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

Abstract

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.

Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma

“…In the DBA/2J, the reduction was equivalent to the one observed for other compounds in the same model. For instance, melatonin or its analogue 5-MCA-NAT reduced IOP between 29 and 32% in the DBA/2J and, as happened in the present paper, the effect on the normotensive animal was not so marked [27]. Other authors who used classical compounds such as the carbonic anhydrase inhibitor dorzolamide have demonstrated a similar effect [28], reducing IOP.…”

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

“…This increase may explain the rise of melatonin in glaucomatous patients and opens the question of why, as melatonin concentrations are abnormally elevated in glaucomatous individuals, this substance cannot reduce IOP as should be expected. In this sense, many studies have reported the hypotensive action of melatonin and analogs either in normotensive and glaucomatous animal models [33,34] as well as in normotensive and ocular hypertensive human beings [12,35]. The reason why the exogenously added melatonin or analogs, produce a reduction in IOP, seems to be related to the dose reached in the aqueous humor.…”

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

“…Indeed, a dysfunction of melatonin signaling triggers elevation of nocturnal IOP and loss of retinal ganglion cells (Figure ) . Additionally, exogenous melatonin and its analogues lower IOP in mammals, including humans (Figure ) . 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 .…”

“…212 Additionally, exogenous melatonin and its analogues lower IOP in mammals, including humans ( Figure 2). [213][214][215][216][217][218][219][220][221] 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. 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.…”