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Editors Selection IGR 16-4

Medical treatment: Extrascleral PG

Comment by Paul Kaufman on:

16969 Direct matrix metalloproteinase enhancement of transscleral permeability, Lindsey JD; Crowston JG; Tran A et al., Investigative Ophthalmology and Visual Science, 2007; 48: 752-755

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Prostaglandin (PG) F2α analogues administered topically to the eyes of humans and non-human primates lower intraocular pressure and are the mainstay of glaucoma treatment. Mediated by the FP receptor they lead to increased synthesis and release of various matrix metalloproteases and consequent degradation of and remodeling of collagen in the ciliary muscle, root of the iris and the sclera external to the ciliary muscle. These PG-induced changes underlie their ability to increase uveoscleral outflow, and demonstrate that the sclera itself is an active and responsive, rather than just a passive, component, of the uveoscleral pathway. The present work by Lindsey et al. (30) extends the findings, showing that PGs induce MMP gene transcription in cultured human sclera, leading to increased MMP production, seen by both Northern (mRNA) and Western (protein) blots, and increased scleral permeability. Further, incubation of human sclera with MMPs enhances scleral permeability.

MMP gene transcription induced by extrascleral placement of PG's implicate facilitation of small molecule drug or protein delivery to the glaucoma or retinal disease target tissues of the target tissues of the posterior ocular segment

This delineates the entire physiological pathway. Importantly, the authors identify another implication of their work; namely, potential enhancement of outside-to-inside scleral permeability to facilitate small molecule drug or protein delivery to the glaucoma or retinal disease target tissues of the posterior ocular segment following extrascleral placement. Knowledge of mechanisms of neuronal death and its prevention, delay or reversal is now sufficient so that we can envision glaucoma therapy directed at retinal ganglion cells, axons, and supporting cells. Strategies that facilitate getting drugs to these posterior segment targets in therapeutic concentrations thus become ever more important.

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