Abstract
Purpose: :
Recent evidence has suggested that VEGF may play a role in the pathogenesis of diabetic retinopathy (DR) since various stimuli relevant to DR have been reported to increase the vascular expression of VEGF. Therapeutic maneuvers that suppress VEGF production or activity should be able to inhibit the development or progression of DR. Retinal glutamate levels are elevated in DR so we investigated whether agents known to decrease retinal glutamate (the α2adrenergic receptor agonist brimonidine, BRI) or block its action (the NMDA receptor antagonist memantine, MEM) can decrease VEGF protein levels in retinae of a rat model of type 1 diabetes.
Methods: :
Male Brown Norway (BN) rats were treated with a single IP injection of vehicle or streptozotocin, STZ (65 mg/kg). Blood glucose of STZ–treated rats reached 400 mg/dl within two days after treatment. After one wk, some of the vehicle and STZ–treated animals were sacrificed to analyze VEGF protein levels in retina. The remaining vehicle treated animals were further treated with vehicle, and the STZ–treated animals were treated with vehicle, MEM (10 mg/kg/day) or BRI (1 mg/kg/day) for another 4 wks using osmotic minipumps. At the end of treatment, body weight and blood glucose were measured. Retinae were collected for analysis of VEGF protein levels.
Results: :
There was no significant difference in body weight of any of the treatment groups. Blood glucose levels of STZ treated animals were significantly higher compared to vehicle treated animals. MEM or BRI did not have any effect on blood glucose. VEGF protein levels increased significantly in retinae of STZ–treated diabetic animals within one wk after treatment and remained elevated for the next four wks (VEGF: 8.5 pg/mg & 13.3 pg/mg one wk after vehicle or STZ, respectively, p<0.01 vs Veh). Four weeks of treatment with MEM or BRI significantly reduced VEGF protein levels in retinae of the diabetic animals (VEGF: 13 pg/mg, 9.9 pg/mg & 8.2 pg/mg after treatment with vehicle, MEM and BRI, respectively, p<0.05 vs veh) so that levels were similar to that of non–diabetic animals (8.1 pg/mg).
Conclusions: :
Treatment with MEM and BRI significantly reduced elevated VEGF protein levels in retinae of STZ–treated diabetic rats. The results indicate that glutamate may play a role in the elevation of VEGF protein levels in the retina. Drugs such as MEM and BRI that interfere with elevated glutamate may be useful for the treatment of the vascular changes in DR, and also other ocular diseases with elevated retinal VEGF protein levels.
Keywords: growth factors/growth factor receptors • drug toxicity/drug effects • diabetic retinopathy