ergoline and Ocular-Hypertension

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.

Topics: Animals; Cabergoline; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Humans; Intraocular Pressure; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Docking Simulation; Molecular Dynamics Simulation; Ocular Hypertension; Protein Conformation; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Receptors, Dopamine D3; Sequence Alignment

The aims of the current studies were to determine the in vitro and in vivo ocular and non-ocular pharmacological properties of cabergoline using well documented receptor binding, cell-based functional assays, and in vivo models. Cabergoline bound to native and/or human cloned serotonin-2A/B/C (5HT(2A/B/C)), 5HT(1A), 5HT(7), alpha(2B), and dopamine-2/3 (D(2/3)) receptor subtypes with nanomolar affinity. Cabergoline was an agonist at human recombinant 5HT(2), 5HT(1A) and D(2/3) receptors but an antagonist at 5HT(7) and alpha(2) receptors. In primary human ciliary muscle (h-CM) and trabecular meshwork (h-TM) cells, cabergoline stimulated phosphoinositide (PI) hydrolysis (EC(50)=19+/-7 nM in TM; 76 nM in h-CM) and intracellular Ca(2+) ([Ca(2+)](i)) mobilization (EC(50)=570+/-83 nM in h-TM; EC(50)=900+/-320 nM in h-CM). Cabergoline-induced [Ca(2+)](i) mobilization in h-TM and h-CM cells was potently antagonized by a 5HT(2A)-selective antagonist (M-100907, K(i)=0.29-0.53 nM). Cabergoline also stimulated [Ca(2+)](i) mobilization more potently via human cloned 5HT(2A) (EC(50)=63.4+/-10.3 nM) than via 5HT(2B) and 5HT(2C) receptors. In h-CM cells, cabergoline (1 microM) stimulated production of pro-matrix metalloproteinases-1 and -3 and synergized with forskolin to enhance cAMP production. Cabergoline (1 microM) perfused through anterior segments of porcine eyes caused a significant (27%) increase in outflow facility. Topically administered cabergoline (300-500 microg) in Dutch-belted rabbit eyes yielded 4.5 microMM and 1.97 microM levels in the aqueous humor 30 min and 90 min post-dose but failed to modulate intraocular pressure (IOP). However, cabergoline was an efficacious IOP-lowering agent in normotensive Brown Norway rats (25% IOP decrease with 6 microg at 4h post-dose) and in conscious ocular hypertensive cynomolgus monkeys (peak reduction of 30.6+/-3.6% with 50 microg at 3h post-dose; 30.4+/-4.5% with 500 microg at 7h post-dose). In ketamine-sedated monkeys, IOP was significantly lowered at 2.5h after the second topical ocular dose (300 microg) of cabergoline by 23% (p<0.02) and 35% (p<0.004) in normotensive and ocular hypertensive eyes, respectively. In normotensive eyes, cabergoline increased uveoscleral outflow (0.69+/-0.7 microL/min-1.61+/-0.97 microL/min, n=13; p<0.01). However, only seven of the eleven ocular hypertensive monkeys showed significantly increased uveoscleral outflow. These data indicate that cabergoline's most prominent agonist activity

Topics: Animals; Antihypertensive Agents; Aqueous Humor; Biological Availability; Cabergoline; Calcium; Cats; Cells, Cultured; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Drug Evaluation, Preclinical; Ergolines; Humans; Intraocular Pressure; Macaca fascicularis; Ocular Hypertension; Rabbits; Rats; Species Specificity

Although it has been suggested that ergot derivatives may play a role in antiglaucoma therapy, little attention has been paid to the ocular hypotensive action of these drugs. Having previously reported that topical natural ergot alkaloids ergocristine alpha-ergocryptine and ergocornine dose-dependently reduce intraocular pressure in ocular normotensive and alpha-chymotrypsin-induced ocular hypertensive rabbits, the aim of the present work was to compare the effect of ergocristine, alpha-ergocryptine and ergocornine on the intraocular pressure and aqueous humor dynamics in ocular normotensive and alpha-chymotrypsin-induced ocular hypertensive rabbits, in order to further explore the ocular actions of these compounds.. Experiments were conducted in albino ocular normotensive and hypertensive rabbits by intracameral injection of alpha-chymotrypsin. Intraocular pressure responses to drug vehicle and seven different doses of topical natural ergot alkaloids were examined, in order to obtain dose-response relationships for comparing the intraocular pressure-lowering effect and potency of these drugs. Tonographies were also performed to ascertain the actions of natural ergot alkaloids on aqueous humor dynamics.. All natural ergot alkaloids tested reduced intraocular pressure in a dose-related fashion. The ocular hypotensive effect was greater in alpha-chymotrypsin-induced ocular hypertensive rabbits for the three compounds tested. All natural ergot alkaloids tested decreased both tonographic outflow facility and, to a greater extent, aqueous humor inflow in ocular normotensive and in alpha-chymotrypsin-induced ocular hypertensive rabbits.. Taken together, our data suggest that these compounds decrease both tonographic outflow facility and, to a greater extent, aqueous humor inflow, which explains their final effect in ocular normotensive and in alpha-chymotrypsin-induced ocular hypertensive rabbits. Reductions in aqueous humor inflow observed after topical application of natural ergot alkaloids in alpha-chymotrypsin-induced ocular hypertensive rabbits can only be explained by a marked inhibition of active secretion of aqueous humor, since processes involved in aqueous humor formation may probably be altered after alpha-chymotrypsin injection.

Topics: Administration, Topical; Animals; Aqueous Humor; Chymotrypsin; Disease Models, Animal; Dose-Response Relationship, Drug; Ergolines; Ergot Alkaloids; Intraocular Pressure; Ocular Hypertension; Rabbits; Tonometry, Ocular

We previously reported that topical natural ergot alkaloids ergocristine, alpha-ergocryptine and ergocornine dose-dependently reduce intraocular pressure in ocular normotensive rabbits, most likely by decreasing aqueous humor inflow. In the present study, the effects of these compounds on intraocular pressure and aqueous humor dynamics in a rabbit model for ocular hypertension were assessed.. Experiments were conducted in albino rabbits made ocular hypertensive by intracameral injection of alpha-chymotrypsin. Intraocular pressure responses to drug vehicle and seven different doses of topical natural ergot alkaloids were examined in order to obtain dose-response relationships for comparing the intraocular pressure-lowering effect and potency of these drugs. Tonographies were also performed to ascertain the actions of natural ergot alkaloids on aqueous humor dynamics in alpha-chymotrypsin-induced ocular hypertensive rabbits.. Topical application of the natural ergot alkaloids ergocristine, alpha-ergocryptine and ergocornine lowered intraocular pressure in alpha-chymotrypsin-induced ocular hypertensive rabbits in a dose-related fashion, with ergocristine displaying the greatest intraocular pressure-lowering effect. Tonographic studies revealed a decrease in the tonographic outflow facility following topical application of natural ergot alkaloids, although only the effects of both ergocristine and alpha-ergocryptine reached statistical significance. All natural ergot alkaloids tested significantly reduced the calculated aqueous humor inflow.. This study suggests that the natural ergot alkaloids ergocristine, alpha-ergocryptine and ergocornine effectively decrease intraocular pressure in the alpha-chymotrypsin-induced model of ocular hypertension. Since these compounds reduce the tonographic aqueous humor outflow facility, their final ocular antihypertensive effect appears to result from a remarkable reduction of the aqueous humor inflow.

Topics: Administration, Topical; Animals; Aqueous Humor; Chymotrypsin; Dose-Response Relationship, Drug; Ergolines; Intraocular Pressure; Ocular Hypertension; Ophthalmic Solutions; Rabbits; Tonometry, Ocular

LY141865 (LY), an ergoline derivative, was investigated for ocular effects in rabbits and monkeys. LY lowered intraocular pressure (IOP) bilaterally in monkeys and rabbits, prevented the bilateral rise in IOP caused by oral waterloading in rabbits and slowed the rate of IOP recovery bilaterally in rabbits. The ocular hypotensive activity of LY in rabbits was inhibited by sympathectomy and pretreatment with sulpiride. Since LY has cardiovascular effects that are centrally mediated, ocular responses may also be mediated, in part, by an action in the CNS.

Topics: Animals; Cebus; Dopamine Agents; Ergolines; Eye; Intraocular Pressure; Male; Mydriatics; Ocular Hypertension; Pupil; Quinpirole; Rabbits; Sulpiride; Sympathectomy, Chemical

Dopamine (DA1 and DA2) receptors have been demonstrated functionally in the anterior segment of the eye. Previous results have indicated that bromocriptine, a relatively selective DA2 agonist, can lower intraocular pressure (IOP) in laboratory animals as well as in normal and glaucomatous humans. Other ergoline derivatives (pergolide, lergotrile, LY141865) have also been demonstrated to lower IOP in laboratory animals. Cianergoline, a new ergoline derivative, was tested for: 1) ocular hypotensive activity in normal and sympathectomized (SX) rabbits and in normal capuchin monkeys, 2) inhibition of induced ocular hypertension by waterloading in rabbits and 3) suppression of contractions of the cat nictitating membrane (CNM) elicited by electrical stimulation of sympathetic nerves and by intraarterial (i.a.) injection of norepinephrine (NE). Topically administered cianergoline (0.022-0.22 mg) produced dose-related, unilateral ocular hypotension in normal but not in SX rabbits. In addition, cianergoline (0.5 mg) produced a slight reduction of IOP in capuchin monkeys. There were no significant effects on iris function in rabbits, however, miosis did occur in the monkeys. Cianergoline (0.22mg) suppressed ocular hypertension induced by waterloading in rabbits, and this effect was antagonized by metoclopramide, a relatively selective DA2 antagonist. Cianergoline (1-333 micrograms, i.a.) also produced dose-related inhibition of neuronally mediated contractions of the CNM. Cianergoline inhibited low frequency (2 & 4 Hz) contractile responses of the CNM more than high frequency (6 & 8 Hz) responses. Contractions of the CNM caused by i.a. NE were also inhibited by higher concentrations of cianergoline. These data demonstrate that cianergoline, like bromocriptine, can lower IOP and that the predominant mechanism involves inhibition of sympathetic neuronal function at prejunctional (DA2) and postjunctional (alpha 1) adrenoceptors.

Topics: Animals; Cats; Cebus; Decerebrate State; Dose-Response Relationship, Drug; Ergolines; Female; Hyperemia; Intraocular Pressure; Male; Muscle Contraction; Neural Inhibition; Neurons; Nictitating Membrane; Ocular Hypertension; Rabbits; Sclera; Sympathectomy; Sympathetic Nervous System