Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY333531.
OBJECTIVE
The authors tested the antiangiogenic properties of an orally administered protein kinase-Cbeta inhibitor, LY333531, in a pig model of preretinal neovascularization caused by retinal branch vein occlusion to determine the effectiveness of this therapy in preventing intraocular neovascularization from an ischemic stimulus.


METHODS
In 20 eyes of 10 pigs, branch retinal vein occlusions were created in a standardized manner using photodynamic thrombosis with rose bengal dye and thermal burns from an argon laser with green light. Five animals received 1 mg/kg LY333531 daily in two oral doses, and five animals were untreated. The eyes were followed clinically for 12 weeks with ophthalmoscopy, fundus photography, and fluorescein angiography. A standardized grading system permitted masked assessment of disc proliferations using stereo fundus photographs. After the pigs were killed, all neovascularization was confirmed histopathologically in a masked fashion and a final grade was assigned to each eye. The Mann-Whitney test was used for statistical analysis of the median values of the unpaired data between the two eyes of each animal (data were rounded up).


RESULTS
Significant inhibition of neovascularization was observed in eyes from animals treated with the study drug (P = 0.03). Although some of the treated eyes demonstrated no clinically evident new vessels, histopathologic and photographic analysis demonstrated fine new vessels on the optic disc in all eyes (mean grade 1.9). All the untreated eyes developed clinically evident neovascularization (mean grade 3.1). The oral drug was well tolerated, and no side effects were documented.


CONCLUSIONS
A specific protein kinase-Cbeta inhibitor, LY333531, effectively inhibited preretinal and optic nerve head neovascularization in the pig model of branch retinal vein occlusion. This was consistent with the known pathways of signal transduction by growth factors in activated cells and suggested that inhibition of this key regulatory isozyme is effective in the treatment of ischemia-mediated neovascular diseases.
Danis
R P
RP
Department of Ophthalmology, Indiana University Medical School, Indianapolis, USA.
Bingaman
D P
DP
Jirousek
M
M
Yang
Y
Y
D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D007211:Indoles / Q000494:pharmacology*; D007511:Ischemia / Q000150:complications* / Q000473:pathology; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D010781:Photography; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D015861:Retinal Neovascularization / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D012170:Retinal Vein Occlusion / Q000150:complications* / Q000473:pathology; D013552:Swine
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C