Lipid mediators regulating intraocular pressure and therapeutic target for glaucoma

抄録

Glaucoma is the second leading cause of blindness in the world next to cataract, and will be the first in future. Intraocular pressure (IOP) is the most important physiological mechanism to maintain the visual function of the retina and the optic nerve for the visual cortex. Both low and high IOP affect the structure of the retina and optic nerve head leading to the obstruction of the axon and blood flow. The pathogenesis of glaucoma is a progressive optic nerve atrophy at the optic disc by high and unstable IOP. Thus, IOP reduction is the only and most effective therapy for glaucoma, and many IOP-lowering drugs are currently available. Nevertheless, the physiological mechanism of IOP regulation and the pathogenesis of IOP increase in glaucoma have not been fully understood.

So far, we have investigated the biological function of lipid mediators in ocular diseases, especially in glaucoma. First, prostaglandins and prostanoid receptors were found to be quite important for IOP regulation. FP receptor is indispensable to reduce IOP by the current prostaglandin-related drugs, but EP3 is also additive function with FP to lower IOP. In addition, it was found that EP2 and EP4 agonists reduced IOP in the different mechanism of action from FP. Now, FP/EP3 dual agonist and EP2 agonist has been developed as new targets for glaucoma treatment. Next, we have recently found lysophosphatidic acid (LPA) and its producing enzyme, autotaxin (ATX), have an important role in IOP regulation. In clinical samples of glaucoma, LPA and ATX significantly increased dependent of the level of IOP, glaucoma subtypes categorized by the causes of pre-existing ocular diseases, and the failure rate of filtration surgery aiming for IOP reduction. Especially, in point of the regulation of extracellular matrix in the aqueous outflow pathway and wound scarring of the related tissue, it is possible that LPA and ATX had an important pathological role. LPA-ATX pathway will be a new biomarker to identify the pathogenesis of glaucoma, and a new therapeutic target for glaucoma.