Nasal administration of osteopontin peptide mimetics confers neuroprotection in stroke.
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.
Doyle
Kristian P
KP
Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon, USA.
Yang
Tao
T
Lessov
Nikola S
NS
Ciesielski
Thomas M
TM
Stevens
Susan L
SL
Simon
Roger P
RP
King
Jeffrey S
JS
Stenzel-Poore
Mary P
MP
D000281:Administration, Intranasal; D000595:Amino Acid Sequence; D000818:Animals; D040761:Biomimetic Materials / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D053495:Osteopontin / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors
D016023:Integrins; D018696:Neuroprotective Agents; D010455:Peptides; D053495:Osteopontin; D013917:Thrombin