Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy.

Age-related macular degeneration (AMD) is the leading cause of central retinal vision loss worldwide, with an estimated 1 in 10 people over the age of 55 showing early signs of the condition. There are currently no forms of therapy available for the end stage of dry AMD, geographic atrophy (GA). Here, we show that the inner blood-retina barrier (iBRB) is highly dynamic and may play a contributory role in GA development. We have discovered that the gene CLDN5, which encodes claudin-5, a tight junction protein abundantly expressed at the iBRB, is regulated by BMAL1 and the circadian clock. Persistent suppression of claudin-5 expression in mice exposed to a cholesterol-enriched diet induced striking retinal pigment epithelium (RPE) cell atrophy, and persistent targeted suppression of claudin-5 in the macular region of nonhuman primates induced RPE cell atrophy. Moreover, fundus fluorescein angiography in human and nonhuman primate subjects showed increased retinal vascular permeability in the evening compared with the morning. These findings implicate an inner retina-derived component in the early pathophysiological changes observed in AMD, and we suggest that restoring the integrity of the iBRB may represent a novel therapeutic target for the prevention and treatment of GA secondary to dry AMD.

Evidencing the modulation of P-glycoprotein at blood-ocular barriers using gamma scintigraphy.

PURPOSE: To evaluate the effect of P-glycoprotein modulation at blood-ocular barriers using gamma scintigraphy. METHODS: Ofloxacin, a fluoroquinolone, was selected as a substrate to study the drug efflux transporter (P-glycoprotein) modulation after labeling with Technetium ((99m)Tc) in rabbits. New Zealand albino rabbits were randomized into two groups of 4 each. Group I received labeled ofloxacin intravitreally (100 micro Ci) and Group II animals were given verapamil intravitreally 15 min before the labeled ofloxacin. Static imaging was done at predetermined time, and dynamic images were also taken after 30 min of intravitreal injection. RESULTS: The radio-chemical purity of labeled ofloxacin was found to be 90-95% with the labeling efficiency of 90%. The static anterior planar images of verapamil pre-treated group showed marginal increase in the uptake of labeled ofloxacin, and dynamic images showed less systemic pool as compared to its control. CONCLUSION: This study further confirms the findings of our laboratory regarding the involvement of P-glycoprotein in the intraocular disposition of susceptible drugs.