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Abram Akopian, Sandeep Kumar, Hari Ramakrishnan, Stewart A Bloomfield; Delayed blockade of retinal gap junctions still promotes neuroprotection in a mouse model of glaucoma. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6141.
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We previously reported that pharmacological blockade of retinal gap junctions (GJs) prior to induction of elevated intraocular pressure (IOP) offers significant neuroprotection in a mouse model of glaucoma (Akopian et al., 2017, J. Clin. Invest.). Here, we examined the potential long-term neuroprotective action of GJ blockade initiated at various time points after the onset of elevated IOP to simulate treatment in the clinical setting
Experimental glaucoma was induced in C57BL/6 mice by intracameral injections of polystyrene microbeads to raise IOP. At 8 weeks after initial microbead injection, structural and functional retinal changes were evaluated by: ganglion (RGC) and amacrine (AC) cell counts; measure of active gliosis by GFAP immunolabeling; measure of Cx36 immunolabeling in the IPL; and ERG recordings. Comparisons were made with results from animals in which retinal GJs were blocked by administration of meclofenamic acid (MFA) by osmotic minipumps placed 2 or 4 weeks after initial microbead injection. Statistical significance was determined using Student’s t-test
Using specific neuronal markers, we found that delivery of MFA 2 or 4 weeks after induction of glaucoma with microbead injection significantly reduced the loss of both RGCs and ACs as compared to that seen in control glaucomatous eyes. Likewise, application of MFA 2 or 4 weeks after microbead injection suppressed active gliosis assayed by GFAP expression as compared to levels seen in control glaucomatous retinas. Induction of glaucoma resulted in an upregulation of Cx36 protein in the IPL of glaucomatous retinas. However, application of MFA delayed for 2 or 4 weeks after microbead injection suppressed the upregulation. Finally, we found that delayed blockade of GJs still preserved retinal function as indicated by amplitude measures for STRs and OPs components of the ERG that were not statistically different from those recorded in control animals
Our findings indicate that delayed blockade of retinal GJs still provided significant structural and functional neuroprotection of glaucomatous eyes. These data reinforce the idea that GJs can serve as effective therapeutic targets for novel treatments of patients with ongoing glaucoma
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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