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 b 2 /a 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 b 2 -adrenergic receptor downregulation as well as a 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 b-adrenergic receptor (timolol) and a selective a 2 -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% 6 5.8% or 16.75% 6 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% 6 5.21% or 39.07% 6 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% 6 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 a 2 -adrenergic receptor agonists but also of b-adrenergic antagonists.

Effect of Melatonin and 5-Methoxycarbonylamino-N-Acetyltryptamine on the Intraocular Pressure of Normal and Glaucomatous Mice

“…Long-term effects of melatonin and 5-MCA-NAT have been described in the eye. These effects are mainly due to the modulation of carbonic anhydrase and regulation of adrenergic receptor gene expression (Crooke et al, 2011(Crooke et al, , 2012b(Crooke et al, , 2013. Altogether, we have demonstrated not only the acute and long-term effect of 5-MCA-NAT on IOP but also that 3-month treatment in a glaucoma situation helps ameliorate the elevation of IOP in our mouse model.…”

“…This molecule and some of its analogs, such as 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT), produce a marked reduction in IOP in normotensive and hypertensive conditions (Serle et al, 2004;Crooke et al, 2013;Martínez-Águila et al, 2013;Pescosolido et al, 2015).…”

The role and therapeutic potential of melatonin in age‐related ocular diseases

“…This ocular hypotensive effect seems to be mediated by ciliary body receptors (MT 2 and an unidentified receptor classically named MT 3 ) and final inhibition of ciliary chloride secretion . Furthermore, melatonergic compounds provide a sustained reduction in IOP through regulation of ciliary genes expression and potentiate the hypotensive action of classic antiglaucomatous drugs such as timolol and brimonidine …”

“…In addition to its pleiotropic actions, melatonin possesses an advantage over other possible candidates due to its amphiphilic character, which enables it to enter any fluid, cell, or subcellular structures including mitochondria . Furthermore, Crooke and colleagues have demonstrated that the melatonin combination with classical antiglaucoma drugs potentiates their effects on animals . Therefore, the combination of melatonin with other drugs could improve the efficacy of classical drugs in patients with the mentioned diseases.…”

“…29,31,222,223 Furthermore, melatonergic compounds provide a sustained reduction in IOP through regulation of ciliary genes expression and potentiate the hypotensive action of classic antiglaucomatous drugs such as timolol and brimonidine. [224][225][226] Belforte and colleagues have proved in a model of chronic pressure-induced glaucoma that melatonin also increases retinal antioxidant defenses (eg, it increases SOD activity and glutathione level; Figure 2). 227 It also reduces lipid peroxidation, NOS activity, the loss of retinal ganglion cells, and the extracellular glutamate level (increasing glutamate uptake as well as glutamine synthetase activity and reducing glutaminase activity; Figure 2).…”