Increased intraocular pressure in mice treated with dexamethasone.
OBJECTIVE
Glucocorticoids are potent modulators of the immune system and are useful in treating systemic and ocular diseases, but they can increase intraocular pressure (IOP) in susceptible persons. Steroid-induced ocular hypertension resembles several characteristics observed in primary open angle glaucoma (POAG). Elucidating genetic and environmental mechanisms impacting steroid-induced ocular hypertension may provide important insight into pathophysiological drivers of POAG. The purpose of this study was to create a mouse model of steroid-induced ocular hypertension.


METHODS
Osmotic mini-pumps delivering dexamethasone or PBS were implanted into C57BL/6J-Tyr(c-Brd) × 129S5/SvEvBrd (B6.129) mice. Repeated IOP measurements were obtained over a 4-week study using a tonometer before and after pump implantation. Body weights, complete blood counts (CBCs), and blood pressure were obtained to further characterize the model. Pharmacologic effects of timolol, latanoprost, and Y-39983 were studied in hypertensive mice.


RESULTS
Administration of dexamethasone to B6.129 hybrid mice resulted in significant increases in IOP in most animals compared with baseline or mice treated with PBS. No significant change in IOP was observed in PBS-treated mice. Interestingly, dexamethasone failed to increase IOP in a subset of mice, though steroid delivery was successful as measured using CBC analysis. Moreover, topical agents that lower IOP in normotensive mice also produced significant decreases in mice exhibiting elevated IOP in response to dexamethasone.


CONCLUSIONS
Systemic treatment with dexamethasone significantly increased IOP in most genetically heterogeneous mice used in this study. This mouse model should facilitate studies aimed at understanding mechanisms affecting steroid-induced ocular hypertension in humans.
Whitlock
N Andrew
NA
Department of Ophthalmology, Lexicon Pharmaceuticals, Inc., The Woodlands, TX 77381, USA. awhitlock@lexpharma.com
McKnight
Beth
B
Corcoran
Katie N
KN
Rodriguez
Lawrence A
LA
Rice
Dennis S
DS
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003907:Dexamethasone / Q000633:toxicity*; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000633:toxicity*; D015918:Infusion Pumps, Implantable; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009798:Ocular Hypertension / Q000139:chemically induced* / Q000188:drug therapy; D014065:Tonometry, Ocular
D000959:Antihypertensive Agents; D005938:Glucocorticoids; D003907:Dexamethasone