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Abstract #22058 Published in IGR 10-4
Latanoprost-induced changes in rat intraocular pressure: Direct or indirect?
Husain S; Yates PW; Crosson CEJournal of Ocular Pharmacology and Therapeutics 2008; 24: 367-372
INTRODUCTION: The topical application of prostaglandin F(2α) (FP)-receptor agonists has been shown to significantly lower intraocular pressure (IOP) in humans and is now considered the first-line treatment for ocular hypertension. Despite the prominent role FP-receptor agonists play in the treatment of glaucoma, our understanding of how these agents lower IOP remains incomplete. The present study was designed to evaluate the role of matrix metalloproteinase (MMP) activation and the cytokine, tumor necrosis factor alpha (TNF-α), in latanoprost-induced changes in IOP. METHODS: Changes in IOP following an acute topical administration of latanoprost (60 ng) in normotensive Brown Norway rats were evaluated by means of a commercially available rebound tonometer. To examine the role of MMPs and TNF-α in this response, the rats were pretreated with a broad-spectrum MMP inhibitor, GM-6001 (100 μg), or the TNF-α inhibitor, thalidomide (25 μg). RESULTS: The topical administration of latanoprost (60 ng) alone produced a biphasic change in ipsilateral IOP: an initial hypertension (4.21 ± 0.52), followed by a prolonged hypotension (-4.79 ± 0.65). In rats, pretreatment with GM-6001 blocked the latanoprost-induced reduction in IOP but did not prevent the initial rise in IOP. Pretreatment with thalidomide also blocked the ocular hypotension induced by latanoprost; however, thalidomide pretreatment enhanced the duration of the initial hypertension. CONCLUSIONS: These results provide evidence that the secretion and activation of MMPs and the release of TNF-α play a central role in the ocular hypotension induced by FP-agonists. The administration of FP-agonists appears to lower IOP directly by inducing the activation of MMPs within the ciliary body, leading to improved uveoscleral outflow and indirectly through the release of TNF within the ciliary body. Secreted TNF-α may then activate TNF-receptors in the uvea and trabecular meshwork, increasing both uveoscleral and conventional outflow.
Dr. S. Husain, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, 167 Ashley Avenue, Charleston, SC 29425, USA. husain@musc.edu
