Neuroprotection by osteopontin in stroke

Robert Meller, Susan L. Stevens, Manabu Minami, Jennifer A. Cameron, Sonya King, Holly Rosenzweig, Kristian Doyle, Nikola S. Lessov, Roger P. Simon, Mary P. Stenzel-Poore

Research output: Contribution to journalArticle

138 Citations (Scopus)

Abstract

Osteopontin (OPN) is a secreted extracellular phosphoprotein involved in diverse biologic functions, including inflammation, cell migration, and antiapoptotic processes. Here we investigate the neuroprotective potential of OPN to reduce cell death using both in vitro and in vivo models of ischemia. We show that incubation of cortical neuron cultures with OPN protects against cell death from oxygen and glucose deprivation. The effect of OPN depends on the Arg-Gly-Asp (RGD)-containing motif as the protective effect of OPN in vitro was blocked by an RGD-containing hexapeptide, which prevents integrin receptors binding to their ligands. Osteopontin treatment of cortical neuron cultures caused an increase in Akt and p42/p44 MAPK phosphorylation, which is consistent with OPN-inducing neuroprotection via the activation of these protein kinases. Indeed, the protective effect of OPN was reduced by inhibiting the activation of Akt and p42/p44 MAPK using LY294002 and U0126, respectively. The protective effect of OPN was also blocked by the protein synthesis inhibitor cycloheximide, suggesting that the neuroprotective effect of OPN required new protein synthesis. Finally, intracerebral ventricular administration of OPN caused a marked reduction in infarct size after transient middle cerebral artery occlusion in a murine stroke model. These data suggest that OPN is a potent neuroprotectant against ischemic injury.

Original languageEnglish (US)
Pages (from-to)217-225
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume25
Issue number2
DOIs
StatePublished - Feb 2005
Externally publishedYes

Fingerprint

Osteopontin
Stroke
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Neuroprotective Agents
Neuroprotection
Cell Death
Neurons
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Protein Synthesis Inhibitors
Middle Cerebral Artery Infarction
Phosphoproteins
Cycloheximide
Integrins
Protein Kinases
Cell Movement
Ischemia
Phosphorylation

Keywords

  • Akt
  • MCAO p42/p44 MAPK
  • Neuron
  • Osteopontin
  • Stroke

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this

Meller, R., Stevens, S. L., Minami, M., Cameron, J. A., King, S., Rosenzweig, H., ... Stenzel-Poore, M. P. (2005). Neuroprotection by osteopontin in stroke. Journal of Cerebral Blood Flow and Metabolism, 25(2), 217-225. https://doi.org/10.1038/sj.jcbfm.9600022

Neuroprotection by osteopontin in stroke. / Meller, Robert; Stevens, Susan L.; Minami, Manabu; Cameron, Jennifer A.; King, Sonya; Rosenzweig, Holly; Doyle, Kristian; Lessov, Nikola S.; Simon, Roger P.; Stenzel-Poore, Mary P.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 25, No. 2, 02.2005, p. 217-225.

Research output: Contribution to journalArticle

Meller, R, Stevens, SL, Minami, M, Cameron, JA, King, S, Rosenzweig, H, Doyle, K, Lessov, NS, Simon, RP & Stenzel-Poore, MP 2005, 'Neuroprotection by osteopontin in stroke', Journal of Cerebral Blood Flow and Metabolism, vol. 25, no. 2, pp. 217-225. https://doi.org/10.1038/sj.jcbfm.9600022
Meller R, Stevens SL, Minami M, Cameron JA, King S, Rosenzweig H et al. Neuroprotection by osteopontin in stroke. Journal of Cerebral Blood Flow and Metabolism. 2005 Feb;25(2):217-225. https://doi.org/10.1038/sj.jcbfm.9600022
Meller, Robert ; Stevens, Susan L. ; Minami, Manabu ; Cameron, Jennifer A. ; King, Sonya ; Rosenzweig, Holly ; Doyle, Kristian ; Lessov, Nikola S. ; Simon, Roger P. ; Stenzel-Poore, Mary P. / Neuroprotection by osteopontin in stroke. In: Journal of Cerebral Blood Flow and Metabolism. 2005 ; Vol. 25, No. 2. pp. 217-225.
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