Peroxynitrite decomposition catalyst, FP15, and poly(ADP-ribose) polymerase inhibitor, PJ34, inhibit leukocyte entrapment in the retinal microcirculation of diabetic rats.
OBJECTIVE
Oxidative and nitrosative stress and activation of poly(ADP ribose) polymerase (PARP) play a role in the pathogenesis of diabetic complications. We evaluated the effectiveness of the peroxynitrite decomposition catalyst, FP15, and the PARP inhibitor, PJ34, in the treatment of leukocyte entrapment in the retinal microcirculation of diabetic rats.


METHODS
Diabetes was induced in rats by intraperitoneal injection of 60 mg/kg of streptozotocin. Rats were divided into four groups: controls; untreated diabetes; diabetes treated with FP15 (10 mg/kg oral gavage twice daily) and diabetes treated with PJ34 (10 mg/kg oral gavage twice daily). All experiments were performed 4 weeks after initiation of treatment. Leukocyte entrapment in the retinal microcirculation was quantitatively evaluated in vivo with acridine orange digital fluorography.


RESULTS
The density of leukocytes trapped in the retinal microcirculation 30 minutes after dye injection was significantly greater in untreated diabetes (32.1 +/- 4.7 cells/mm2) than in controls (11.3 +/- 4.5 cells/mm2) (p < 0.05). Compared with untreated diabetes, the density of trapped leukocytes significantly decreased in diabetes treated with FP15 (14.5 +/- 5.1 cells/mm2) (p < 0.0001) and diabetes treated with PJ34 (24.1 +/- 4.2 cells/mm2) (p < 0.05).


CONCLUSIONS
Treatment with FP15 and PJ34 decreased enhanced leukocyte entrapment in the retinal microcirculation during the early diabetic period. The current study suggests a role for peroxynitrite production and for PARP activation in the pathogenesis of retinal microvascular leukostasis in early diabetes.
Sugawara
R
R
Department of Ophthalmology, Asahikawa Medical College, Midorogaoka Higashi 2-1. Asahikawa 078-8510, Japan.
Hikichi
T
T
Kitaya
N
N
Mori
F
F
Nagaoka
T
T
Yoshida
A
A
Szabo
C
C
D000165:Acridine Orange; D000284:Administration, Oral; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects*; D004396:Coloring Agents; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000517:prevention & control; D015590:Fluorophotometry; D007962:Leukocytes / Q000378:metabolism*; D018921:Leukostasis / Q000378:metabolism; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D008833:Microcirculation; D030421:Peroxynitrous Acid / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D011914:Rats, Inbred BN; D012171:Retinal Vessels / Q000378:metabolism*
D004396:Coloring Agents; C471469:FeCl tetrakis-2-(triethyleneglycolmonomethylether)pyridylporphyrin; D008665:Metalloporphyrins; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D030421:Peroxynitrous Acid; D000165:Acridine Orange