Neuroprotective effect of cilostazol against retinal ischemic damage via inhibition of leukocyte-endothelial cell interactions.
BACKGROUND
Cilostazol, a selective platelet phosphodiesterase inhibitor, has been shown to reduce neuronal injury after transient cerebral ischemia. Its neuroprotective effect is thought to result from an antiplatelet function. This study was designed to evaluate the inhibitory effects of cilostazol against retinal ischemic damage focusing on leukocyte-endothelial cell interactions.


METHODS
Retinal ischemia was induced for 60 min in male Sprague-Dawley rats (n = 144) by temporary ligation of the optic sheath. Cilostazol was administered just before ischemia induction. Leukocyte behavior in the retinal microcirculation was evaluated in vivo with scanning laser ophthalmoscopy and ex vivo with fluorescence microscopy. Retinal expression of P-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular endothelial growth factor were evaluated by real-time quantitative reverse transcriptase-polymerase chain reaction. Ischemia-induced retinal damage was evaluated histologically.


RESULTS
Treatment with cilostazol significantly suppressed leukocyte-endothelial cell interactions; the maximal numbers of rolling leukocytes were reduced by 77.6% (P < 0.01) 12 h after ischemia. Twenty-four hours after ischemia, adherent and accumulated leukocytes were also suppressed by treatment with cilostazol (36.1% and 20.4% respectively, P < 0.01). The expressions of P-selectin and ICAM-1 mRNA were suppressed significantly in cilostazol-treated retinas (P < 0.05). The retinal histological examination demonstrated a significant protective effect of cilostazol against ischemia-induced retinal damage (P < 0.01).


CONCLUSIONS
The present study demonstrates that cilostazol attenuates retinal injury after transient ischemia via inhibition of leukocyte-endothelial cell interactions. This inhibitory effect on postischemic leukocyte-endothelial cell interactions might partially contribute to its neuroprotective effects.
Iwama
D
D
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan.
Miyamoto
K
K
Miyahara
S
S
Tamura
H
H
Tsujikawa
A
A
Yamashiro
K
K
Kiryu
J
J
Yoshimura
N
N
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002450:Cell Communication; D000077407:Cilostazol; D004730:Endothelium, Vascular / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D007511:Ischemia / Q000188:drug therapy*; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010973:Platelet Adhesiveness / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012171:Retinal Vessels / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*
D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D013777:Tetrazoles; D000077407:Cilostazol