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Intranasal Delivery of RGD Motif-Containing Osteopontin Icosamer Confers Neuroprotection in the Postischemic Brain via αvβ3 Integrin Binding
- Source :
- Molecular neurobiology. 53(8)
- Publication Year :
- 2015
-
Abstract
- Osteopontin (OPN) is a phosphorylated glycoprotein possessing an arginine-glycine-aspartate (RGD)-motif, which binds to several cell surface integrins and mediates a wide range of cellular processes. Inductions of OPN have been reported in the postischemic brain, and the neuroprotective effects of OPN have been demonstrated in animal models of stroke. In the present study, we showed a robust neuroprotective effect of RGD-containing icosamer OPN peptide (OPNpt20) in a rat model of focal cerebral ischemia (middle cerebral artery occlusion, MCAO). Intranasally administered OPNpt20 reduced mean infarct volume by 79.7 % compared to the treatment-naive MCAO control animals and markedly ameliorated neurological deficits. In addition, OPNpt20 significantly suppressed the inductions of iNOS and of inflammatory markers in postischemic brains and in primary microglial cultures, demonstrating anti-inflammatory effects. Administration of a mutant peptide, in which RGD was replaced by arginine-alanine-alanine (RAA), failed to suppress infarct volumes in MCAO animals and co-administration of OPNpt20 with anti-αvβ3 integrin antibody failed to suppress iNOS induction in primary microglia culture, indicating that the RGD motif in OPNpt20 and endogenous αvβ3 integrin play critical roles. Furthermore, pull-down assay revealed a direct binding between OPNpt20 and αvβ3 integrin in primary microglia culture. Together, these results indicate that RGD-containing OPN icosamer has therapeutic potential in the postischemic brain and αvβ3 integrin-mediated anti-inflammatory effect might be an underlying mechanism.
- Subjects :
- 0301 basic medicine
Male
Anti-Inflammatory Agents
Nitric Oxide Synthase Type II
Pharmacology
Brain Ischemia
Brain ischemia
Rats, Sprague-Dawley
0302 clinical medicine
Drug Delivery Systems
Protein Isoforms
Osteopontin
Phosphorylation
Cells, Cultured
RGD motif
Integrin alphaVbeta3
biology
Microglia
Brain
Infarction, Middle Cerebral Artery
Neuroprotection
medicine.anatomical_structure
STAT1 Transcription Factor
Neurology
medicine.symptom
Oligopeptides
Protein Binding
Integrin
Neuroscience (miscellaneous)
Inflammation
Motor Activity
Nitric Oxide
03 medical and health sciences
Cellular and Molecular Neuroscience
medicine
Animals
Amino Acid Sequence
Administration, Intranasal
Nitrites
business.industry
medicine.disease
030104 developmental biology
Immunology
biology.protein
business
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15591182
- Volume :
- 53
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Molecular neurobiology
- Accession number :
- edsair.doi.dedup.....cfdbe142e98f7899a47ac783d1e15183