Anales RANF

Hanan Awad Alkozi @Real Academia Nacional de Farmacia. Spain 50 Several studies indicated the pharmacological effect of melatonin in the eye, moreover, the eye is a very special organ since it synthesizes this hormone and comprises its local machinery giving that several ocular structures are able to produce it. For instance, melatonin synthesizing enzymes were found first in the retina (7), then it was shown to be present in the iris, ciliary body, crystalline lens, and the harderian gland (8-10). Furthermore, studies confirmed its multitasking characteristics, exceeding the classical and once thought to be the only function of regulating the circadian rhythm (11). An interesting observation about melatonin and the physiology of the eye is the synchronization between melatonin levels and the intraocular pressure, where the later reaches its lowest levels at night while melatonin is at the highest (12, 13). Intraocular pressure is one of main factors in maintaining our ocular system healthy, since its elevation could lead to the second leading cause of blindness worldwide, glaucoma disease (14). Glaucoma is defined as a heterogenous group of progressive disorders characterized by optic neuropathy and retinal ganglion cell death (15). Many risk factors are involved in the development of this disease, such as the age, gender, genetics, intraocular pressure (IOP), and ethnicity. For instance, glaucoma cases accounts 8% of all blindness worldwide, but this percentage raise to 15% in African population (16). Glaucoma lacks primary symptoms and it leads gradually to a loss of the peripheral vision, as it is an under-diagnosed disease (17). In all the cases, intraocular pressure is the only risk factor which can be controlled in order to slow the progression of glaucoma. A variety of glaucoma medication are currently in use, and all of them function in order to keep IOP within healthy and normal limits (18). In the current review, light will be shed on melatonin in the eye with a special focus on glaucoma disease. Also, melanopsin role in regulating melatonin levels within the eye and its signalling pathways will be discussed. 2. MELATONIN HISTORY AND SYNTHESIS The history of melatonin goes back to many cultures and ages, by the reason of the pineal gland´s shape and location, and before being conscious about the neurohormone itself. For instance, in the greek culture, the pineal gland was given this name because it is shaped similar to the pine nut (19), and in the pharaonic Egypt, the pineal was considered the eye of Horus. Another speculation by the Hindu, describing the pineal gland as the third eye for spiritual enlightenment (20). However, one of the most remarkable historical definition of this curious gland was by the philosopher Descartes (1594– 1650), where he described the pineal gland as the seat of the soul and the region where our thoughts were formed (21). The pineal gland gained its importance through history, until 1958, when the dermatologist Aaron Lerner was looking for a cure for vitiligo, and he discovered the hormone secreted by this gland, melatonin (4). Therefore, this hormone was given the name melatonin as “mela” from melanin and “toni” from serotonin (4). Melatonin is first synthesized from tryptophan which is converted into serotonin (22). Certain amount of this hormone goes through acetylation by the first enzyme in melatonin synthesis, arylalkymine N-acetyltransferase (AANAT), to get N-acetylserotonin (NAS), which in turn is converted to melatonin with the help of the last enzyme involved in this process, hydroxyindole O- methyltransferase (HIOMT), which catalyses the O- methylation of NAS by S-adenosyl methionine to form melatonin (Fig.1) (23). Several studies haves indicated the importance of AANAT enzyme in the process of melatonin synthesis, and it is named the Timezyme, since its activity increases up to 100-fold at night, thus it is considered a key in regulating melatonin levels (24, 25). As commented in the introduction, melatonin was found to be produced by several ocular structures. But more importantly, in 1984 the synthesis of melatonin in the eye has gained additional interest after some experiments done in white leghorn cockerels, when Rohde and collaborators performed a pinealectomy procedure and then measured melatonin in several structures in the eye. Two important discoveries were made from this work, first, melatonin was measured in the retina, iris, and ciliary body resulted similar to the control. And second, melatonin concentration in the studied structures followed the same pattern as the pineal gland, raising during the night and decreasing at daylight (26).