Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma

Abstract

Administration of glucocorticoids induces ocular hypertension in some patients. If untreated, these patients can develop a secondary glaucoma that resembles primary open-angle glaucoma (POAG). The underlying pathology of glucocorticoid-induced glaucoma is not fully understood, due in part to lack of an appropriate animal model. Here, we developed a murine model of glucocorticoid-induced glaucoma that exhibits glaucoma features that are observed in patients. Treatment of WT mice with topical ocular 0.1% dexamethasone led to elevation of intraocular pressure (IOP), functional and structural loss of retinal ganglion cells, and axonal degeneration, resembling glucocorticoid-induced glaucoma in human patients. Furthermore, dexamethasoneinduced ocular hypertension was associated with chronic ER stress of the trabecular meshwork (TM). Similar to patients, withdrawal of dexamethasone treatment reduced elevated IOP and ER stress in this animal model. Dexamethasone induced the transcriptional factor CHOP, a marker for chronic ER stress, in the anterior segment tissues, and Chop deletion reduced ER stress in these tissues and prevented dexamethasone-induced ocular hypertension. Furthermore, reduction of ER stress in the TM with sodium 4-phenylbutyrate prevented dexamethasone-induced ocular hypertension in WT mice. Our data indicate that ER stress contributes to glucocorticoid-induced ocular hypertension and suggest that reducing ER stress has potential as a therapeutic strategy for treating glucocorticoid-induced glaucoma.

Dexamethasone-Induced Ocular Hypertension in Mice

“…Therefore, it is essential to use freshly prepared formulations every 2 weeks. Consistent with other previously reported studies 13,20,22,40,45 that show DEX-induced biochemical changes in the TM, we found similar biochemical changes in TM of our mouse model after DEX-Ac treatment. The expression of fibronectin, collagen I, myocilin, and a-smooth muscle actin increased in the TM of DEXAcetreated mice compared to vehicle-treated mice.…”

“…Furthermore, the conventional outflow facility measured at 5 weeks of DEX-Ac treatment was significantly reduced in DEX-Acetreated mice by 33% compared to vehicle-treated mice, and there was a correlation between elevated IOP and decreased conventional outflow facility. These results are consistent with previous studies of GC-induced OHT, including Whitlock et al 43 and Overby et al 45 using systemic DEX delivery, as well as Zode et al 40 using topical ocular DEX treatment. Kumar et al 44 used subconjunctival delivery of triamcinolone acetonide to show decreased conventional outflow facility, but this was not correlated with IOP elevation.…”

“…Systemic DEX delivery in mice used surgical implantation of minipumps into the backs of mice, 43,45 whereas topical ocular DEX administration required administration of eye drops three times daily for multiple weeks by a trained technician. 40 We tried formulating DEX and DEX-Ac, which are not soluble in aqueous formulations and require suspension formulations. Although DEX-21-phosphate is soluble in aqueous solutions, it did not provide prolonged delivery and did not reproducibly elevate IOP when administered by periocular CF injections.…”

“…43,45 Topical DEX (0.1%) elevated the IOP by 7 to 8 mmHg at 6 weeks and was associated with loss of retinal ganglion cells and optic nerve axons, but this method requires administering eye drops three times daily for multiple weeks by a trained technician. 40 The subconjunctival triamcinolone acetonide injection reduced the aqueous outflow facility but was not able to significantly elevate IOP. 44 There is a significant need for an easy and reproducible mouse model of GC-OHT.…”

“…Both systemic and topical delivery of DEX has been shown to induce OHT in mice. 40, 43 Kumar et al 44 used subconjunctival delivery of triamcinolone acetonide in attempt to induce GC-OHT. However, these models have their benefits as well as drawbacks.…”