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Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma

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Abstract

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 Ap4A to reduce IOP. The topical application of Ap4A 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 P2Y1 receptor and in the glaucomatous model the P2Y6, although the participation of other P2 receptors cannot be ruled out. The long-term effect of Ap4A 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 Ap4A as an effective compound for the treatment of glaucoma.

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Acknowledgements

This work has been supported by the Spanish Ministry of Economy and Competitiveness SAF2013-44416-R, SAF2016-77084R and RETICS R12/0034/0003. B. F and A. M-Á. are fellowship holders of Universidad Complutense de Madrid. We thank Penny Rollinson for her help in the preparation of this manuscript.

Author information

Correspondence to Jesús Pintor.

Ethics declarations

The animal treating procedures were approved by the Committee for the Welfare of Laboratory Animals of the University Complutense de Madrid and the Comunidad de Madrid laws and experiments conducted in the accordancewith the guidelines of the European Community Council (Directive 86/609/EEC) and the ARVO Statment for the use of Animals in Ophthalmic and Vision Research. All efforts were made to minimize the number of animals used and their suffering.

Conflict of interest

Begoña Fonseca declares that she has no conflict of interest.

AlejandroMartínez-Águila declares that he has no conflict of interest.

María J. Pérez de Lara declares that she has no conflict of interest.

Jesús Pintor declares that he has no conflict of interest.

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Fonseca, B., Martínez-Águila, A., de Lara, M.J.P. et al. Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma. Purinergic Signalling 13, 171–177 (2017). https://doi.org/10.1007/s11302-016-9547-y

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Keywords

  • Ap4A
  • Diadenosine tetraphosphate
  • DBA/2 J
  • Glaucoma
  • P2 receptors