, Zhou J et al (2006) Essential roles for GSK-3s and GSK-3-primed substrates in neurotrophin-induced and hippocampal axon growth. Neuron 52:981–996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bhat RV, Shanley J, Correll MP et al (2000) Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc Natl Acad Sci USA 97:11074–11079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65:391–426

    Article  CAS  PubMed  Google Scholar 

  32. Linseman DA, Butts BD, Precht TA et al (2004) Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci 24:9993–10002

    Article  CAS  PubMed  Google Scholar 

  33. Rehni AK, Singh N (2007) Role of phosphoinositide 3-kinase in ischemic postconditioning-induced attenuation of cerebral ischemia-evoked behavioral deficits in mice. Pharmacol Rep 59:192–198.

    CAS  PubMed  Google Scholar 

  34. Zheng Y, Hou J, Liu J et al (2014) Inhibition of autophagy contributes to melatonin-mediated neuroprotection against transient focal cerebral ischemia in rats. J Pharmacol Sci 124:354–364

    Article  CAS  PubMed  Google Scholar 

  35. Xing XS, Liu F, He ZY (2015) Akt regulates beta-catenin in a rat model of focal cerebral ischemia-reperfusion injury. Mol Med Rep 11:3122–3128

    CAS  PubMed  Google Scholar 

  36. Liu H, Ou S, Xiao X et al (2015) Diabetes worsens ischemia–reperfusion brain injury in rats through GSK-3beta. Am J Med Sci 350:204–211

    Article  PubMed  PubMed Central  Google Scholar 

  37. Zhao S, Fu J, Liu X et al (2012) Activation of Akt/GSK-3beta/beta-catenin signaling pathway is involved in survival of neurons after traumatic brain injury in rats. Neurol Res 34:400–407

    Article  CAS  PubMed  Google Scholar 

  38. Ma Y, Li Y, Zhang C et al (2014) Neuroprotective effect of 4-methylcyclopentadecanone on focal cerebral ischemia/reperfusion injury in rats. J Pharmacol Sci 125:320–328

    Article  CAS  PubMed  Google Scholar 

  39. Collino M, Thiemermann C, Mastrocola R et al (2008) Treatment with the glycogen synthase kinase-3beta inhibitor, TDZD-8, affects transient cerebral ischemia/reperfusion injury in the rat hippocampus. Shock 30:299–307

    Article  CAS  PubMed  Google Scholar 

  40. Perez-Alvarez MJ, Mateos L, Alonso A et al (2015) Estradiol and progesterone administration after pMCAO stimulates the neurological recovery and reduces the detrimental effect of ischemia mainly in hippocampus. Mol Neurobiol 52:1690–1703

    Article  CAS  PubMed  Google Scholar 

  41. Kim AH, Khursigara G, Sun X et al (2001) Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol 21:893–901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Brown AM, Ransom BR (2007) Astrocyte glycogen and brain energy metabolism. Glia 55:1263–1271

    Article  PubMed  Google Scholar 

  43. Yoo DY, Lee KY, Park JH et al. (2016) Glucose metabolism and neurogenesis in the gerbil hippocampus after transient forebrain ischemia. Neural Regen Res 11:1254

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by the Bio-Synergy Research Project (NRF-2015M3A9C4076322) of the Ministry of Science, ICT and Future Planning through the National Research Foundation, and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by Ministry of Science, ICT and Future Planning (NRF-2014R1A1A3051721).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Moo-Ho Won or Joong Bum Moon.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Bai Hui Chen and Ji Hyeon Ahn they have 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

Chen, B.H., Ahn, J.H., Park, J.H. et al. Transient Cerebral Ischemia Alters GSK-3β and p-GSK-3β Immunoreactivity in Pyramidal Neurons and Induces p-GSK-3β Expression in Astrocytes in the Gerbil Hippocampal CA1 Area. Neurochem Res 42, 2305–2313 (2017). https://doi.org/10.1007/s11064-017-2245-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-017-2245-5

Keywords

Navigation