Abstract
Multidrug resistance protein 4 (MRP4; ABCC4) is a member of the MRP/ATP-binding cassette family serving as a transmembrane transporter involved in energy-dependent efflux of anticancer/antiviral nucleotide agents and of physiological substrates, including cyclic nucleotides and prostaglandins (PGs). Phenotypic consequences of mrp4 deficiency were investigated using mrp4-knockout mice and derived immortalized mouse embryonic fibroblast (MEF) cells. Mrp4 deficiency caused decreased extracellular and increased intracellular levels of cAMP in MEF cells under normal and forskolin-stimulated conditions. Mrp4 deficiency and RNA interference-mediated mrp4 knockdown led to a pronounced reduction in extracellular PGE(2) but with no accumulation of intracellular PGE(2) in MEF cells. This result was consistent with attenuated cAMP-dependent protein kinase activity and reduced cyclooxygenase-2 (Cox-2) expression in mrp4-deficient MEF cells, suggesting that PG synthesis is restrained along with a lack of PG transport caused by mrp4 deficiency. Mice lacking mrp4 exhibited no outward phenotypes but had a decrease in plasma PGE metabolites and an increase in inflammatory pain threshold compared with wild-type mice. Collectively, these findings imply that mrp4 mediates the efflux of PGE(2) and concomitantly modulates cAMP mediated signaling for balanced PG synthesis in MEF cells. Abrogation of mrp4 affects the regulation of peripheral PG levels and consequently alters inflammatory nociceptive responses in vivo.
Highlights
One alternative approach to trabecular meshwork (TM) drug delivery, which can avoid the cornea toxicity, would be to deliver drugs through the sclera
One of the main risk factors for primary openangle glaucoma is elevated intraocular pressure (IOP); and lowering IOP is the only effective therapy currently available [3]. It has been known for nearly 40 years that the locus of this hydrodynamic disease resides in the trabecular meshwork (TM) outflow pathway [4,5,6], but there are currently no specific treatments targeted to the TM [2]
Most potential TM drugs, e.g., ethacrynic acid (ECA) that influences the cytoskeleton in TM cells, are currently delivered topically, which is limited by the induced corneal toxicity observed at the drug dosage required for adequate transport across the cornea [7,8]
Summary
Purpose: One of the current limitations in developing novel glaucoma drugs that target the trabecular meshwork (TM) is the induced corneal toxicity from eyedrop formulations. To avoid the corneal toxicity, an alternative approach would be to deliver TM drugs through the sclera To this end, we quantified ex vivo diffusion coefficient of a potential TM drug, ethacrynic acid (ECA), and investigated mechanisms of ECA transport in the sclera. One of the main risk factors for primary openangle glaucoma is elevated intraocular pressure (IOP); and lowering IOP is the only effective therapy currently available [3] It has been known for nearly 40 years that the locus of this hydrodynamic disease resides in the trabecular meshwork (TM) outflow pathway [4,5,6], but there are currently no specific treatments targeted to the TM [2]. Most potential TM drugs, e.g., ethacrynic acid (ECA) that influences the cytoskeleton in TM cells, are currently delivered topically, which is limited by the induced corneal toxicity observed at the drug dosage required for adequate transport across the cornea [7,8]
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