**1. Introduction**

Melatonin [N-acetyl-5-methoxytryptamine] is a neuroendocrine hormone and was firstly isolated from the bovine pineal gland in 1958 by Lerner et al. [1]. The pineal gland is originating from the prosencephalon and was first identified by Herophilus in 325–280 BC. Photic data is received by photoreceptors in the retina and transmitted to the superior cervical ganglion via sympathetic preganglionic adrenergic neurons. Melatonin is synthesized from tryptophan through a number of enzymatic reactions in pinealocytes [2]. Melatonin secretion is regulated by the day/night events. In addition, while norepinephrine stimulates beta1-adrenoreceptors synthesis and secretion of melatonin, stimulation of alpha1-adrenoreceptors increases the reaction [3, 4]. While melatonin is mainly secreted from the pineal gland, melatonin is also secreted from the retina, gastrointestinal tract tissues, skin, platelets, and bone marrow. Melatonin production is described in **Figure 1**.

**Figure 1.** *Synthesis of melatonin from tryptophan.*

Melatonin is given to the body by oral or intravenous which is rapidly absorbed and metabolized mainly in the liver and secondarily in the kidneys. Two types of membrane receptors [MT1 and MT2] and one type of cytoplasmic receptor [MT3] for melatonin were determined in humans [5]. Melatonin is both a lipid- and water-soluble hormone, with three types of high-affinity G-protein-coupled receptors mainly MT1, MT2, and MT3. MT1 is a receptor located mainly in the suprachiasmatic nucleus (SCN) and to a lesser extent in the pituitary and cerebral vascular systems (CVSs). MT2 is found in the retina. In addition, melatonin receptors in coronary arteries have been demonstrated [5]. Besides CVSs, melatonin receptors are found in multiple tissues. MT3 receptors are nuclear binding sites of melatonin located in the cytosol [6], acting as an enzyme and responsible for the detoxification of harmful agents. MT1 receptors are mainly found in the cardiovascular system. It can also be found in the immune system, placenta, retina, spleen, liver, breast, kidney, skin, testis, ovary, pancreas, adrenal cortex, retina, and brain [4]. MT2 is found in the immune system, mammary glands, retinal pituitary gland, adipose tissue, SCN, blood vessels, testicles, gastrointestinal tract, kidney, and skin.

### **2. Melatonin and CVDs relationship**

Nowadays, deaths due to CVD are among the most important causes of death, approximately one-third of all deaths. Considering the pathophysiology of cardiovascular diseases, preventive measures and effective substances will reduce the formation and development of these disorders [7].

Melatonin is gaining more and more important in the pathophysiology of CVD. Because low secretion of melatonin has been reported to be associated with various CVDs, including myocardial infarction (MI), coronary heart disease, congestive heart failure, and nocturnal hypertension [8, 9]. Furthermore, working in illuminated environments also causes glucose intolerance, insulin resistance, metabolic circadian irregularity and sleep disturbance with aging, and lack of melatonin secretion [10].

Melatonin receptors have been identified within the cardiovascular system, including various vascular tissues. Hypertension and peripheral vasoconstriction have been reported in animals undergoing pinealectomy [8, 11].

### **3. Antioxidant and free radical scavenger activity of melatonin**

Melatonin is a powerful antioxidant substance and also has protective effects on the mitochondria [12–15]. A study showed beneficial effects on plasma MDA, GSH, PCO, and NO levels after the administration of 5 mg of melatonin (twice a day) for 12 weeks in diabetic patients [15]. Melatonin performs its antioxidant and free radical scavenging activity through two main mechanisms. In the first mechanism, melatonin binds to the MT3 receptor and acts as an antioxidant by suppressing the electron transfer reactions of quinones [16]. In the second pathway, they scavenge free radicals [17]. Depending on the dose of endogenous or exogenous melatonin, it acts by receptor-dependent or receptor-independent mechanisms [18].

Additionally, the aforementioned two mechanisms, melatonin indirectly increases antioxidant enzymes such as glutathione peroxidase, glutathione reductase superoxide dismutase, and glucose-6-phosphate dehydrogenase and suppresses molecular damage under conditions of severe oxidative stress [19]. Antioxidant enzymes realize this stimulation via MT1 and MT2 receptors. Due to its high lipophilicity, melatonin can easily pass through cell membranes and reach intracellular compartments including the nucleus and mitochondria. Melatonin reduces cell death while maintaining normal mitochondrial function [20].

Melatonin and metabolites of melatonin [cyclic 3-hydroxymelatonin and N1-acetyl-N2-formyl-5-methoxyquinuramine] are free radical scavengers [18]. Therefore, melatonin and its metabolites support the main molecule in terms of the antioxidant effect. In addition, the total antioxidant capacity of melatonin is higher than that of other known antioxidants such as vitamin E and vitamin C under in vivo and in vitro conditions [4]. Recent studies have reported that melatonin decreases mammalian Mst1 phosphorylation and increases Sirt3 expression and modulates the autophagic cell death process. Autophagy is a lysosomal cell death process that removes damaged organelles and misfolded proteins to maintain cellular homeostasis [21]. Disruption in autophagy causes cardiac hypertrophy [22], heart failure [Thomas et al. 2013], and ischemia/reperfusion [I/R] damage [23]. Melatonin administration alleviated the left ventricular remodeling. Melatonin also reduces cardiac dysfunction in diabetic animals [24] and has shown a significant protective effect on ischemia/reperfusion [I/R] injury and hypertension [23, 25].
