Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma

Glaucoma is a neurodegenerative disease that produces blindness. The main factor associated with this disease is an abnormally elevated intraocular pressure (IOP). To date, some attempts have been made to demonstrate the role of nucleotides modulating IOP, but never in a model of glaucoma. The DBA/2J mouse is an animal that develops the pathology spontaneously, starting from the typical rise in IOP at 9 months of age. Using this animal model, together with a control mouse, C57BL/6J, it has been possible to monitor the elevation in IOP in the glaucomatous mice and to check the ability of the dinucleotide diadenosine tetraphosphate AKA Ap(4)A to reduce IOP. The topical application of Ap(4)A when IOP is maximal (9-12 months) reduced IOP 30.6 +/- 6.6% in the DBA/2J and 17.9 +/- 4.0% in the C57BL/6J mice. Concentration response curves in both animal strains produced similar pD2 values; these being 4.9 +/- 0.5 and 5.1 +/- 0.4 for the normotensive C57BL/6J and the glaucomatous DBA/2J respectively. Antagonist studies showed differences between the control and the glaucomatous animals. In particular, the main receptor reducing IOP in the control animal was the P2Y(1) receptor and in the glaucomatous model the P2Y(6), although the participation of other P2 receptors cannot be ruled out. The long-term effect of Ap(4)A applied three times a week for 3 months showed a clear stop in the elevation of IOP in the glaucomatous model, thus indicating the possibility of using Ap(4)A as an effective compound for the treatment of glaucoma.