The role of dinucleoside polyphosphates on the ocular surface and other eye structures

Abstract

a b s t r a c tDinucleoside polyphosphates comprises a group of dinucleotides formed by two nucleosides linked by a variable number of phosphates, abbreviated NpnN (where n represents the number of phosphates). These compounds are naturally occurring substances present in tears, aqueous humour and in the retina. As the consequence of their presence, these dinucleotides contribute to many ocular physiological processes. On the ocular surface, dinucleoside polyphosphates can stimulate tear secretion, mucin release from goblet cells and they help epithelial wound healing by accelerating cell migration rate. These dinucleotides can also stimulate the presence of proteins known to protect the ocular surface against microorganisms, such as lysozyme and lactoferrin. One of the latest discoveries is the ability of some dinucleotides to facilitate the paracellular way on the cornea, therefore allowing the delivery of compounds, such as antiglaucomatous ones, more easily within the eye. The compound Ap 4 A has been described being abnormally elevated in patient's tears suffering of dry eye, Sjogren syndrome, congenital aniridia, or after refractive surgery, suggesting this molecule as biomarker for dry eye condition. At the intraocular level, some diadenosine polyphosphates are abnormally elevated in glaucoma patients, and this can be related to the stimulation of a P2Y 2 receptor that increases the chloride efflux and water movement in the ciliary epithelium. In the retina, the dinucleotide dCp 4 U, has been proven to be useful to help in the recovery of retinal detachments. Altogether, dinucleoside polyphosphates are a group of compounds which present relevant physiological actions but which also can perform promising therapeutic benefits.

Understanding the Presence and Roles of Ap4A (Diadenosine Tetraphosphate) in the Eye

“…Ap 4 A increases the mucin production by goblet cells but in lesser amounts than Up 4 U. 41 Ap 4 A is also involved in protein secretion in tears, mainly lysozyme and lactoferrin. Lysozyme constitutes around 20%-40% of the total tear protein 42 and has the capacity to dissolve gram-negative bacterial walls by the enzymatic digestion of mucopolysaccharides.…”

Mutations inKARScause a severe neurological and neurosensory disease with optic neuropathy

“…Among the cellular functions of this P-S207 KARS, its role in the production of the second messenger Ap4A has already been studied in the eye in various conditions such as a biomarker for raised intraocular pressure in glaucoma were higher levels of Ap4A were observed as well as in the tears from patients suffering of other ocular pathologies, as dry eye and congenital aniridia (Castany et al, 2011;Guzman-Aranguez, Crooke, Peral, Hoyle, & Pintor, 2007;Peral et al, 2006;Peral et al, 2015). The potential therapeutic effects of dinucleotide polyphosphates have been proposed for various eye conditions including regulation of intraocular pressure in a mouse model (Carracedo et al, 2016;Crooke, Guzman-Aranguez, Carracedo, de Lara, & Pintor, 2017). In this respect, it is interesting to underline that our patient presented with a nonglaucomatous optic neuropathy developed in the context of downregulation of KARS effectors suggesting that Ap4A supplementation could have been protective if Ap4A deficiency had been proven.…”

Synthetic Strategies for Dinucleotides Synthesis

“…On the other hand, the P2Y2 receptor responds to both ATP and UTP. Natural dinucleoside tetraphosphates Ap4A and Up4U have agonist potencies comparable to those of ATP and UTP at P2Y2 receptors [31][32][33][34]. It should be noted that dinucleotides are more resistant to hydrolysis than their parent mononucleotides, but are generally less potent, and lack selectivity in many cases [9,23].…”

“…DED results from either decreased aqueous tear production (aqueous tear-deficient dry eye) or increased tear evaporation (evaporative dry eye), or both. Several studies demonstrated the presence of P2X and P2Y receptors in ocular tissues (retina, ciliary body, and lens), and indicated that P2Y 2 receptors may be the main subtype of purinergic receptor located at the ocular surface [33]. Clinical data show that diquafosol tetrasodium improves ocular surface staining and may improve tear film volume and stability.…”