Parstatin suppresses ocular neovascularization and inflammation.
OBJECTIVE
Parstatin is a 41-mer peptide formed by proteolytic cleavage on activation of the PAR1 receptor. The authors recently showed that parstatin is a potent inhibitor of angiogenesis. The purpose of the present study was to evaluate the therapeutic effect of parstatin on ocular neovascularization.


METHODS
Choroidal neovascularization was generated in mice using laser-induced rupture of Bruch's membrane and was assessed after 14 days after perfusion of FITC-dextran. Oxygen-induced retinal neovascularization was established in neonatal mice by exposing them to 75% O(2) at postnatal day (P)7 for 5 days and then placing them in room air for 5 days. Evaluation was performed on P17 after staining with anti-mouse PECAM-1. The effect of parstatin was tested after intravitreal administration. The effects of subconjunctival-injected parstatin on corneal neovascularization and inflammation in rats were assessed 7 days after chemical burn-induced corneal neovascularization. Retinal leukostasis in mice was assessed after perfusion with FITC-conjugated concanavalin A.


RESULTS
Parstatin potently inhibited choroidal neovascularization with an IC(50) of approximately 3 μg and a maximum inhibition of 59% at 10 μg. Parstatin suppressed retinal neovascularization with maximum inhibition of 60% at 3 μg. Ten-microgram and 30-μg doses appeared to be toxic to the neonatal retina. Subconjunctival parstatin inhibited corneal neovascularization, with 200 μg the most effective dose (59% inhibition). In addition, parstatin significantly inhibited corneal inflammation and VEGF-induced retinal leukostasis. In all models tested, scrambled parstatin was without any significant effect.


CONCLUSIONS
Parstatin is a potent antiangiogenic agent of ocular neovascularization and may have clinical potential in the treatment of angiogenesis-related ocular disorders.
Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Hu
H
Huang
Panagiotis
P
Vasilakis
Xiufeng
X
Zhong
Ji-Kui
JK
Shen
Katerina
K
Geronatsiou
Helen
H
Papadaki
Michael E
ME
Maragoudakis
Sotirios P
SP
Gartaganis
Stanley A
SA
Vinores
Nikos E
NE
Tsopanoglou
D000818:Animals; D020256:Choroidal Neovascularization / Q000473:pathology / Q000517:prevention & control*; D003228:Conjunctiva / Q000187:drug effects; D016510:Corneal Neovascularization / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D058449:Intravitreal Injections; D007634:Keratitis / Q000473:pathology / Q000517:prevention & control*; D018921:Leukostasis / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044463:Receptor, PAR-1 / Q000627:therapeutic use*; D012164:Retinal Diseases / Q000517:prevention & control; D015861:Retinal Neovascularization / Q000473:pathology / Q000517:prevention & control
C535229:PAR-1 receptor (1-41), human; D010446:Peptide Fragments; D044463:Receptor, PAR-1