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Article

Intranasal Delivery of RGD-Containing Osteopontin Heptamer Peptide Confers Neuroprotection in the Ischemic Brain and Augments Microglia M2 Polarization

Department of Anatomy, Inha University School of Medicine, Incheon 22212, Korea
*
Author to whom correspondence should be addressed.
The authors are equal contribution.
Academic Editors: Cristina Martínez-Villaluenga and Blanca Hernández-Ledesma
Int. J. Mol. Sci. 2021, 22(18), 9999; https://doi.org/10.3390/ijms22189999
Received: 11 August 2021 / Revised: 7 September 2021 / Accepted: 13 September 2021 / Published: 16 September 2021
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
Osteopontin (OPN), a phosphorylated glycoprotein, is induced in response to tissue damage and inflammation in various organs, including the brain. In our previous studies, we reported the robust neuroprotective effects of the icosamer OPN peptide OPNpt20, containing arginine-glycine-aspartic acid (RGD) and serine-leucine-alanine-tyrosine (SLAY) motifs, in an animal model of transient focal ischemia and demonstrated that its anti-inflammatory, pro-angiogenic, and phagocytosis inducing functions are responsible for the neuroprotective effects. In the present study, we truncated OPNpt20 to 13 or 7 amino acid peptides containing RGD (R) and/or SLAY (S) motifs (OPNpt13RS, OPNpt7R, OPNpt7RS, and OPNpt7S), and their neuroprotective efficacy was examined in a rat middle cerebral artery occlusion (MCAO) model. Intranasal administration of all four peptides significantly reduced infarct volume; OPNpt7R (VPNGRGD), the 7-amino-acid peptide containing an RGD motif, was determined to be the most potent, with efficacy comparable to that of OPNpt20. Additionally, sensory–motor functional deficits of OPNpt7R-administered MCAO animals were significantly improved, as indicated by the modified neurological severity scores and rotarod test. Notably, the expression of M1 markers was suppressed, whereas that of M2 markers (Arginase 1, CD206, and VEGF) was significantly enhanced in OPNpt7R-treated primary microglia cultures. Inflammation resolution by OPNpt7R was further confirmed in MCAO animals, in which upregulation of anti-inflammatory cytokines (Arg1, IL-10, IL-4, and CD36) and enhanced efferocytosis were detected. Moreover, studies using three mutant peptides (OPNpt7R-RAA or OPNpt7R-RAD, where RGD was replaced with RAA or RAD, respectively, and OPNpt7R-sc containing scrambled sequences) revealed that the RGD motif plays a vital role in conferring neuroprotection. In conclusion, the RGD-containing OPN heptamer OPNpt7R exhibits neuroprotective effects in the post-ischemic brain by suppressing M1 markers and augmenting M2 polarization of microglia and the RGD motif plays a critical role in these activities. View Full-Text
Keywords: osteopontin; stroke; M2 microglia; heptamer; RGD osteopontin; stroke; M2 microglia; heptamer; RGD
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MDPI and ACS Style

Davaanyam, D.; Kim, I.-D.; Lee, J.-K. Intranasal Delivery of RGD-Containing Osteopontin Heptamer Peptide Confers Neuroprotection in the Ischemic Brain and Augments Microglia M2 Polarization. Int. J. Mol. Sci. 2021, 22, 9999. https://doi.org/10.3390/ijms22189999

AMA Style

Davaanyam D, Kim I-D, Lee J-K. Intranasal Delivery of RGD-Containing Osteopontin Heptamer Peptide Confers Neuroprotection in the Ischemic Brain and Augments Microglia M2 Polarization. International Journal of Molecular Sciences. 2021; 22(18):9999. https://doi.org/10.3390/ijms22189999

Chicago/Turabian Style

Davaanyam, Dashdulam, Il-Doo Kim, and Ja-Kyeong Lee. 2021. "Intranasal Delivery of RGD-Containing Osteopontin Heptamer Peptide Confers Neuroprotection in the Ischemic Brain and Augments Microglia M2 Polarization" International Journal of Molecular Sciences 22, no. 18: 9999. https://doi.org/10.3390/ijms22189999

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