gw-7647 and Myopia

To determine if drug-induced peroxisome proliferator-activated receptor α (PPARα) signal pathway modulation affects refractive development and myopia in guinea pigs.. Pigmented guinea pigs were randomly divided into normal vision (unoccluded) and form deprivation myopia (FDM) groups. Each group received daily peribulbar injections of either a vehicle or (1) PPARα agonist, GW7647, clofibrate, or bezafibrate or (2) PPARα antagonist, GW6471, for 4 weeks. Baseline and posttreatment refraction and ocular biometric parameters were measured. Immunofluorescent staining of PPARα and two of its downstream readouts, cytosolic malic enzyme 1 (ME1) and apolipoproteinA II (apoA-II), was undertaken in selected scleral sections. Western blot analysis determined collagen type I expression levels.. GW6471 induced a myopic shift in unoccluded eyes, but had no effect on form-deprived eyes. Conversely, GW7647 inhibited FDM progression without altering unoccluded eyes. Bezafibrate and clofibrate had effects on refraction similar to those of GW7647 in unoccluded and form-deprived eyes. GW6471 downregulated collagen type I expression in unoccluded eyes whereas bezafibrate inhibited collagen type I decreases in form-deprived eyes. GW6471 also reduced the density of ME1- and apoA-II-stained cells in unoccluded eyes whereas bezafibrate increased apoA-II-positive cell numbers in form-deprived eyes.. As GW7647 and GW6471 had opposing effects on myopia development, PPARα signaling modulation may be involved in this condition in guinea pigs. Fibrates are potential candidates for treating myopia since they reduced both FDM and the associated axial elongation. Bezafibrate also inhibited form deprivation-induced decreases in scleral collagen type I expression and the density of apoA-II expressing cells.

Topics: Animals; Apolipoprotein A-II; Bezafibrate; Biometry; Blotting, Western; Butyrates; Clofibrate; Collagen Type I; Disease Models, Animal; Electroretinography; Fluorescent Antibody Technique, Indirect; Guinea Pigs; Intraocular Pressure; Malate Dehydrogenase; Myopia; Oxazoles; Phenylurea Compounds; PPAR alpha; Refraction, Ocular; Sensory Deprivation; Tyrosine

Good visual acuity requires that the axial length of the ocular globe is matched to the refractive power of the cornea and lens to focus the images of distant objects onto the retina. During the growth of the juvenile eye, this is achieved through the emmetropization process that adjusts the ocular axial length to compensate for the refractive changes that occur in the anterior segment. A failure of the emmetropization process can result in either excessive or insufficient axial growth, leading to myopia or hyperopia, respectively. Emmetropization is mainly regulated by the retina, which generates two opposite signals: "GO/GROW" signals to increase axial growth and "STOP" signals to block it. The presence of GO/GROW and STOP signals was investigated by a proteomics analysis of the retinas from chicken with experimental myopia and hyperopia. Of 18 differentially expressed proteins that were identified, five displayed an expression profile corresponding to GO/GROW signals, and two corresponded to STOP signals. Western blotting confirmed that apolipoprotein A-I (apoA-I) has the characteristics of a STOP signal both in the retina as well as in the fibrous sclera. In accordance with this, intraocular application of the peroxisome proliferator-activated receptor alpha agonist GW7647 resulted in up-regulation of apoA-I levels and in a significant reduction of experimental myopia. In conclusion, using a comprehensive functional proteomics analysis of chicken ocular growth models we identified targets for ocular growth control. The correlation of elevated apoA-I levels with reduced ocular axial growth points toward a functional relationship with the observed morphological changes of the eye.

Topics: Animals; Apolipoprotein A-I; Blotting, Western; Butyrates; Chickens; Disease Models, Animal; Eye Proteins; Myopia; Phenylurea Compounds; PPAR alpha; Proteome; Proteomics; Retina; Sclera; Vimentin