Inhibition of Vitreoretinal VEGF Elevation and Blood-Retinal Barrier Breakdown in Streptozotocin-Induced Diabetic Rats by Brimonidine
JYOTIRMOY KUSARI 1*,
Sheila X. Zhou 2,
Edwin Padillo 2,
Kenneth G. Clarke 3,
and
Daniel W. Gil 2
1 Biological Sciences, ALLERGAN, INC., IRVINE, California, United States
2 Biological Sciences, ALLERGAN, INC., Irvine, California, United States
3 Biostatistics, ALLERGAN, INC., Irvine, California, United States
* To whom correspondence should be addressed. E-mail: kusari_jyoti{at}allergan.com.
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Abstract |
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Purpose. To determine whether chronic brimonidine (BRI) treatment prevents the hyperglycemia-induced increase in vitreoretinal vascular endothelial growth factor (VEGF) expression and breakdown of the blood-retinal barrier (BRB) in streptozotocin (STZ)-induced diabetic rats.
Methods. Brown Norway/Long Evans rats were divided into 3 groups with similar distributions of blood glucose and body weight. Two groups received a single intravenous injection of STZ (65 mg/kg) and the remaining control group received vehicle. Drug treatment using mini-osmotic pumps was initiated 1 or 6 weeks later. The STZ-induced diabetic rats were treated with BRI (1 mg/kg/day) or vehicle (VEH) and control nondiabetic rats were treated with VEH for 4 weeks. Vitreoretinal VEGF protein, vitreal glutamate, and BRB breakdown were then measured.
Results. At 5 weeks after STZ treatment, STZ-treated diabetic rats demonstrated significantly elevated vitreoretinal VEGF expression, vitreal glutamate concentrations, and BRB leakage compared with nondiabetic control rats. Chronic BRI treatment had no effect on vitreal glutamate concentrations in diabetic animals but significantly decreased vitreoretinal VEGF and BRB breakdown to levels similar to those observed in controls. BRI also significantly reduced BRB breakdown in aged diabetic rats at 10 weeks after STZ treatment.
Conclusions. BRI produced marked decreases in vitreoretinal VEGF and inhibition of BRB breakdown in diabetic rats. The mechanism for these effects may involve attenuation of retinal NMDA receptor activity by BRI. The results suggest that BRI could be useful for treatment of ocular diseases associated with BRB leakage such as diabetic macular edema and retinopathy.
Key Words:
blood-retinal barrier, macular edema, diabetic retinopathy, vascular endothelial growth factor, brimonidine, streptozotocin
