Use of Melatonin as a Feed Additive

*Oğuzhan Kahraman, Zekeriya Safa İnanç, Huzur Derya Arık and Mustafa Selçuk Alataş*

### **Abstract**

Melatonin is a molecule that plays an active role in reducing many stress factors in plants and has important functions in the growth, development and reproduction of plants. It has many physiological functions that directly affect feed consumption, feed efficiency, energy metabolism and immune system in animal organisms. In addition, its anti-inflammatory, antioxidant, anticancer and antiapoptotic effects are also known. While melatonin has an antioxidative effect at low doses, it can exert a prooxidant effect at high doses. It has been suggested that when melatonin is used as a silage additive, it increases the total acid content of the silage and significantly improves the silage fermentation quality by lowering the pH level and butyric acid. Although it has positive effects on mammary gland involution and general health in ruminants, its effects on yield parameters have not been proven. Broilers and layers are expected high productivity and performance, in this regard, they are faced with stress factors such as intensive feeding and housing conditions. Considering its positive effects on stress factors, health and productivity, melatonin is a promising feed additive. Effects of melatonin additive or supplements on animal productivity and health should be revealed in further studies.

**Keywords:** additive, melatonin, poultry, ruminant

#### **1. Introduction**

Melatonin is recognized as an active oxygen scavenger, which can inhibit peroxidation, effectively scavenge reactive oxygen radicals, delay the wilting of plants, and alleviate salt, drought, heavy metal, cold, pathogens and other adversities [1]. Melatonin, a derivative of tryptophan, has a low molecular weight and an indole ring structure and is an evolutionarily conserved pleiotropic molecule ubiquitous in living organisms. Melatonin is a molecule that plays an active role in reducing many stress factors in plants and has important functions in the growth, development and reproduction of plants [2]. It is accepted that melatonin can regulate vegetative growth and flowering processes such as rooting, photosynthetic yield and biomass yield, and plays a potential regulator role in the formation and maturation of fruits and seeds [3].

Melatonin is a substance secreted by the pineal gland in the darkness and can regulate biological rhythms in many physiological systems in animals, including the behavioral, cardiovascular, reproductive, immune, excretory, thermoregulatory and neuroendocrine systems [4]. Melatonin has many physiological functions that directly affects feed consumption, feed efficiency, energy metabolism and immune system in animals. Studies on the effects of melatonin on animals have shown different results [5, 6]. In a study on the use of melatonin as a silage additive, Li et al. stated that it significantly improved the quality of the silage by increased volatile fatty acid levels and decreased pH. In addition to these positive effects, melatonin had curative effects on silage fermentation by increasing microbial diversity [1].

The use of melatonin as an additive is not common. Because, melatonin has not been studied sufficiently in animals as a feed additive and its effects have not been adequately explained. In this chapter, the effects of melatonin as a feed additive especially in ruminants, broiler and layer chickens on production, yield and animal health were reviewed in order to popularize the use of melatonin as an additive and supplement. Also, the effects and functions of melatonin on plants were tried to be explained.

#### **2. Synthesis and functional properties of melatonin in animals**

Melatonin was isolated from the pituitary gland in 1958. A lot of research has been conducted about the effects and usage areas of melatonin. It was discovered as a skin lightening molecule that acts on frog and fish melanocytes, and found to be an important hormone rhythmically secreted by the brain's pineal gland [7, 8]. The relationship between the pineal gland and light has caused it to be called the third eye. Melatonin can be synthesized in almost every living creatures, including many vertebrates and invertebrates, bacteria, protozoa, plants and fungi. Melatonin has immunostimulatory and cytoprotective agent functions that regulate the sleep-wake cycle. Also, it activates T and B lymphocytes, monocytes and stimulates the reproduction of thymocyte cells and the release of cytokines. In addition to these, its anti-inflammatory, antioxidant, anticancer and antiapoptotic effects are also known [9].

Apart from the pineal gland, melatonin is also secreted from the ovary, lens of the eye, bone marrow cells, gall bladder and gastrointestinal tract. However, the level of circulating melatonin reflects the production of melatonin in the pineal gland. While there is no difference in terms of human and animal health in matters such as the mode of action, release and chemical structure of melatonin, its usage areas vary. The antioxidant properties of melatonin and its effect on sleep disorders are at the forefront on humans. But, it has also been reported to have protective effects in neuronal degeneration and neuroprotective properties in oxidative stress-induced neuronal apoptosis [10, 11].

Light exposure level is the most effective factor that determines the rate of melatonin secretion. In general, light decreases melatonin production, while darkness increases it. The starting material of melatonin synthesis is tryptophan, an indole amino acid taken from plasma [12]. Tryptophan is hydroxylated to 5-hydroxytryptophan in pinealocytes by the enzyme tryptophanhydroxylase. 5-hydroxytryptophan is decarboxylated to 5-hydroxytryptamine (seratonin) by aromatic-l-amino acid decarboxylase. Seratonin is converted to N-acetylseratonin by N-acetyltransferase (NAT) enzyme, and this is converted to melatonin (N-acetyl-5-methoxytryptamine) by the effect of hydroxyindole-o-methyl transferase (HOMT). It has been determined that NAT and HOMT activities, which enable the conversion of serotonin to melatonin, are higher at night. It has been demonstrated by immunohistochemical methods that

#### *Use of Melatonin as a Feed Additive DOI: http://dx.doi.org/10.5772/intechopen.105999*

the enzymes required for melatonin synthesis are also present in the suprachiasmatic nucleus, retina and small intestine, apart from pinealocytes [13, 14].

After melatonin is synthesized in the pineal gland, it quickly passes into the capillaries without being stored in the organism. Due to its high lipophilic effect, it can be distributed to many biological tissues and fluids in the organism. Approximately 70% of plasma is transported bound to albumin. While melatonin can be metabolized in the kidney, this process generally takes place in the liver. Melatonin is converted to 6-hydroxymelatonin in the liver; this, in turn, binds to sulfate and glucuronic acid through the kidneys and is excreted in the urine [15].

Morphological, biochemical and molecular studies in both animals and humans in recent years have shown that oxidative stress plays a primary role in the development of degenerative changes in cells and tissues in our body. The highest degree of oxidative damage usually occurs in organs such as the brain, heart, and skeletal muscle. Melatonin inhibits free radicals from their pyrrole rings and interacts with them, reducing their activity. It also shows its effect by inducing the production of antioxidants. Melatonin has the ability to scavenge all free radicals formed in the cell. Thus, an increase is observed in the expression of genes encoding antioxidants, while genes that cause an increase in free radicals are suppressed metabolites such as melatonin also have very protective effects against oxidative stress. Lipid peroxidation, which occurs as a result of oxidative damage and accumulation of free radicals in cells, causes deterioration in cell membranes. As a result of damage, signal transmission and activation of signal pathways in cells are affected and various metabolic functions become ineffective. Melatonin prevents this lipid peroxidation and minimizes cell damage. Melatonin also neutralizes radicals caused by nitrogen and prevents nitric oxide formed [16].

### **3. Effects of melatonin in plants**

Under extreme stress conditions, the natural defense mechanisms of plants do not provide adequate protection; In this case, exogenous biostimulants can be used to improve plant stress tolerance [17]. Recent studies have indicated that plant growth regulators manage stress mechanisms. Among these regulators, melatonin (N-acetyl-5-methoxytryptamine) is a functional natural antioxidant widely used among plants [18]. While melatonin plays an important role in plant growth and development, it promotes root and hypocotyl growth and increases the biomass of plants with its auxin-like functions [19]. Studies on the functions of melatonin in plants have revealed that melatonin plays a very important role in plant growth and development under abiotic stress conditions. Melatonin is known to increase plant tolerance under salinity stress, improve photosynthesis capacity to maintain plant ionic balance (Na+/K+ ratio), protect chlorophyll and carotenoids, and reduce photorespiration [1]. The transcriptome analysis results showed that melatonin particularly affected the pathways of plant hormone signal transduction and biosynthesis of secondary metabolites.

Melatonin is a powerful antioxidant and has the ability to purify reactive oxygen species, reactive nitrogen species and various chemical pollutants. It has been suggested that melatonin detoxifies the oxidative stress caused by excess cadmium in tomatoes by stimulating antioxidant enzymatic activity [20]. In another study, it was reported that antioxidants suppress H2O2 production, reduce malondialdehyde and regulate various physiological processes. In addition, exogenous application of

melatonin improves the chlorophyll content and photosynthesis capacity of various plant species under salt stress by decreasing the production of reactive oxygen species and increasing the soluble protein content [21].

### **4. Use of melatonin as silage and feed additive in ruminants**

Fresh roughage is fermented to preserve its nutrient content for a long time by ensiling. The purpose of silage additives is to control the fermentation products by ensuring domination of lactic acid bacteria during fermentation and to preserve the nutrients in the feed as much as possible. In recent years, the popularity of silage additives has increased and has found a wide range of uses. Many additives have been studied for many years to support the fermentation process. Additives improve feed consumption, feed efficiency and performance in animals with their positive effects on silage quality together with an efficient ensiling [22]. Many silage additives are produced biotechnologically. Among them, bacterial inoculants and enzymes are used to provide fast and effective silage fermentation. The purpose of using melatonin as an additive is to control silage fermentation, form the desired end products and obtain appropriate quality silage. Melatonin has antioxidant and bacteriostasis properties as a natural preservative. With these properties, it can be considered as a silage additive. There is no literature on the use of melatonin as an additive in corn or mazie silages used in dairy cattle feeding. However, *Stylosanthes guianensis* (stylo), one of the hot season legume forage plants, was ensiled with the addition of melatonin at different rates (5, 10, 20 mg/kg), and the rate of 5 mg/kg increased the lactic acid and total acid level, decreasing the pH value and butyric acid content. It was revealed that the silage fermentation quality was significantly improved. With its antioxidation effect, it inhibited unwanted bacteria and managed to protect the silage [23]. Melatonin is a promising silage additive as it improves the silage properties of one of the legume feeds, which is difficult to ensilage due to its high buffer capacity and low sugar content. It affected the silage microbiota and metabolism of the stylo plant [23]. There is insufficient literature on its use as a silage additive in various plants. The effects of melatonin on the quality of silage feeds, which are most commonly used in ruminant feeding, should be investigated by comparing them with other additives.

Cessation of milking initiates the dry period in dairy cattle, but milk production continues and begins to accumulate in the mammary. With accumulation, milk leaks may occur. In this case, the mammary becomes open to infection. Cows are at high risk of developing intramammary infections due to udder enlargement and altered immune functions during the transition period. When the mammary gland is completely involved, it becomes more resistant to infections. Therefore, it is beneficial to suppress milk yield and accelerate the involution process before the dry period [24]. The melatonin hormone is physiologically secreted at nights in cows. It has been determined that there is a higher rate of melatonin in milk in the morning. While prolonged exposure to sunlight is beneficial for lactating animals, it should be the opposite for animals in dry period. Exposure to sunlight for a short time or administration of melatonin during late lactation may accelerate mammary gland involution by reducing milk yield before the dry period. Several studies have found that the addition of melatonin to feed reduces blood prolactin levels. For example, the addition of melatonin at a dose of 4 mg/kg BW decreased the prolactin level in prepubertal heifers [25]. It has been reported that prolactin level decreased with the addition of melatonin to the rations of cows in the late lactation period for 8 weeks. However,

#### *Use of Melatonin as a Feed Additive DOI: http://dx.doi.org/10.5772/intechopen.105999*

melatonin mixed into the ration did not affect milk yield [26]. It has been reported that the application of melatonin in the form of implants without mixing with the feed did not affect the milk yield of the cows in the postpartum period [27].

The effect of melatonin feeding on prolactin hormone in prepartum heifers and cows was not as effective as "short day photoperiod" (SDPP, 16 s dark-8 s light) application [24]. The positive effects of melatonin supplementation in prepartum period on milk production in postpartum period are not certain. This may also be related to short trial duration or insufficient number of cows. Lacasse et al. applied "long day photoperiod" (LDPP, 16 s light-8 s dark) to cows starting 8 weeks before calving and added 25 mg melatonin to feed. It was stated that the milk yield of the cows treated with SDPP in the early lactation period was higher than those treated with LDPP + melatonin [28]. This situation can be explained by the source of the melatonin used. Because not all sources of melatonin may have the same effect. SDPP application in the dry period has a positive effect on feed utilization as well as postpartum milk yield. In the studies, adding melatonin instead of applying SDPP in the dry period did not show the same effects. More studies are needed on the relationship between melatonin feeding and performance in dairy cattle. Milk yield parameters in sheep and goats depend on melatonin and prolactin concentrations as much as dairy cows. Using melatonin as a feed additive can reduce the stress caused by injection and implant applications. The use of exogenous melatonin as a subcutaneous implant together with naturally produced endogenous melatonin under SDPP conditions had no effect on lactation performances in different breeds of sheep with different levels of milk production level [29, 30]. This situation can be associated with the stress created in animals.

Rumen fermentation is an issue to be considered when using melatonin as a feed additive or oral preparation. Digestive enzymes and microorganisms in the rumen can metabolize melatonin. If melatonin is involved in rumen fermentation, its bioavailability may be significantly reduced. Therefore, melatonin should be tried in different forms (preserved or by-pass) and by adding it to the rations at different levels. Because it has been reported that the protein, fat and dry matter of milk increased in cows given melatonin in rumen protected from [31]. These researchers also emphasized that milk lactose level decreased with the addition of melatonin. The effect of preserved melatonin on nutrient digestibility or nutrient availability of cows should be considered as reasons for these results. Melatonin is an environmentally friendly molecule that is not toxic in the organism and its preserved forms are quite useful. For the treatment of mastitis, it may be recommended to use protected form of melatonin instead of antibiotics. Thus, the treatment cost would decrease, and the milk quality would increase. It has been determined that melatonin has an effect on some carcass parameters in beef cattle. In heifers given melatonin (4 mg/100 kg body weight) daily for 59 days, rib and longissimus muscle adiposity increased, carcass protein deposition decreased, but body weight gain was not affected [32].
