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Ayan Chatterjee, Guadalupe Villarreal, Dong-Jin Oh, Douglas J Rhee; Treatment with AICAR decreases intraocular pressure in perfused ex vivo human anterior segments. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3542.
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Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide and elevated intraocular pressure (IOP) is the only rigorously tested modifiable risk factor. IOP is a function of aqueous humor production in the ciliary body and outflow facility through the eye’s primary drain, the trabecular meshwork (TM). AMP-activated protein kinase (AMPK) has been shown to regulate extracellular matrix (ECM) turnover and cytoskeletal organization in primary cultured human TM cells. Mice who lack the gene encoding the catalytic alpha-2 subunit of AMPK have increased intraocular pressure as well as decreased aqueous humor outflow facility.
In order to examine the effects of AMPK activation on IOP, a previously published system of perfused constant flow ex vivo human anterior segments was employed. All donor pairs of eyes (aged 71, 82, and 84 years) were obtained within 24 hours after death from National Disease Research Interchange. No donors were known to have a history of glaucoma or other ocular disorder. After a process that included removal of vitreous, lens, and iris, anterior segments were rinsed thoroughly with culture media and mounted into custom plexiglass culture chambers. Anterior segments were perfused at a constant flow rate of 2.5 µL/min. Perfused tissue was allowed to equilibrate at 37oC and 5% CO2 until a stable baseline IOP was achieved. Then one eye was perfused with 2.5 µl of 1x PBS per 1 mL of ex vivo media as a control while the opposite eye received 2.5 µL of 200 mM 5-amino-1-β-Dffff-ribofuranosyl-imidazole-4-carboxamide (AICAR)—an adenosine analog and AMPK activator—per 1 mL of ex vivo media.
Treatment with 2.5µL of 200mM AICAR in 1mL of ex vivo media results in a mean decrease in IOP of 18.54±1.78% by day 7 (p<0.05 for paired t-tests; n=3), compared with paired opposite eye controls.
Our findings in perfused ex vivo human anterior segments suggests that AMPK is a regulatory element for IOP and possible novel therapeutic target in POAG. Assessing the effects of topical administration of AMPK-activating agents in an in vivo animal model will yield a more complete understanding of the role of AMPK signaling in regulating aqueous humor outflow and may further strengthen the possibility of future therapeutic applications in humans.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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