Melatonin as the basis of a new therapeutic strategy in the treatment of various ophthalmopathology (literature review)

Melatonin as the basis of a new therapeutic strategy in the treatment of various ophthalmopathology (literature review)

Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous indoleamine, which is synthesized from the neurotransmitter serotonin primarily in the pineal gland [1] and is an extremely multifunctional molecule. First of all, it plays a key role in the regulation of circadian rhythms, and also participates in the functioning of the reproductive, cerebrovascular, neuroendocrine, immune and visual systems [2]. The implementation of the numerous biological effects of melatonin is achieved due to its production, in addition to the pineal gland, in a number of organs in situ. Functionally, many cells producing melatonin belong to the so-called diffuse neuroendocrine system – the universal system of adaptation and maintenance of homeostasis of the body. Within this system, two links of melatonin-producing cells are distinguished: central (includes the pineal gland and the visual analyzer), in which the melatonin secretion rhythm coincides with the light-dark rhythm, and the implementation of its functions is receptor-dependent in nature, and the peripheral – all other cells where the secretion of the hormone does not depend on light, and the functioning is receptor-independent in nature [3].

Melatonin has been proven to be one of the most highly effective endogenous antioxidants. It and its metabolites interact with various active forms of oxygen, nitrogen and organic radicals, preventing the development of lipid peroxidation processes, and also can increase the synthesis of antioxidant enzymes (including glutathione peroxidase and glutathione reductase) and reduce the production of prooxidant enzymes (nitric oxide synthase and lipoxygenase) [4 ]. In addition, melatonin has anti-inflammatory properties, reducing the production of pro-inflammatory cytokines and chemokines, as well as the mobilization of polymorphonuclear leukocytes in the focus of inflammation [5]. A number of studies have studied its antiangiogenic and neuroprotective properties [6-8].

Melatonin preparations are widely used throughout the world to prevent the development of “aging symptoms”, improve sleep quality, alleviate the symptoms of biorhythms and treat depression [9]. Numerous studies are devoted to studying the effectiveness of melatonin in the treatment of so-called diseases associated with oxidative stress, in particular, developing in children in the neonatal period – chronic lung disease, perinatal brain damage, necrotizing enterocolitis [10]. The effectiveness of melatonin in preventing oxidative damage in cultured neuronal cells and in the brain of animals when exposed to various neurotoxic agents confirms that melatonin has a potential therapeutic effect in the treatment of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, the effects of stroke and traumatic brain injury [eleven].

Prospects for the use of melatonin in ophthalmology

In vertebrate retina, melatonin is synthesized in photoreceptors and exhibits its properties by interacting with a family of G-protein-binding receptors of various subtypes. These receptors were found in all layers of the retina, and were also found in eye structures such as the cornea, lens, ciliary body, choroid, and sclera [9, 12]. It is important to note that exposure to different subtypes of melatonin receptors can lead to various physiological and biochemical changes in specific tissues [9].

Continuous melatonin regeneration provides a constant level of antioxidant protection for the anterior and posterior eyeball segments. The importance of such protection for the retina is due to the extremely high level of oxidative processes observed in the retinal tissue, which are a consequence of a number of its morpho-functional features. First, due to its functional purpose, the retina is almost constantly exposed to light, the active initiator of the formation of free oxygen radicals; secondly, the retinal tissue contains the highest level of polyunsaturated fatty acids, which are known to be “favorite” substrates for damaging peroxidase reactions; thirdly, retinal cells are rich in mitochondria, which are the main source of generation of reactive oxygen species [13].

To date, there are a number of works devoted to the study of the role of melatonin in the functioning of the organ of vision and the development of various ophthalmopathologies; the therapeutic potential of melatonin and melatonergic drugs in diseases such as diabetic retinopathy, age-related macular degeneration, glaucoma, uveitis, retinopathy of premature infants [6, 14-26 ]. At the same time, for obvious reasons, the absolute majority of the work is experimental.

Melatonin and diabetic retinopathy

Melatonin as the basis of a new therapeutic strategy in the treatment of various ophthalmopathology (literature review)

Diabetic retinopathy (DR) is one of the leading causes of blindness in people of working age worldwide. The study of the possibility of using melatonin in the treatment of DR, as well as the pathogenetic basis of the effectiveness of its use, is an actual problem of modern ophthalmology. Thus, in one of the works, the effect of melatonin on developing oxidative stress and retinal vascular changes in rats with induced diabetes was evaluated [14]. It was shown that in conditions of hyperglycemia in the retina, the levels of nitrotyrosine and malondialdehyde increase, reflecting the level of oxidative processes in the retina, as well as the level of HIF-1αVEGF-A and PEDF. Intraperitoneal injections of melatonin resulted in a decrease in the level of all studied parameters, and also had a positive effect on the course of retinopathy in diabetic rats, preventing the development of characteristic retinal vascular changes. In another study, melatonin-mediated cytoprotection was investigated against hyperglycemic damage to Müller cells [15], which, as has been shown, play a key role in the development of DR and VEGF production. The results of the study showed that melatonin membrane receptors are expressed in cultured primary Müller cells and their number increases under the influence of elevated glucose levels. Both basic and elevated glucose production of VEGF decreased with the use of melatonin, which was dose-dependent. Moreover, it was found that melatonin is a potential activator of protein kinase (Akt) in Müller cells, indicating that, in addition to its functioning as a “direct trap” for free radicals, melatonin can affect cellular signaling pathways that play protective role in retinal damage in the development of DR.

Melatonin and age-related macular degeneration

The age-related decrease in the content of melatonin is considered as one of the main mechanisms of aging and the development of “aging-associated” diseases, including age-related macular degeneration (AMD). In one of the works, it was shown that patients with AMD had a significantly lower content of melatonin and its metabolite 6-sulfatoxymelatonin in serum compared with a group of healthy people [16].

To date, there are a number of experimental studies on the possibility of using melatonin in the treatment and prevention of AMD. In particular, one study examined the effect of melatonin on the development of retinopathy, similar to AMD, in OXYS rats. According to the results of an ophthalmoscopic examination, melatonin significantly slowed down the development of clinical manifestations of retinopathy in rats, prevented structural and functional changes in cells of the retinal pigment epithelium (RPE), reduced the severity of microcirculation disorders in the choroid, which probably increased the safety of neurosensory cells and associated ganglionic circuits. ]. In another work, it was shown that melatonin is able to prevent the breakdown of the internal hemato-retinal barrier during AMD, which may be crucial for preventing the development of its exudative form [18].

The results of a clinical trial showed that oral administration of 3 mg of melatonin at bedtime for 3 months. in patients with AMD, reduced pathological changes in the macula [19].

Melatonin and glaucoma

The ability of melatonin to reduce intraocular pressure, as well as its neuroprotective and antioxidant properties open up broad prospects for its use in the complex therapy of glaucoma [20].

Experimental studies are conducted in which the biochemical status is studied, as well as the functional and histological changes in the retina of animals with induced hypertension against the background of the use of melatonin [21, 22]. In addition, the synthesis of new 2-oxindole derivatives, with the properties of melatonin receptor ligands, with more pronounced and prolonged hypotensive and antioxidant properties, is carried out [20]. Work is underway in which melatonin is encapsulated into cationic solid lipid cSLN nanoparticles in order to increase its efficacy and safety in the treatment of glaucoma [23].

Melatonin as the basis of a new therapeutic strategy in the treatment of various ophthalmopathology (literature review)

Melatonin and uveitis

Uveitis is a severe pathology that leads to irreversible impairment of visual functions, which is a pressing issue for ophthalmologists and a serious public health problem.

Back in 1986, Y. Touitou showed that the melatonin night peak was significantly reduced in patients with uveitis compared with healthy individuals [24]. In 1994, H.A. Wollmann, which studied the interaction of the neuroendocrine and immune systems in people with uveitis. To this end, serum levels of melatonin, prolactin (PRL) and interleukin-2 (IL-2) were measured. A total of 100 patients with various forms of uveitis and 30 healthy donors were included in the study. The daily level of melatonin was significantly reduced (p < или = 0,01) у пациентов с иридоциклитом и еще более значительно снижен (р < или = 0,001) – у пациентов с периферическим увеитом, хориоретинитом и панувеитом. У 38% пациентов дневные уровни мелатонина в плазме были даже ниже предела обнаружения [25]. Полученные данные нашли подтверждение и в экспериментальной работе, где у крыс с индуцированным аутоиммунным увеитом и пациентов с увеитом определялся значительно более низкий уровень сывороточного мелатонина в ночное время [26].

In a number of experimental studies using Syrian hamsters, anti-inflammatory efficacy of melatonin was shown at the start of its use before the induction of inflammation by injection of bacterial lipopolysaccharide [27], as well as after the manifestation of uveitis [28].

Melatonin and retinopathy of prematurity

Retinopathy of prematurity (PH) is a severe vasoproliferative disease that develops due to the incompleteness of vascularization and the immaturity of the structure of the retina by the time of premature birth. It is known that one of the links in the pathogenesis of pH is oxidative stress, which is the result of fluctuations in the oxygen level in the blood of premature infants due to hemocirculatory disorders, bronchopulmonary dysplasia, developing in some cases apnea, and incorrect oxygen supply patterns during nursing. This approach formed the basis for experimental modeling of the disease, which is used to study various pathogenesis of pH, and is to affect newborn animals with an immature retina with fixed or variable elevated oxygen concentrations [13].

Today, there are only a few experimental studies in the literature devoted to the study of the possibility of using melatonin in the treatment and prevention of PH. In 2013, Kaur and colleagues investigated the neuroprotective effect of melatonin on the hypoxia-induced death of retinal ganglion cells in newborn rats [8]. They found that in the cultures of microglial cells susceptible to hypoxia, when melatonin was used, there was a significant decrease in the release of pro-inflammatory cytokines TNF-αα and IL-1? compared to “untreated” cells. It was also noted an increased release of cytochrome C in the cytosol of ganglion cells, subject to retinal hypoxia, accompanied by activation of cytosolic caspases, which induce apoptosis. At the same time, the level of cytochrome C and caspase-3 in these cells significantly decreased after melatonin administration. The study also showed that under hypoxia conditions, the level of lipid peroxidation products increased in the retina, while the level of reduced glutathione, on the contrary, decreased, so that this effect of hypoxia was completely leveled against the background of melatonin use. Thus, it was shown that under conditions of hypoxic damage, melatonin exhibits neuroprotective properties against the ganglion cells of the developing retina by manifesting its antioxidant, anti-inflammatory and anti-apoptotic properties.

In another study, the effect of exogenous melatonin on the state of the hematoretinal barrier and the oxidative status of the vitreous body of rats with an experimental pH was evaluated [6]. It was shown that the development of retinopathy was accompanied by a sharp increase in antioxidant activity and protein concentration in the vitreous body. Intraperitoneal administration of melatonin in the period of the initial developmental disorder and maturation of the retinal vessels with experimental pH led to a decrease in these indices in the vitreous body of the experimental rats almost to control values ​​during all periods of observation. This proved that exogenous melatonin contributes to the stabilization of the hematoretinal barrier and the local antioxidant status due to its pronounced antiangiogenic and antioxidant effects in the development of experimental pH.

Thus, given the limited number of works available to date, as well as many unresolved issues, the study of the possibility of using melatonin in the treatment and prevention of various ophthalmopathologies, as well as the pathogenetic mechanisms of its influence, is an extremely promising area of ​​research. An important issue is the use of selective agonists (or antagonists) of specific melatonin receptors, which will increase the effectiveness of the treatment chosen while reducing possible side effects.

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