PKC-beta inhibitor (LY333531) attenuates leukocyte entrapment in retinal microcirculation of diabetic rats.
OBJECTIVE
The activity of protein kinase C (PKC), preferentially beta isoform of PKC, has been shown to be elevated in the diabetic retina. Recently, LY333531, a specific inhibitor of PKC-beta, has been reported to improve the decrease of retinal blood flow in early diabetes. Increased leukocyte entrapment has been suggested to be involved in blood flow disturbances in the early diabetic retina. This study was designed quantitatively to evaluate leukocyte entrapment in the retinal microcirculation of diabetic rats and the effect of LY333531 on leukocyte entrapment.


METHODS
Diabetes was induced in male Long-Evans rats by intraperitoneal injection of streptozotocin (60 mg/kg). LY333531 (0.1, 1.0, or 10.0 mg/kg/d) was administered orally during a 4-week diabetic period. Leukocyte entrapment in the retinal microcirculation was quantitatively evaluated in vivo with acridine orange digital fluorography.


RESULTS
The number of leukocytes trapped in the retinal microcirculation of diabetic rats (mean +/- SEM; 14.3 +/- 1.3 cells/mm2) was significantly increased, compared with nondiabetic control rats (7.5 +/- 0.3 cells/mm2; P < 0.0001). Oral administration of LY333531 significantly decreased the number of leukocytes trapped in the retinal microcirculation of diabetic rats (10.9 +/- 0.6, 11.3 +/- 0.7, and 10.4 +/- 0.4 cells/mm2 with LY333531 0.1, 1.0, and 10.0 mg/kg/d, respectively; P < 0.05).


CONCLUSIONS
Treatment with LY333531 attenuated the increase of leukocyte entrapment in the retinal microcirculation during the period of early diabetes. This effect may contribute to the improvement of abnormal retinal blood flow in early diabetes with LY333531. LY333531 might have a therapeutic efficacy in preventing microcirculatory flow disturbances by trapped leukocytes in the early diabetic retina.
Nonaka
A
A
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Japan.
Kiryu
J
J
Tsujikawa
A
A
Yamashiro
K
K
Miyamoto
K
K
Nishiwaki
H
H
Honda
Y
Y
Ogura
Y
Y
D000165:Acridine Orange; D000284:Administration, Oral; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005456:Fluorescent Dyes; D015590:Fluorophotometry; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008301:Maleimides / Q000008:administration & dosage / Q000494:pharmacology*; D008833:Microcirculation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D020318:Rats, Long-Evans; D012171:Retinal Vessels / Q000378:metabolism* / Q000473:pathology
D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D000165:Acridine Orange