Dose–Dependant Effect of Pitavastatin on Fluorescein Angiography Leakage and VEGF Expression in a Mouse Model of Choroidal Neovascularisation

Abstract

Abstract: : Purpose: To evaluate the relation between statin therapy, vascular endothelial growth factor (VEGF) expression, vascular leakage and CNV size in experimentally–induced choroidal neovascularisation (CNV). Methods:Normal wild type (C57 Bl/6J) mice received pitavastatin 1.8 mg/kg/day (NK 0.03) or 18 mg/kg/day (NK 0.3) by oral gavage for 3 days prior to laser–induced CNV, and continued for 14 days. Control mice received carboxymethyl cellulose 0.5 % (vehicle). Tail vein cholesterol levels were measured prior to commencement of the study and at the time of sacrifice. Fluorescein angiography was performed 14 days following laser–induced CNV formation and graded by masked graders using angiographic standards. VEGF protein levels from retinal lysates were measured by ELISA 3 days following laser. CNV area was assessed using histology. Results:Cholesterol levels did not change significantly between baseline and the time of sacrifice. Vascular leakage was seen in 19 of 24 (83%) CNV lesions in control mice, 15 of 24 (62%) CNV lesions in the NK 0.03 mice and 23 of 24 (95%) CNV lesions in the NK 0.3 mice. The differences in vascular leakage between pitavastatin–treated mice and control mice did not reach statistical significance (fisher’s exact test, p = 0.24). Mean VEGF level normalized to total protein was lower in the NK 0.03 mice compared to control mice (47.23 +/– 1.92 and 58.97 +/– 3.66 pg/mg total protein respectively, p = 0.02), but did not change significantly in the NK 0.3 mice (71.2 +/– 23.6, p = 0.63). Mean CNV area was not significantly different in the NK 0.03 mice compared to control mice (p = 0.3), but increased significantly in the NK 0.3 mice by a factor of 2.8 (p = 0.03). Conclusions:Pitavastatin therapy for experimental CNV in the mouse resulted in a trend towards reduced leakage and CNV size at a dose of 1.8 mg/kg/day, consistent with its effects on VEGF levels. The higher dose of 18 mg/kg/day resulted in an increase in CNV size indicating a potential detrimental effect in choroidal neovascular disease.

Keywords: choroid: neovascularization • age-related macular degeneration • imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound)