Cilostazol promotes survival of axotomized retinal ganglion cells in adult rats.
Cilostazol (CLZ), a selective inhibitor of cyclic nucleotide phosphodiesterase 3, has been shown to reduce neuronal cell death after a transient cerebral infarction. The mechanism for this reduction was suggested to be an elevation of intracellular cAMP or an inhibition of tumor necrosis factor alpha. Optic nerve injury leads to retinal ganglion cell (RGC) death possibly from a deprivation of neurotrophic factors and/or the down-regulation of intracellular cAMP. The purpose of this study was to determine if CLZ can rescue RGCs after optic nerve transection by inhibiting cyclic nucleotide phosphodiesterase 3. To examine this, the mean densities of surviving RGCs after optic nerve transection were determined in retinas that received an intravitreal injection of CLZ and in retinas that received vehicle. Our results showed that the density of surviving RGCs in the retina with intravitreal CLZ were significantly higher than that with vehicle injection on day 7. The CLZ was effective in promoting the survival at more than 0.05% concentration. The neuroprotective effects induced by 0.05% CLZ could be observed even 14 days after optic nerve transection. Furthermore, combined application of protein kinase A (PKA) inhibitor, KT5720 (10 microM) and 0.05% CLZ significantly decreased the density of surviving RGCs compared to that with only 0.05% CLZ. Based on these data, we concluded that CLZ enhances the survival of axotomized RGC in vivo, possibly depending on the activation of PKA pathway.
Kashimoto
Ryosuke
R
Department of Ophthalmology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
Kurimoto
Takuji
T
Miyoshi
Tomomitsu
T
Okamoto
Norio
N
Tagami
Yuichi
Y
Oono
Shinichirou
S
Ito
Yoshimasa
Y
Mimura
Osamu
O
D000818:Animals; D019771:Axotomy / Q000379:methods*; D002227:Carbazoles / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D000077407:Cilostazol; D003505:Cyclodextrins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D020221:Optic Nerve Injuries / Q000473:pathology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D013266:Stilbamidines; D013777:Tetrazoles / Q000494:pharmacology*
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D002227:Carbazoles; D003505:Cyclodextrins; D010726:Phosphodiesterase Inhibitors; D011758:Pyrroles; D013266:Stilbamidines; D013777:Tetrazoles; C057416:KT 5720; D000077407:Cilostazol