Intranasal administration of RGD-motif-containing osteopontin heptamer confers anti-inflammatory and neuroprotective effects in the postischemic brain
Ja-Kyeong Lee, Il-Doo Kim, Hahnbie Lee, Ja-Kyeong Lee Department of Anatomy, Inha University School of Medicine, Medical Research Center, Inha University School of Medicine, Inchon, Korea
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 examined neuroprotective potency of RGD and SLAYGLR-containing OPN-peptide icosamer (OPNpt20) and compared it with that of RGD-containing OPNpt13, OPNpt10, or OPNpt7 in an animal model of transient focal ischemia (middle cerebral artery occlusion, MCAO). We found that OPN heptamer (OPNpt7) confers comparable neuroprotective effect to OPNpt20. Intranasally administered OPNpt7 reduced mean infarct volume by 52.5% compared to the treatment-naïve MCAO control animals and markedly ameliorated neurological deficits. In addition, OPNpt7 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 OPNpt7 with anti-αvβ3 integrin antibody failed to suppress iNOS induction in primary microglia culture, indicating that the RGD motif in OPNpt7 and endogenous αvβ3 integrin play critical roles. Together these results indicate RGD-containing OPN heptamer has therapeutic potential in the postischemic brain and αvβ3 integrin-mediated anti-inflammatory effect might be an underlying mechanism.
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