Melatonin and its analog 5-methoxycarbonylamino-N-acetyltryptamine potentiate adrenergic receptor-mediated ocular hypotensive effects in rabbits: significance for combination therapy in glaucoma.

Abstract

Melatonin is currently considered a promising drug for glaucoma treatment because of its ocular hypotensive and neuroprotective effects. We have investigated the effect of melatonin and its analog 5-methoxycarbonylamino-N-acetyltryptamine, 5-MCA-NAT, on β₂/α(2A)-adrenergic receptor mRNA as well as protein expression in cultured rabbit nonpigmented ciliary epithelial cells. Quantitative polymerase chain reaction and immunocytochemical assays revealed a significant β₂-adrenergic receptor downregulation as well as α(2A)-adrenergic receptor up-regulation of treated cells (P < 0.001, maximal significant effect). In addition, we have studied the effect of these drugs upon the ocular hypotensive action of a nonselective β-adrenergic receptor (timolol) and a selective α₂-adrenergic receptor agonist (brimonidine) in normotensive rabbits. Intraocular pressure (IOP) experiments showed that the administration of timolol in rabbits pretreated with melatonin or 5-MCA-NAT evoked an additional IOP reduction of 14.02% ± 5.8% or 16.75% ± 5.48% (P < 0.01) in comparison with rabbits treated with timolol alone for 24 hours. Concerning brimonidine hypotensive action, an additional IOP reduction of 29.26% ± 5.21% or 39.07% ± 5.81% (P < 0.001) was observed in rabbits pretreated with melatonin or 5-MCA-NAT when compared with animals treated with brimonidine alone for 24 hours. Additionally, a sustained potentiating effect of a single dose of 5-MCA-NAT was seen in rabbits treated with brimonidine once daily for up 4 days (extra IOP decrease of 15.57% ± 5.15%, P < 0.05, compared with brimonidine alone). These data confirm the indirect action of melatoninergic compounds on adrenergic receptors and their remarkable effect upon the ocular hypotensive action mainly of α₂-adrenergic receptor agonists but also of β-adrenergic antagonists.

• Authors: Almudena Crooke, Fernando Huete-Toral, Alejandro Martínez-Águila, Alba Martín-Gil, Jesús Pintor
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 346 Issue 1 Pg. 138-45 (Jul 2013) ISSN: 1521-0103 [Electronic] United States
• PMID: 23591996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-methoxycarbonylamino-N-acetyltryptamine
• Adrenergic Agonists
• Adrenergic alpha-2 Receptor Agonists
• Adrenergic beta-Antagonists
• Nerve Tissue Proteins
• Neuroprotective Agents
• Ophthalmic Solutions
• Receptors, Adrenergic, alpha-2
• Receptors, Adrenergic, beta-2
• Tryptamines
• Melatonin

Topics

• Adrenergic Agonists (adverse effects, pharmacology, therapeutic use)
• Adrenergic alpha-2 Receptor Agonists (chemistry, pharmacology, therapeutic use)
• Adrenergic beta-Antagonists (chemistry, pharmacology, therapeutic use)
• Animals
• Cells, Cultured
• Ciliary Body (cytology, drug effects, metabolism)
• Drug Synergism
• Epithelial Cells (metabolism)
• Gene Expression Regulation (drug effects)
• Glaucoma (drug therapy, physiopathology)
• Intraocular Pressure (drug effects)
• Male
• Melatonin (adverse effects, analogs & derivatives, pharmacology, therapeutic use)
• Nerve Tissue Proteins (agonists, antagonists & inhibitors, genetics, metabolism)
• Neuroprotective Agents (adverse effects, pharmacology, therapeutic use)
• Ocular Hypotension (chemically induced)
• Ophthalmic Solutions (pharmacology)
• Rabbits
• Receptors, Adrenergic, alpha-2 (chemistry, genetics, metabolism)
• Receptors, Adrenergic, beta-2 (chemistry, genetics, metabolism)
• Tryptamines (adverse effects, pharmacology, therapeutic use)