Skip to main content
SpringerLink
Log in

Geldanamycin Treatment During Cerebral Ischemia/Reperfusion Attenuates p44/42 Mitogen-Activated Protein Kinase Activation and Tissue Damage

  • Conference paper
  • First Online:
Brain Edema XV

Part of the book series: Acta Neurochirurgica Supplement ((NEUROCHIRURGICA,volume 118))

Abstract

Background: Heat-shock protein 90 (Hsp90) inhibitor geldanamycin was found to be neuroprotective in various experimental models of brain disease. The effect was attributed to the induction of heat-shock proteins and/or disruption of cellular signaling. Methods: In Sprague–Dawley rats, the middle cerebral artery was occluded for 90 min using the intraluminal suture method. Geldanamycin (300 mg/kg) or vehicle was injected intraperitoneally 15 min before onset of ischemia or reperfusion. Animals were sacrificed at 2, 4 or 24 h after ischemia onset and brain samples were processed for infarct volume measurement, Western blot analysis or immunofluorescent staining of Hsp90, Raf-1, p38, and p44/42 mitogen-activated protein kinases (MAPKs). Results: Geldanamycin treatment during ischemia or reperfusion reduced infarct volume by 79 and 61 % respectively. Geldanamycin decreased Raf-1 and activated p44/42 MAPK proteins, but did not alter levels of activated p38 MAPK during early reperfusion. Hsp90 was co-localized with Raf-1 and activated p44/42 MAPK in the cytoplasm of ischemic neurons. Conclusion: Geldanamycin-induced protection against transient focal cerebral ischemia may in part be based upon depletion of Raf-1 and blockade of p44/42 MAPK activation.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Alessandrini A, Namura S, Moskowitz MA, Bonventre JV (1999) MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci U S A 96:12866–12869

    Article  CAS  PubMed  Google Scholar 

  2. Ali A, Bharadwaj S, O’Carroll R, Ovsenek N (1998) HSP90 interacts with and regulates the activity of heat shock factor 1 in Xenopus oocytes. Mol Cell Biol 18:4949–4960

    CAS  PubMed  Google Scholar 

  3. Barone FC, Irving EA, Ray AM, Lee JC, Kassis S, Kumar S, Badger AM, Legos JJ, Erhardt JA, Ohlstein EH, Hunter AJ, Harrison DC, Philpott K, Smith BR, Adams JL, Parsons AA (2001) Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia. Med Res Rev 21:129–145

    Article  CAS  PubMed  Google Scholar 

  4. Chu CT, Levinthal DJ, Kulich SM, Chalovich EM, DeFranco DB (2004) Oxidative neuronal injury. The dark side of ERK1/2. Eur J Biochem 271:2060–2066

    Article  CAS  PubMed  Google Scholar 

  5. Conde AG, Lau SS, Dillmann WH, Mestril R (1997) Induction of heat shock proteins by tyrosine kinase inhibitors in rat cardiomyocytes and myogenic cells confers protection against simulated ischemia. J Mol Cell Cardiol 29:1927–1938

    Article  CAS  PubMed  Google Scholar 

  6. Ferrer I, Friguls B, Dalfo E, Planas AM (2003) Early modifications in the expression of mitogen-activated protein kinase (MAPK/ERK), stress-activated kinases SAPK/JNK and p38, and their phosphorylated substrates following focal cerebral ischemia. Acta Neuropathol 105:425–437

    CAS  PubMed  Google Scholar 

  7. Gass P, Schroder H, Prior P, Kiessling M (1994) Constitutive expression of heat shock protein 90 (HSP90) in neurons of the rat brain. Neurosci Lett 182:188–192

    Article  CAS  PubMed  Google Scholar 

  8. Harper SJ, Wilkie N (2003) MAPKs: new targets for neurode­generation. Expert Opin Ther Targets 7:187–200

    Article  CAS  PubMed  Google Scholar 

  9. Hu BR, Liu CL, Park DJ (2000) Alteration of MAP kinase pathways after transient forebrain ischemia. J Cereb Blood Flow Metab 20:1089–1095

    Article  CAS  PubMed  Google Scholar 

  10. Irving EA, Bamford M (2002) Role of mitogen- and stress-activated kinases in ischemic injury. J Cereb Blood Flow Metab 22:631–647

    Article  CAS  PubMed  Google Scholar 

  11. Irving EA, Barone FC, Reith AD, Hadingham SJ, Parsons AA (2000) Differential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat. Brain Res Mol Brain Res 77:65–75

    Article  CAS  PubMed  Google Scholar 

  12. Lu A, Ran R, Parmentier-Batteur S, Nee A, Sharp FR (2002) Geldanamycin induces heat shock proteins in brain and protects against focal cerebral ischemia. J Neurochem 81:355–364

    Article  CAS  PubMed  Google Scholar 

  13. Memezawa H, Smith ML, Siesjo BK (1992) Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke 23:552–559

    Article  CAS  PubMed  Google Scholar 

  14. Namura S, Iihara K, Takami S, Nagata I, Kikuchi H, Matsushita K, Moskowitz MA, Bonventre JV, Alessandrini A (2001) Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia. Proc Natl Acad Sci U S A 98:11569–11574

    Article  CAS  PubMed  Google Scholar 

  15. Schulte TW, An WG, Neckers LM (1997) Geldanamycin-induced destabilization of Raf-1 involves the proteasome. Biochem Biophys Res Commun 239:655–659

    Article  CAS  PubMed  Google Scholar 

  16. Schulte TW, Blagosklonny MV, Ingui C, Neckers L (1995) Disruption of the Raf-1-Hsp90 molecular complex results in destabilization of Raf-1 and loss of Raf-1-Ras association. J Biol Chem 270:24585–24588

    Article  CAS  PubMed  Google Scholar 

  17. Schulte TW, Blagosklonny MV, Romanova L, Mushinski JF, Monia BP, Johnston JF, Nguyen P, Trepel J, Neckers LM (1996) Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway. Mol Cell Biol 16:5839–5845

    CAS  PubMed  Google Scholar 

  18. Stancato LF, Chow YH, Hutchison KA, Perdew GH, Jove R, Pratt WB (1993) Raf exists in a native heterocomplex with hsp90 and p50 that can be reconstituted in a cell-free system. J Biol Chem 268:21711–21716

    CAS  PubMed  Google Scholar 

  19. Sugino T, Nozaki K, Takagi Y, Hattori I, Hashimoto N, Moriguchi T, Nishida E (2000) Activation of mitogen-activated protein kinases after transient forebrain ischemia in gerbil hippocampus. J Neurosci 20:4506–4514

    CAS  PubMed  Google Scholar 

  20. Wang X, Wang H, Xu L, Rozanski DJ, Sugawara T, Chan PH, Trzaskos JM, Feuerstein GZ (2003) Significant neuroprotection against ischemic brain injury by inhibition of the MEK1 protein kinase in mice: exploration of potential mechanism associated with apoptosis. J Pharmacol Exp Ther 304:172–178

    Article  CAS  PubMed  Google Scholar 

  21. Wu DC, Ye W, Che XM, Yang GY (2000) Activation of mitogen-activated protein kinases after permanent cerebral artery occlusion in mouse brain. J Cereb Blood Flow Metab 20:1320–1330

    Article  CAS  PubMed  Google Scholar 

  22. Xi G, Keep RF, Hua Y, Xiang J, Hoff JT (1999) Attenuation of thrombin-induced brain edema by cerebral thrombin preconditioning. Stroke 30:1247–1255

    Article  CAS  PubMed  Google Scholar 

  23. Xiao N, Callaway CW, Lipinski CA, Hicks SD, DeFranco DB (1999) Geldanamycin provides posttreatment protection against glutamate-induced oxidative toxicity in a mouse hippocampal cell line. J Neurochem 72:95–101

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants NS-017760, NS-039866. and NS-057539 from the National Institutes of Health (NIH) and 0840016 N from the American Heart Association (AHA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH and AHA.

Conflict of InterestWe declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA

    Murat Karabiyikoglu

  2. Department of Neurosurgery, University of Michigan Medical School, 5018 BSRB, 109 Zina Pitcher Pl, Ann Arbor, MI, 48109-2200, USA

    Ya Hua MD, Richard F. Keep & Guohua Xi MD

Authors
  1. Murat Karabiyikoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ya Hua MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard F. Keep
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guohua Xi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guohua Xi MD .

Editor information

Editors and Affiliations

  1. School of Medicine, Dept. Neurological Surgery, Nihon University, Oyaguchikami-machi 30-1, Tokyo, 173-8610, Japan

    Yoichi Katayama

  2. School of Medicine, Departments of Neurological Surgery and, Nihon University, 30-1 Oyaguchi Kamimachi, Itabashi-ku, Tokyo, 173-8610, Japan

    Takeshi Maeda

  3. , Department of Clinical Laboratory, Namegata District General Hospital, 98-8 Inouefujii, Namegata 98-8, Ibaraki, 311-3516, Japan

    Toshihiko Kuroiwa

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Wien

About this paper

Cite this paper

Karabiyikoglu, M., Hua, Y., Keep, R.F., Xi, G. (2013). Geldanamycin Treatment During Cerebral Ischemia/Reperfusion Attenuates p44/42 Mitogen-Activated Protein Kinase Activation and Tissue Damage. In: Katayama, Y., Maeda, T., Kuroiwa, T. (eds) Brain Edema XV. Acta Neurochirurgica Supplement, vol 118. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1434-6_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-7091-1434-6_6

  • Published:

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-7091-1433-9

  • Online ISBN: 978-3-7091-1434-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation