Nasal administration of osteopontin peptide mimetics confers neuroprotection in stroke

Kristian P. Doyle, Tao Yang, Nikola S. Lessov, Thomas M. Ciesielski, Susan L. Stevens, Roger P. Simon, Jeffrey S. King, Mary Stenzel-Poore

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Osteopontin (OPN), a large secreted glycoprotein with an arginine, glycine, aspartate (RGD) motif, can bind and signal through cellular integrin receptors. We have shown previously that OPN enhances neuronal survival in the setting of ischemia. Here, we sought to increase the neuroprotective potency of OPN and improve the method of delivery with the goal of identifying a treatment for stroke in humans. We show that thrombin cleavage of OPN improves its ability to ligate integrin receptors and its neuroprotective capacity in models of ischemia. Thrombin-cleaved OPN is a twofold more effective neuroprotectant than the untreated molecule. We also tested whether OPN could be administered intranasally and found that it is efficiently targeted to the brain via intranasal delivery. Furthermore, intranasal administration of thrombin-treated OPN confers protection against ischemic brain injury. Osteopontin mimetics based on the peptide sequences located either N or C terminal to the thrombin cleavage site were generated and tested in models of ischemia. Treatment with successively shorter N-terminal peptides and a phosphorylated C-terminal peptide provided significant neuroprotection against ischemic injury. These findings show that OPN mimetics offer promise for development into new drugs for the treatment of stroke.

Original languageEnglish (US)
Pages (from-to)1235-1248
Number of pages14
JournalJournal of Cerebral Blood Flow and Metabolism
Volume28
Issue number6
DOIs
Publication statusPublished - Jun 30 2008

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Keywords

  • Integrin
  • Nasal administration
  • Osteopontin
  • RGD
  • Stroke

ASJC Scopus subject areas

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

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