Melatonin analogue agomelatine reduces rabbit's intraocular pressure in normotensive and hypertensive conditions

Martínez-Águila, Alejandro; Fonseca, Begoña; Bergua, Antonio; Pintor, Jesús

doi:10.1016/j.ejphar.2012.12.009

Cited by 42 publications

(56 citation statements)

References 24 publications

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“…Prior studies reported on the action of these two compounds in normotensive animals, such as rabbits (Pintor et al, 2001(Pintor et al, , 2003, or in hypertensive/glaucoma conditions (Serle et al, 2004;Martínez-Águila et al, 2013). The reduction in IOP in models of hypertension (e.g., monkeys) presented a reduction pattern that was different from that observed in our exfoliative model.…”

contrasting

confidence: 47%

“…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).…”

Section: Introductionmentioning

confidence: 99%

“…Pigment accumulation in the trabecular meshwork causes clogging and reduced flow of aqueous humor, causing a moderate increase in IOP between 2 and 6 months and a strong increase between 8 and 12 months (Saleh et al, 2007;Harazny et al, 2009). The increase in IOP produces changes in the retina and optic nerve (Libby et al, 2005;Pérez de Lara et al, 2014) Most of the experiments performed to date with melatonin and 5-MCA-NAT have been carried out in either normotensive animals (Pintor et al, 2001) or in hypertensive/glaucoma conditions (Serle et al, 2004;Martínez-Águila et al, 2013), but not in an animal model that develops the disease spontaneously. In addition, 5-MCA-NAT has not yet been tested as a possible preventive treatment for glaucoma.…”

Section: Introductionmentioning

confidence: 99%

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

Martínez-Águila

Fonseca

Lara

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Melatonin is a neurohormone that is produced not only by the pineal gland but also by several ocular structures. One of the main physiologic roles of melatonin is the reduction of intraocular pressure (IOP). Using both control C57BL/6J and glaucomatous DBA/2J mice as well as TonoLab tonometry, this study evaluated the effect of melatonin and 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) when glaucomatous pathology was fully established and compared pharmacological behavior in treated mice versus control mice. In addition, 5-MCA-NAT was tested to determine its effects on ameliorating increased IOP in a glaucoma model. The results demonstrate that melatonin and 5-MCA-NAT can reduce IOP in a concentration-dependent manner. The EC 50 values for melatonin in control and glaucomatous animals were 34 mM and 50 mM, respectively. Interestingly, melatonin decreased IOP in 19.4% 6 3.7% and 32.6% 6 6.0% of control and glaucomatous mice, respectively, when the animals were studied at age 12 months. 5-MCA-NAT reduced IOP in the same manner and was able to stop IOP progression in glaucomatous mice. Use of melatonin receptor antagonists showed that hypotensive effects were blocked by the MT 2 receptor antagonists luzindole and 4-phenyl-2-propionamidotetralin in the case of melatonin and by only 4-phenyl-2-propionamidotetralin in the case of 5-MCA-NAT. In conclusion, melatonin and 5-MCA-NAT can effectively reduce IOP in a glaucoma model, and their hypotensive effects are more profound in the glaucoma model than in control animals.

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contrasting

confidence: 47%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Martínez-Águila

Fonseca

Lara

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…Furthermore, we have recently demonstrated that the application of melatoninergic compounds reduces the IOP of rabbits with ocular hypertension induced by the Trendelenburg position (Martinez-Aguila et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Melatonin and Its Analog 5-Methoxycarbonylamino-N-Acetyltryptamine Potentiate Adrenergic Receptor-Mediated Ocular Hypotensive Effects in Rabbits: Significance for Combination Therapy in Glaucoma

Crooke

Huete-Toral

Martínez-Águila

et al. 2013

J Pharmacol Exp Ther

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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.

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“…The only risk factor that can be controlled in glaucoma is the elevated intraocular pressure. Studies have shown that melatonin and its analogs are able to bring down IOP by exogenous consumption [12,13]. Surprisingly, a recent study analyzing melatonin levels in human aqueous humors has demonstrated that those patients with elevated intraocular pressure present higher melatonin concentrations than healthy subjects [14,15].…”

Section: Introductionmentioning

confidence: 99%

TRPV4 Stimulation Induced Melatonin Secretion by Increasing Arylalkymine N-acetyltransferase (AANAT) Protein Level

Alkozi

Lara

Sanchez-Naves³

et al. 2017

IJMS

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Melatonin is a molecule which has gained a great deal of interest in many areas of science; its synthesis was classically known to be in the pineal gland. However, many organs synthesize melatonin, such as several ocular structures. Melatonin is known to participate in many functions apart from its main action regulating the circadian rhythm. It is synthesized from serotonin in two steps, with a rate-limiting step carried out by arylalkymine N-acetyltransferase (AANAT). In this report, the role of TRPV4 channel present in human ciliary body epithelial cells in AANAT production was studied. Several experiments were undertaken to verify the adequate time to reach the maximal effect by using the TRPV4 agonist GSK1016790A, together with a dose–response study. An increase of 2.4 folds in AANAT was seen after 18 h of incubation with 10 nM of GSK1016790A (p < 0.001, n = 6). This increment was verified by antagonist assays. In summary, AANAT levels and therefore melatonin synthesis change after TRPV4 channel stimulation. Using this cell model together with human ciliary body tissue it is possible to suggest that AANAT plays an important role in pathologies related to intraocular pressure.

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Melatonin analogue agomelatine reduces rabbit's intraocular pressure in normotensive and hypertensive conditions

Cited by 42 publications

References 24 publications

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

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

Melatonin and Its Analog 5-Methoxycarbonylamino-N-Acetyltryptamine Potentiate Adrenergic Receptor-Mediated Ocular Hypotensive Effects in Rabbits: Significance for Combination Therapy in Glaucoma

TRPV4 Stimulation Induced Melatonin Secretion by Increasing Arylalkymine N-acetyltransferase (AANAT) Protein Level

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