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Shereen Nizari, Li Guo, Eduardo M. Normando, M. Francesca Cordeiro; Is Abeta Implicated in Brimonidine Effect on Reducing RGC Apoptosis in Ocular Hypertensive Model?. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6589.
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We have previously shown in a rat model of chronic ocular hypertension that systemic Brimonidine (BMD) treatment significantly reduced the level of RGC apoptosis without affecting the IOP. In this same model we have demonstrated that Abeta is associated with RGC apoptosis. In this study we have investigated a possible mechanism for this non-IOP effect, by studying the expression of Amyloid Beta (Abeta) and related proteins in the RGCL in relation to BMD treatment.
Using our established chronic ocular hypertension (OHT) rat model, IOP was elevated in 36 animals, with DARC (Detection of Apoptosing Retinal Cell) imaging performed at 3 and 8 weeks after IOP elevation. Animals were randomly assigned to no treatment (untreated OHT) or intraperitoneal BMD (0.1 mg/kg) at the time of IOP elevation. The IOP of both eyes in each rat was measured at regular intervals using a Tonolab Tonometer. Immunohistological analysis of Abeta (Abcam; 1:750), APP (Abcam; 1:1000), sAPPα (Covance; 1:100) and P-Bad (Ser136) (Santa Cruz; 1:500) expression was performed on sequential 5 µm thick paraffin sections from enucleated eyes (n=4 per time point), with analysis performed by measuring the average intensity of the RGCL by image processing.
As shown before, intraperitoneal Brimonidine did not significantly reduce IOP compared to control but did significantly reduce RGC apoptosis in vivo (p<0.05). The histological analysis revealed that Abeta levels in the RGCL were significantly decreased at 3 weeks in the BMD treated group compared to the untreated group (p<0.05). In contrast, sAPPα staining was significantly increased in the BMD treated group compared to the untreated group at 3 and 8 weeks (p=0.0165 and 0.00927 respectively). P-Bad (Ser136) staining was also significantly increased at 3 weeks in BMD treated animals in the RGCL (p=0.0107).
Brimondine reduces RGC apoptosis in this OHT model but the mechanism in our study appears to be associated with its down-regulation of Abeta production. This is strongly supported by the sAPPα results suggesting that BMD may promote the non-amyloidgenic pathway. It could be that BMD suppresses the caspase cascade which is implicated in APP cleavage and Abeta production. This is supported by our finding of an increase in P-Bad (Ser136). The association of Brimonidine with the Abeta pathway in glaucoma is a new finding which needs further investigation.
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