Hypotensive Effect of Nanomicellar Formulation of Melatonin and Agomelatine in a Rat Model: Significance for Glaucoma Therapy

Abstract

Background: Melatoninergic agents are known to reduce intraocular pressure (IOP). The present study was performed to evaluate the effect of nanomicellar formulations of melatoninergic agents on IOP in the rat. Methods: Tonometry was used to measure IOP in eyes instilled with melatonin or agomelatine. Ocular hypertension was induced by the injection of methylcellulose in the anterior chamber. Results: Melatonin formulated in nanomicelles had a longer lasting hypotonizing effect on IOP with respect to melatonin in saline. Nanomicellar formulations of melatonin and agomelatine, either alone or in combination, had lowering effects that did not depend on their concentration or their combination, which, however, resulted in an increased duration of the hypotonizing effect. The duration of the lowering effect was further increased by the addition of lipoic acid. Conclusions: We demonstrated the effective hypotonizing activity of melatonin and agomelatine in combination with lipoic acid. Although results in animals cannot be directly translated to humans, the possibility of developing novel therapeutical approaches for patients suffering from hypertensive glaucoma should be considered.

A Dietary Combination of Forskolin with Homotaurine, Spearmint and B Vitamins Protects Injured Retinal Ganglion Cells in a Rodent Model of Hypertensive Glaucoma

“…As shown in Figure 1, MCE injection in the anterior chamber induced a significant increase in IOP within 24 h from the injection. This is in line with previous findings in rabbits and rats injected with MCE and in mice injected with an MCE derivative, hydroxypropyl MCE [23][24][25]29]. The IOP increase was maintained for up to two weeks (from 14.3 ± 2.4 to 28.7 ± 0.7 mmHg, p < 0.001).…”

“…MCE is a molecule that causes a viscosity-dependent ocular hypertension by blocking the trabecular meshwork and preventing the outflow of the aqueous humor [23]. The MCE model in the rat is characterized by an early elevation of IOP that, after a return to its basal level, is followed by a second peak, thus reaching a steady state that remains stable for at least two weeks [24,29]. This is in line with additional models in which IOP elevation has been obtained through the blockade of the trabecular meshwork (see for instance [35]).…”

“…This is in line with additional models in which IOP elevation has been obtained through the blockade of the trabecular meshwork (see for instance [35]). The MCE model has been recently used to demonstrate the hypotensive efficacy of topical nanomicellar formulations of melatonin and agomelatine in the rat eye [29]. In respect to additional models that mimic the human acute angle-closure glaucoma, for instance the ischemia/reperfusion model characterized by a transient acute IOP elevation [36], the prolonged IOP elevation of the MCE model more closely simulates the human hypertensive glaucoma.…”

The Therapeutic Trip of Melatonin Eye Drops: From the Ocular Surface to the Retina

“…The addition of lipoic acid (0.1% w / v ) as an antioxidant increased the duration of the lowering effect of melatonin and agomelatine by approximately 50%. Moreover, the hypotensive efficacy of topical nanomicellar formulations of melatonin (0.4% w / v ) and agomelatine (0.4% w / v ) in rat eyes was demonstrated using the MCE model [ 44 ]. The nanomicellar formulation, prepared with 11.5% Soluplus ® in Tris buffer, included lipoic acid (0.1% w / v ) as a stabilizing excipient and antioxidant.…”

Food Supplements in the Treatment of Ophthalmic Diseases: Preclinical and Clinical Studies

“…Circadian changes of the IOP appear to be linked to melatonin [108], which has shown hypotensive effects on IOP [109], apparently mediated by the MT3 receptor [110,111]. Most recently, it has been shown that a nanomicellar formulation of melatonin and agomelatin given topically as eye drops is able to decrease by over 30% the IOP of normotensive rats, and by over 50% the IOP of hypertensive rats, after clogging of the TM [112]. Clinically, it has been reported that oral treatment with agomelatine could further decrease by 30% on average the IOP of 10 glaucomatous patients under maximum tolerated medical therapy (MTMT) with different hypotonizing drugs [113].…”