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Raul de la Flor, Matthew Wright, Anthony Adamis, Jason Ehrlich, David Shima; The dual PPAR-α/γ agonist aleglitazar attenuates retinopathy in streptozotocin diabetic rats. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4596.
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The ACCORD Eye and FIELD clinical studies suggest that the peroxisome proliferator-activated receptor (PPAR)-α agonist fenofibrate has beneficial effects on diabetic retinopathy severity. Aleglitazar is a balanced PPAR-α/γ agonist in Phase III development for reduction of cardiovascular risk in post-acute coronary syndrome patients with type 2 diabetes. We assessed effects of aleglitazar in comparison with fenofibrate or rosiglitazone on retinal vascular permeability and leukostasis in the streptozotocin (STZ) diabetic rat.
Diabetes was induced by a single dose of STZ (60 mg/kg, i.p.) in 56 juvenile Long Evans rats. Blood glucose was assessed to confirm presence of diabetes and animals were randomized into 5 treatment groups. Aleglitazar (0.3 mg/kg or 3 mg/kg), fenofibrate (50 mg/kg), rosiglitazone (10 mg/kg) or vehicle were dosed once daily by oral gavage for 2 weeks. A parallel group that had not received STZ served as non-diabetic control. Vascular blood-retinal barrier breakdown was assessed by fluorophotometry. Leukostasis was determined by visual quantification of concanavalin A-labeled retina-adherent leukocytes by epifluorescence microscopy.
Aleglitazar has balanced affinity for human PPAR-γ and PPAR-α, but reduced affinity for rodent PPAR-α, due to amino acid differences in the human and rodent PPAR-α ligand-binding domain. Aleglitazar at 3mg/kg (expected to activate both PPAR-α and -γ) significantly decreased retinal vascular hyperpermeability to levels of non-diabetic animals, while aleglitazar at 0.3 mg/kg (expected to primarily activate PPAR-γ) had no effect (figure 1). Rosiglitazone and fenofibrate both exhibited trends to reduce retinal vascular hyperpermeability (not statistically significant). Aleglitazar at both doses significantly reduced leukostasis to levels comparable to non-diabetic rats (figure 2).
Aleglitazar was effective in reducing both retinal vascular permeability and leukostasis in the diabetic rat. Leukocyte adhesion was reduced by aleglitazar at both doses, suggesting a PPAR-γ-dependent mechanism. Retinal vascular permeability was reduced only by the higher dose, suggesting a PPAR-α-dependent mechanism. These data support a role for both the PPAR-α and PPAR-γ activity of aleglitazar on important pathologic aspects of diabetic retinopathy.
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