Neuroprotective Effects of Cilostazol on Retinal Ganglion Cell Damage in Diabetic Rats

Abstract

Neurodegeneration is an important component of diabetic retinopathy, with increasing evidence that retinal ganglion cell (RGC) death occurs early in diabetes. We investigated the effects of cilostazol, which has been widely used to manage diabetic complications, on retinal ganglion cell death in the diabetic retina. Four-week-old Otsuka Long-Evans Tokushima fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats as matched nondiabetic controls were treated with daily oral cilostazol at 30 mg/kg or 0.9% saline solution. In OLETF rats at the age of 40 weeks, glial fibrillary acidic protein (GFAP) immunofluorescence staining was upregulated in vertical sections, and showed a more ramified pattern in whole-mount retinas compared with that in LETO rats. Vascular endothelial growth factor (VEGF) expression was limited to the ganglion cell layer in LETO rats, but extended into the outer plexiform layer in OLETF rats. Immunofluorescence staining and Western blotting demonstrated that cilostazol treatment reduced GFAP and VEGF expression in the retinas of OLETF rats. Terminal deoxynucleotidyl transferase-mediated terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling (TUNEL) staining revealed an increase in the RGC layer in OLETF compared with LETO rats (P , 0.05), and cilostazol treatment reduced the number of TUNEL-positive cells in OLETF rats (P , 0.05). Relieving retinal ischemia by systemic cilostazol treatment had a noticeable protective effect on RGCs in diabetic rats. Cilostazol treatment may be useful for the management of diabetic retinal vascular dysfunction and neuronal degeneration.

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

“…In the retinas of OLETF rats, cilostazol treatment reduced GFAP and VEGF expression and the number of TUNEL-positive cells ( Jung et al, 2013). Berberine and rosiglitazone significantly decreased PPARg expression in diabetic retina, while berberine and fenofibrate obviously increased PPARa and PPARd expressions in diabetic retina.…”

“…GFAP immunofluorescence staining was upregulated in vertical sections and showed a more ramified pattern in whole-mount retinas. VEGF expression extended into the OPL ( Jung et al, 2013). The INL decreased from 3-4 rows to 2 rows, whereas the photoreceptor cell nuclei decreased from 8 rows to 3-6 rows.…”

Effect of cilostazol in treating diabetes-associated microvascular complications

“…In the trials reviewed above, cilostazol did not change body mass index, hemoglobin A1c, fasting glucose, and anklebrachial index [8,15,24,26]. Since blood glucose levels were not improved, good glycemic control in patients with diabetes is essential and is likely the rationale for appro-priate glycemic control as an inclusion criterion [15,26].…”

“…Glucose toxicity causes endothelial dys-function, which increases permeability allowing circulating macrophages and pro-inflammatory cytokines to enter and cause neuronal damage [22]. Both hyperglycemia and hypoxia damage the endothelium by triggering cells to produce signal proteins such as vascular endothelial growth factor (VEGF) [23,24]. Current treatments for diabetic retinopathy focus on inhibiting VEGF since overproduction results in disordered angiogenesis [25].…”

“…However, reducing rather than blocking VEGF may be an alternative strategy since VEGF initially protects cells by re-establishing oxy-gen delivery [25]. In a preclinical study performed in rats, the effects of oral cilostazol (30 mg/kg) on retinal neurodegeneration were compared with 0.9% saline solution [24]. Diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and matched nondiabetic Long-Evans Tokushima Otsuka (LETO) control rats were treated daily for 15 weeks with either cilostazol or placebo.…”