Melatonin and Allergic Rhinitis

Atopy is a tendency to produce Ig-E antibodies in response to allergens and to develop allergic clinical symptoms such as allergic rhinitis, allergic bronchial asthma, and atopic dermatitis. Among them, allergic rhinitis (AR) is a chronic inflammatory disease of the intranasal mucosa, characterized by nasal symptoms reducing the quality of life. Management of AR maintains entirely symptomatic and is intended only to relieve the undesirable effects of mediators resulting from the allergic inflammatory reaction. The only disease-modifying treatment is immunotherapy, which can eliminate the pathophysiology of the disease. However, it is a long-lasting modality with several limitations and contraindications. In recent years, melatonin has been evaluated in various allergic inflammatory disorders due to its anti-inflammatory and antioxidant properties and has been suggested as a promising therapeutic. The role of melatonin has not been investigated in the treatment of AR, even though AR has a similar pathogenesis to those of atopic dermatitis and allergic bronchial asthma. This review is aimed to examine the pathophysiological mechanism of AR and illuminate the common pathways with atopic dermatitis and allergic bronchial asthma to discuss the potential hypothetical therapeutic role of the melatonin in AR, similar to the other two atopic diseases. Keyword: melatonin, allergic rhinitis, atopy, asthma, atopic dermatitis, interleukin Allergic rhinitis (AR) is a chronic disease of the upper airways, characterized by IgE-mediated inflammation of the nasal mucous membranes in the nose. Atopy and environmental factors play a role in the etiology of AR. The symptoms of AR are a runny nose, nasal congestion, sneezing, and nasal itching (1, 2). When exposed to the allergen, the dendritic cells (Langerhans cells), the antigen-presenting cells in the nasal mucosa, receive the allergen by endocytosis. Then the Langerhans cell proteolyzes the allergen into peptide sequences and expresses the antigen of the allergen in its surface MHC-Class II antigen recognition site. The allergen is then transported to the regional lymph node to be introduced to naive CD4 + T lymphocytes (1). In response, Th0 cells differentiate into Th2 lymphocytes through various cytokines and transcription factors one of which is interleukin (IL)-4 released from Type 2 innate lymphoid cells. Cytokines such as IL-3, IL-4, IL-5, and granulocyte macrophage stimulating factor (GM-CSF) are secreted from T2 lymphocytes to induce the maturation, activation, and chemotaxis of eosinophils (through IL-5); and IgE expression from B lymphocytes (through IL-4 and IL-13). Specific IgE antibodies bind to the membrane receptors of mast cells in tissues and circulating basophils. When exposed to the allergen, the allergen binds to the mast cell with its specific IgE receptors, resulting in degranulation (1-3). Various mediators such as histamines, proteases, proteoglycans, and TNF-α (tumor necrosis factor-alpha) are immediately released by mast cell degranulation. The platelet-activating factor (PAF), leukotrienes (LCT4, LTD4, LTE4) and prostaglandins (PGD2) are synthesized de nova and released in minutes (4). This process is called early phase and manifests itself in increased vascular permeability through substance P, neurokinin-A, vasointestinal peptide (VIP), and calcitonin gene-associated peptide (CGRP); exudation; increased nasal secretions from the submucosal glands; congestion; sneezing; and nasal itching (1, 3). The amount of histamine may not always correlate with findings other than sneezing, and even high levels of histamine may be present in nasal secretions of non-AR individuals. However, the number of leukotrienes and prostaglandins are often correlated with symptoms that occur in the early phase (1). The late phase of AR usually begins within 4-6 hours after the allergen exposure, peaks after 6-12 hours and mainly characterized by the prolongation of early phase symptoms, particularly nasal congestion (1). Interleukins synthesized from mast cells (IL-4, IL-5, Çakır Çetin et al. Melatonin and allergic rhinitis J Basic Clin Health Sci 2020; 1:1-6 2 IL-6, IL-1b, and IL-13), cytokines, and chemokines such as GM-CSF and TNF-α are involved in this phase. These mediators contribute to eosinophilic, basophilic, and T lymphocytic infiltration of the nasal mucosa by increasing the expression of vascular adhesion molecules in endothelial cells (3). Within four to eight hours, these inflammatory cells in the tissue begin to activate and release their inflammatory mediators. Activated epithelial cells release the thymic stromal lymphopoietin (TLSP), IL-25 and IL-33, contributing to the Th2 response, some leading to apoptosis (2). This remodeling process, which is characterized by tissue damage, inflammatory (especially eosinophilic through IL-5) cell infiltration, epithelial atrophy, goblet cell hyperplasia, and extracellular matrix thickening, is the result of the late phase of AR (3). Regulatory T lymphocytes (Treg) also play a role in the exacerbation of Th2 lymphocyte response, particularly through IL-10 (2). A decrease in Treg cell number and function has been demonstrated in patients with AR (5). Th17 plays a role in atopy related autoimmunity and allergic disorders, as well. A balance between Th17 and Treg cells is crucial such that excess in Th17 function and a defect in Treg function may trigger the development and progression of allergic asthma and rhinitis (6). Melatonin as a promising treatment modality Synthesis and release of melatonin Melatonin (5-methoxy N-acetyl tryptamine), released from the suprachiasmatic nucleus in the pineal gland, is a neurohormone that has been under consideration for its known effects on the circadian rhythm as well as its impact on the immune system in recent years (7). In addition to the pineal gland, many tissues are known to synthesize melatonin, such as ovarian, lens and bone marrow cells in mammals, and spleen, thymus, platelets and other immune cells in rats (8). The precursor of melatonin is tryptophan. Tryptophan is converted to N-acetyl serotonin by the enzyme N-acetyltransferase and then to melatonin by the hydroxy indole-O-methyltransferase enzyme. The activity of N-acetyltransferase is regulated periodically in a photosensitive manner. In the presence of light, the suprachiasmatic nucleus and other hypothalamic structures are stimulated, while in the dark serotonin and N-acetyltransferase are released from the stores via noradrenaline. Between 20.00 and 23.00, the melatonin level gradually increases and peaks around 01.00-05.00. Normally, serum melatonin levels are around 0-20 picograms (pg) / milliliters (ml) in daytime and 20-200 pg / ml (average 60-70 pg / ml) at night. Pharmacokinetics of melatonin The hormone is highly lipophilic and partially hydrophilic. It can be administered orally by dissolving in gelatin capsules or intravenously in ethanol, and intraperitoneally. When administered intravenously, melatonin is eliminated in minutes because of its short half-time (0.5 to 5.6 minutes) however after oral administration it takes approximately 60 minutes to reach a peak. After oral administration, plasma distribution follows a biphasic pattern with a half-life of respectively 2 and 20 minutes and serum peak concentration is reached approximately in 60 minutes (8). The bioavailability of melatonin ranges between 10 and 56% (mean 33%). Melatonin is metabolized rapidly and mostly in the liver and to a lesser extent in the kidney. When administered in the oral route, a ratio of 95% is exposed to a hepatic first-pass in which cytochrome P450 enzyme CYP1A2 takes a role and leads the production of a principal urinary extraction metabolite called the “6-sulfatoxymelatonin (6-SM)” (8). Melatonin, of which synthesis is diminished by light activation, has been described in photo-immunomodulation for seasonal and intraday circadian effects on the immune system. According to data from studies on many vertebrates and humans, it is known that, as the duration of exposure to light decreases, especially during sleep and in winter, the level of melatonin increases to strengthen the immune system (7). Mechanisms of action of melatonin The melatonin effects in humans and other mammals by G-protein coupled membrane receptors, nuclear receptors, calmodulin and antioxidant properties (9). Melatonin G-protein coupled membrane receptors are present in the peripheral organs (spleen, thymus and all lymphocyte types, caudal artery, etc.) as well as cerebrum (cortex and suprachiasmatic nucleus) in humans (8, 10, 11). These are the high-affinity Mel1a (ML1, ML1a, MT1, MTNR1A) mainly located in the suprachiasmatic core of the hypothalamus and low-affinity affinity Mel1b (MT2, ML1b, MTNR1B) receptors. Although post-receptor signaling mechanisms are usually carried out via the inhibition of adenylate cyclase and reduction of cAMP, Mel1b receptors also inhibit guanylate cyclase and reduce cGMP, and are known to act through different signaling mechanisms in non-human species, too (8, 10, 11). Mel1a is mainly located in various sites of brain such as the pituitary gland, hypothalamus (suprachiasmatic nucleus), thalamus, cortex, basal ganglia, nucleus accumbens, amygdala, hippocampus, cerebellum, skin, and retina whereas Mel1b is basically seen in retina and cornea, and less frequently in cortex, hippocampus, paraventricular nucleus, and cerebellum (8, 11). MT3 (ML2, Quinone reductase enzyme-2 (NQO2), QR2) receptors are detoxification enzymes and located in liver, kidney, heart, lung, intestine, muscle, and brown fat tissue (11). Melatonin might function through two types of nuclear receptors; the orphan receptor retinoid Z receptor (RZR)β and the retinoic acid related orphan receptor (ROR) α, β, and γ (8, 12). The nuclear receptors of melatonin are crucial for the mast cells to achieve inflammation, immune response, cell proliferation, and apoptos