RESUMEN
PURPOSE: Diabetic macular edema (DME), an accumulation of fluid in the subretinal space, is a significant cause of vision loss. The impact of diabetes on the breakdown of the inner blood-retina barrier (BRB) is an established event that leads to DME. However, the role of the outer BRB in ocular diabetes has received limited attention. We present evidence that the breakdown of normal RPE function in hyperglycemia facilitates conditions conducive to DME pathogenesis. METHODS: Brown Norway rats (130-150 g) were injected intraperitoneally with streptozotocin (STZ; 60 mg/kg) to induce hyperglycemia. After 4 weeks, Evans blue (EB) dye was injected intravenously to determine whether there was leakage of albumin into the retina. Subretinal saline blebs (0.5-1 µL) were placed 4 and 9 weeks after STZ injection, and time-lapse optical coherence tomography tracked the resorption rate. In a subset of rats, intravitreal bevacizumab, a humanized monoclonal antibody targeted to VEGF, was given at 5 weeks and resorption was measured at 9 weeks. RESULTS: The ability of the RPE to transport fluid was reduced significantly after 4 and 9 weeks of hyperglycemia with a reduction of over 67% at 9 weeks. No EB dye leakage from inner retinal vessels was measured in hyperglycemic animals compared to control. The intravitreal administration of bevacizumab at week 5 significantly increased the rate of fluid transport in rats subjected to hyperglycemia for 9 weeks. CONCLUSIONS: These results demonstrate that chronic hyperglycemia altered RPE fluid transport, in part dependent on the actions of VEGF. These results support the idea that RPE dysfunction is an early event associated with hyperglycemia that contributes to fluid accumulation in DME.
Asunto(s)
Barrera Hematorretinal/metabolismo , Diabetes Mellitus Experimental , Retinopatía Diabética/complicaciones , Hiperglucemia/complicaciones , Edema Macular/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Bevacizumab/administración & dosificación , Barrera Hematorretinal/efectos de los fármacos , Células Cultivadas , Enfermedad Crónica , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/metabolismo , Angiografía con Fluoresceína , Fondo de Ojo , Hiperglucemia/diagnóstico , Immunoblotting , Inmunohistoquímica , Inyecciones Intravítreas , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Ratas , Ratas Endogámicas BN , Epitelio Pigmentado de la Retina/patología , Vasos Retinianos/metabolismo , Vasos Retinianos/patología , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The discovery of a pyrrolopyrimidine class of LIM-kinase 2 (LIMK2) inhibitors is reported. These LIMK2 inhibitors show good potency in enzymatic and cellular assays and good selectivity against ROCK. After topical dosing to the eye in a steroid induced mouse model of ocular hypertension, the compounds reduce intraocular pressure to baseline levels. The compounds also increase outflow facility in a pig eye perfusion assay. These results suggest LIMK2 may be an effective target for treating ocular hypertension and associated glaucoma.
