Iok-Hou Pang
Glaucoma Research, Alcon Research, Ltd.
6201 South Freeway, Fort Worth, TX 76134, USA

Purpose. A major risk factor of glaucoma is elevated intraocular pressure (IOP).  Although the exact etiology of ocular hypertension remains unclear, an excessive accumulation of extracellular matrix (ECM) in the trabecular meshwork ?, which hinders the outflow of aqueous humor, likely contributes to the symptom.  Matrix metalloproteinases (MMPs), when activated, can hydrolyze many types ECM and should improve aqueous outflow.  We searched for compounds that increase MMP in the TM, and tested selected compounds for their effects on IOP. 
Methods. ELISA was used to evaluate expression of MMP by cultured human TM cells. Drug effects on IOP were assessed by human ocular perfusion organ culture.
Results.  Various compounds were shown to increased MMP-3 production in TM cells. Among these compounds, two were tested in the perfused human donor eyes.  In non-glaucomatous eyes, tert-butylhydroquinone (tBHQ; 10 ?M) increased outflow facility.  Its effect was statistically significant (p < 0.05; n = 6) on 1- 4 days after start of perfusion.  At Day 4, the increase in outflow was approximately 60% above the vehicle-treated contralateral eyes.  Perfusates of the tBHQ-treated tissues had elevated proMMP-3 levels. Maximal increase (approximately 200% of control) occurred at Day 2 after perfusion.  In glaucomatous eyes, tBHQ also increased the aqueous outflow facility by approximately 60% at Day 3 after perfusion.  Another compound, propentofylline (PPF; 100 ?M), also significantly (p < 0.05) enhanced outflow facility of non-glaucomatous eyes at 1-3 days after treatment started.  Similar to tBHQ, PPF significantly increased proMMP-3 concentration in the perfusate by 20-40% after the initiation of treatment (p < 0.05).
Conclusions.  To improve aqueous outflow by the hydrolysis of excessive ECM in the TM has been proposed for some time.  Until recently, no clinically practical methods were available to accomplish it.  The small molecules described in this study show the conceptual feasibility of this approach.  Their mechanism of action is different from most of the current glaucoma drugs and may allow them to have an additive effect with current medications.  Hence, these results suggest that the induced hydrolysis of ECM in the TM with small molecules may provide a future useful therapy for glaucoma.

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