Skip to main content
Download PDF

Estradiol attenuates down-regulation of PEA-15 and its two phosphorylated forms in ischemic brain injury

Laboratory Animal Research volume 31, pages 40–45 (2015)Cite this article

Abstract

Estradiol exerts a neuroprotective effect against focal cerebral ischemic injury through the inhibition of apoptotic signals. Phosphoprotein enriched in astrocytes 15 (PEA-15) is mainly expressed in brain that perform anti-apoptotic functions. This study investigated whether estradiol modulates the expression of PEA-15 and two phosphorylated forms of PEA-15 (Ser 104 and Ser 116) in middle cerebral artery occlusion (MCAO)-induced injury and glutamate exposure-induced neuronal cell death. Adult female rats were ovariectomized to remove endogenous estradiol and treated with vehicle or estradiol prior to MCAO. Focal cerebral ischemia was induced by MCAO and cerebral cortices were collected 24 h after MCAO. Western blot analysis indicated that estradiol prevents the MCAO-induced decrease in PEA-15, phospho-PEA-15 (Ser 104), phospho-PEA-15 (Ser 116). Glutamate exposure induced a reduction in PEA- 15, phospho-PEA-15 (Ser 104), phospho-PEA-15 (Ser 116) in cultured neurons, whereas estradiol treatment attenuated the glutamate toxicity-induced decrease in the expression of these proteins. It has been known that phosphorylation of PEA-15 is an important step in carrying out its anti-apoptotic function. Thus, these findings suggest that the regulation of PEA-15 phosphorylation by estradiol contributes to the neuroprotective function of estradiol in ischemic brain injury.

References

  1. Behl C, Widmann M, Trapp T, Holsboer F. 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun 1995; 216(2): 473–482.

    Article  CAS  Google Scholar 

  2. Culmsee C, Vedder H, Ravati A, Junker V, Otto D, Ahlemeyer B, Krieg JC, Krieglstein J. Neuroprotection by estrogens in a mouse model of focal cerebral ischemia and in cultured neurons: evidence for a receptor-independent antioxidative mechanism. J Cereb Blood Flow Metab 1999; 19(11): 1263–1269.

    Article  CAS  Google Scholar 

  3. Tnez I, Collado JA, Medina FJ, Pea J, Del C Muoz M, Jimena I, Franco F, Rueda I, Feijo M, Muntan J, Montilla P. 17 beta-Estradiol may affect vulnerability of striatum in a 3-nitropropionic acid-induced experimental model of Huntington’s disease in ovariectomized rats. Neurochem Int 2006; 48(5): 367–373.

    Article  Google Scholar 

  4. Kurata K, Takebayashi M, Morinobu S, Yamawaki S. beta-estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate protect against N-methyl-D-aspartate-induced neurotoxicity in rat hippocampal neurons by different mechanisms. J Pharmacol Exp Ther 2004; 311(1): 237–245.

    Article  CAS  Google Scholar 

  5. Sribnick EA, Ray SK, Nowak MW, Li L, Banik NL. 17beta-estradiol attenuates glutamate-induced apoptosis and preserves electrophysiologic function in primary cortical neurons. J Neurosci Res 2004; 76(5): 688–696.

    Article  CAS  Google Scholar 

  6. Danziger N, Yokoyama M, Jay T, Cordier J, Glowinski J, Chneiweiss H. Cellular expression, developmental regulation, and phylogenic conservation of PEA-15, the astrocytic major phosphoprotein and protein kinase C substrate. J Neurochem 1995; 64(3): 1016–1025.

    Article  CAS  Google Scholar 

  7. Sharif A, Renault F, Beuvon F, Castellanos R, Canton B, Barbeito L, Junier MP, Chneiweiss H. The expression of PEA-15 (phosphoprotein enriched in astrocytes of 15 kDa) defines subpopulations of astrocytes and neurons throughout the adult mouse brain. Neuroscience 2004; 126(2): 263–275.

    Article  CAS  Google Scholar 

  8. Krueger J, Chou FL, Glading A, Schaefer E, Ginsberg MH. Phosphorylation of phosphoprotein enriched in astrocytes (PEA-15) regulates extracellular signal-regulated kinase-dependent transcription and cell proliferation. Mol Biol Cell 2005; 16(8): 3552–3561.

    Article  CAS  Google Scholar 

  9. Renault F, Formstecher E, Callebaut I, Junier MP, Chneiweiss H. The multifunctional protein PEA-15 is involved in the control of apoptosis and cell cycle in astrocytes. Biochem Pharmacol 2003; 66(8): 1581–1588.

    Article  CAS  Google Scholar 

  10. Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andal P, Oriente F, Miele C, Caruso M, Formisano P, Beguinot F. PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis. Oncogene 1999; 18(31): 4409–4415.

    Article  CAS  Google Scholar 

  11. Estells A, Charlton CA, Blau HM. The phosphoprotein protein PEA-15 inhibits Fas-but increases TNF-R1-mediated caspase-8 activity and apoptosis. Dev Biol 1999; 216(1): 16–28.

    Article  Google Scholar 

  12. Kitsberg D, Formstecher E, Fauquet M, Kubes M, Cordier J, Canton B, Pan G, Rolli M, Glowinski J, Chneiweiss H. Knock-out of the neural death effector domain protein PEA-15 demonstrates that its expression protects astrocytes from TNFalpha-induced apoptosis. J Neurosci 1999; 19(19): 8244–8251.

    Article  CAS  Google Scholar 

  13. Araujo H, Danziger N, Cordier J, Glowinski J, Chneiweiss H. Characterization of PEA-15, a major substrate for protein kinase C in astrocytes. J Biol Chem 1993; 268(8): 5911–5920.

    CAS  PubMed  Google Scholar 

  14. Danziger N, Yokoyama M, Jay T, Cordier J, Glowinski J, Chneiweiss H. Cellular expression, developmental regulation, and phylogenic conservation of PEA-15, the astrocytic major phosphoprotein and protein kinase C substrate. J Neurochem 1995; 64(3): 1016–1025.

    Article  CAS  Google Scholar 

  15. Trencia A, Perfetti A, Cassese A, Vigliotta G, Miele C, Oriente F, Santopietro S, Giacco F, Condorelli G, Formisano P, Beguinot F. Protein kinase B/Akt binds and phosphorylates PED/PEA-15, stabilizing its antiapoptotic action. Mol Cell Biol 2003; 23(13): 4511–4521.

    Article  CAS  Google Scholar 

  16. Koh PO, Won CK, Cho JH. Estradiol prevents the injury-induced decrease of Akt/glycogen synthase kinase 3beta phosphorylation. Neurosci Lett 2006; 404(3): 303–308.

    Article  CAS  Google Scholar 

  17. Koh PO. 17Beta-estradiol prevents the glutamate-induced decrease of Akt and its downstream targets in HT22 cells. J Vet Med Sci 2007; 69(3): 285–288.

    CAS  Google Scholar 

  18. Dubal DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM. Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. J Neurosci 1999; 19(15): 6385–6393.

    Article  CAS  Google Scholar 

  19. Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989; 20(1): 84–91.

    Article  CAS  Google Scholar 

  20. Mize AL, Shapiro RA, Dorsa DM. Estrogen receptor-mediated neuroprotection from oxidative stress requires activation of the mitogen-activated protein kinase pathway. Endocrinology 2003; 144(1): 306–312.

    Article  CAS  Google Scholar 

  21. Sung JH, Cho EH, Min W, Kim MJ, Kim MO, Jung EJ, Koh PO. Identification of proteins regulated by estradiol in focal cerebral ischemic injury—a proteomics approach. Neurosci Lett 2010; 477(2): 66–71.

    Article  CAS  Google Scholar 

  22. Sharif A, Canton B, Junier MP, Chneiweiss H. PEA-15 modulates TNFalpha intracellular signaling in astrocytes. Ann N Y Acad Sci 2003; 1010(1): 43–50.

    Article  CAS  Google Scholar 

  23. Dawson DA, Martin D, Hallenbeck JM. Inhibition of tumor necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. Neurosci Lett 1996; 218(1): 41–44.

    Article  CAS  Google Scholar 

  24. Wetzel M, Li L, Harms KM, Roitbak T, Ventura PB, Rosenberg GA, Khokha R, Cunningham LA. Tissue inhibitor of metalloproteinases-3 facilitates Fas-mediated neuronal cell death following mild ischemia. Cell Death Differ 2008; 15(1): 143–151.

    Article  CAS  Google Scholar 

  25. Renganathan H, Vaidyanathan H, Knapinska A, Ramos JW. Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD. Biochem J 2005; 390(3): 729–735.

    Article  CAS  Google Scholar 

  26. Chen J, Chua KW, Chua CC, Yu H, Pei A, Chua BH, Hamdy RC, Xu X, Liu CF. Antioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity. Neurosci Lett 2011; 499(3): 181–185.

    Article  CAS  Google Scholar 

  27. Jin ML, Park S Y, Kim YH, Oh JI, Lee SJ, Park G. The neuroprotective effects of cordycepin inhibit glutamate-induced oxidative and ER stress-associated apoptosis in hippocampal HT22 cells. Neurotoxicology 2014; 41: 102–111.

    Article  CAS  Google Scholar 

  28. Gursoy E, Cardounel A, Kalimi M. Pregnenolone protects mouse hippocampal (HT-22) cells against glutamate and amyloid beta protein toxicity. Neurochem Res 2001; 26(1): 15–21.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anatomy, College of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, 900 Gajwa-dong, Jinju, Gyeongnam, 660-701, Korea

    Phil-Ok Koh

Authors
  1. Phil-Ok Koh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Phil-Ok Koh.

Rights and permissions

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Koh, PO. Estradiol attenuates down-regulation of PEA-15 and its two phosphorylated forms in ischemic brain injury. Lab Anim Res 31, 40–45 (2015). https://doi.org/10.5625/lar.2015.31.1.40

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.5625/lar.2015.31.1.40

Keywords

  • Estradiol
  • neuroprotection
  • PEA-15

Laboratory Animal Research

ISSN: 2233-7660