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Abstract #54599 Published in IGR 15-3
Regulation of intraocular pressure in mice: structural analysis of dopaminergic and serotonergic systems in response to cabergoline
Platania CB; Leggio GM; Drago F; Salomone S; Bucolo CBiochemical Pharmacology 2013; 86: 1347-1356
Elevated intraocular pressure (IOP) is the main recognized risk factor of glaucoma. To investigate the contribution of dopaminergic and serotonergic systems in IOP regulation, we used cabergoline, a mixed dopamine and serotonin agonist, in C57BL/6J WT and dopamine D₃ receptor knock-out (D₃R⁻/⁻) mice with normal eye pressure or steroid-induced ocular hypertension. Furthermore, we studied the structural basis of the cabergoline-mediated activation of the dopaminergic and serotonergic systems by molecular modeling. Topical application of cabergoline, significantly decreased, in a dose-dependent manner, the intraocular pressure in WT mice, both in an ocular normotensive group (-9, -5 and -2 mmHg with 5%, 1%, and 0.1%, respectively) and an ocular hypertensive group, with a prolonged effect in this latter group. No change of intraocular pressure was observed after topical application of cabergoline in D₃R⁻/⁻ mice. We modeled and optimized, with molecular dynamics, structures of hD₃, h5HT(1A) and h5HT(2A-C) receptors; thereafter we carried out molecular docking of cabergoline. Docking revealed that binding of cabergoline into D₃ and 5HT(1A) receptors is associated with a better desolvation energy in comparison to 5HT(2A-C) binding. In conclusion, the present study support the hypothesis that dopaminergic system is pivotal to regulate IOP and that D₃R represents an intriguing target in the treatment of glaucoma. Furthermore, the structure-based computational approach adopted in this study is able to build and refine structure models of homologous dopaminergic and serotonergic receptors that may be of interest for structure-based drug discovery of ligands, with dopaminergic selectivity or with multi-pharmacological profile, potentially useful to treat optic neuropathies.
Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, School of Medicine, University of Catania, 95125, Catania, Italy.
Full articleClassification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
3.8 Pharmacology (Part of: 3 Laboratory methods)
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
6.1.3 Factors affecting IOP (Part of: 6 Clinical examination methods > 6.1 Intraocular pressure measurement; factors affecting IOP)