Purpose
To investigate the role of cabergoline, an anti-Parkinson agent, on intraocular pressure regulation using wild type (WT) and D3R knockout (KO D3R-/-) mice. Further, to assess the precise role of dopaminergic and serotonergic systems on IOP modulation, a computational structure-based study was also carried out.
Methods
WT and KO D3R-/- C57BL6J mice were used. Both mice were used with normal eye pressure or steroid-induced ocular hypertension. All animals were treated according to the ARVO statement for the use of animals in ophthalmic and vision research. Mice were treated with cabergoline at different concentration (0.01%, 0.1%, 1%, 5%) and IOP measured by tonometer. We modeled and optimized the structures of hD3, h5-HT1a, h5-HT2a, h5-HT2b, h5-HT2c receptors by homology modeling and by molecular dynamics respectively. Next we docked, using AutoDock 4.2, cabergoline into the binding sites of these receptors, and rescored the binding modes with DSX-score.
Results
Topical application of cabergoline significantly (p<0.01) decreased, in a dose-dependent manner, the intraocular pressure in WT mice both in an ocular normotensive group and an ocular hypertensive group. No change of intraocular pressure was observed after topical application of cabergoline in KO D3R-/- mice. High correlation (R2=0.92, Pearson=0.94 p=0.02) of DSX-scores compared to experimental Ki was obtained. Cabergoline binds better to the D3 receptor than to the analyzed serotonergic receptors both in computational and experimental studies.
Conclusions
The present study highlighted the dopaminergic system, particularly D3R subtype, as the major target of cabergoline to decrease IOP over the serotonergic system with relevant implications for structure-based drug discovery of selective dopaminergic ligands.
Keywords: 568 intraocular pressure •
502 dopamine •
675 receptors: pharmacology/physiology