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Emerging Highlights on Natural Prodrug Molecules with Multifarious Therapeutic Perspectives
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Mojabir Hussen Ansari, Vaibhav Shende, Debarshi Kar Mahapatra
Melatonin (5-methoxy-N-acetyltryptamine) was first discovered by Aaron Lerner in the year 1958 from bovine pineal. Retina, platelets, bone marrow cells, lymphocytes, skin, Harderian gland, gastrointestinal tract, cerebellum, etc., are also reported as a source of extrapineal supply of melatonin. Melatonin is mainly prepared by the pinealocytes from an essential amino acid tryptophan. Tryptophan is synthesized by hydroxylation of 5-hydroxytryptophan by the enzyme tryptophan-5-hydroxylase then further changed into decarboxylated form with the aid of the 5-hydroxytryptophan decarboxylase enzyme. The synthesis and secretion of melatonin are enhanced by the way of darkness and inhibited by the way of light.13 Melatonin is an omnipresent molecule having natural and powerful antioxidant proprieties and it is safe when administered exogenously. Melatonin also possesses potential anti-inflammatory effects due to inhibiting inflammasome activation. Melatonin also owns its anti-apoptotic activities particularly by inhibiting Caspase-3 cleavage and mPTP opening. The presence and the inter-distance of 5-methoxy group and the N-acetyl chain are the two critical factors in the determination of specificity and amphiphilicity of melatonin.14 Scientific studies on MT1 and MT2 receptor knockout mice have resulted that MT1 and MT2 receptors play specific roles in sleep. Melatonin and melatonin agonists also play essential roles in the remedy of insomnia by activating MT1 and MT2 melatonin receptors.15
The Pineal Gland and Melatonin
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
Jerry Vriend, Nancy A.M. Alexiuk
Although the pinealocyte is the most numerous and most extensively studied cell type in the mammalian pineal, other cell types have been observed. Glial cells have been estimated to account for up to 12% of the total number of cells in the rat pineal.100 Immunocytochemical studies of glial cells in the rat pineal provide evidence that the glial cells are primarily astrocytes.101 Astrocyte-specific glial antigens, vimenten, glial fibrillary acid protein (GFAP) and S-100 were localized in the pineal gland of rats, hamsters, and gerbils.23,102 Glial processes were also found in the pineal stalk, where they are described as encircling neural and vascular elements of the stalk.103
Pineal Gland
Published in Paul V. Malven, Mammalian Neuroendocrinology, 2019
The primary secretory product of the pineal gland is melatonin and Figure 10-1 summarizes melatonin biosynthesis. Pinealocytes take up blood-borne tryptophan and convert it into 5-hydroxytryptophan using the enzyme tryptophan hydroxylase. The 5-hydroxytryptophan is then decarboxylated to yield the indolamine compound serotonin (also known as 5-hydroxytryptamine or 5-HT). Neither enzymatic conversion leading to the formation of serotonin is thought to be rate-limiting to biosynthesis of melatonin. However, the conversion of serotonin into N-acetylserotonin by the enzyme N-acetyltransferase (NAT) is a highly regulated and very rate-limiting reaction in melatonin synthesis. The final biosynthetic step involves the conversion of N-acetylserotonin to melatonin (also known as 5-methyoxy N-acetylserotonin) by the enzyme hydroxyindole-O-methyltransferase (abbreviated HIOMT). Most of the melatonin synthesized in pinealocytes is secreted into blood. A small portion is secreted into the cerebrospinal fluid (CSF) of the third ventricle, and some may be metabolized within the pinealocytes to biologically weaker compounds. Although the concentrations of melatonin in blood and in CSF are approximately equivalent, quantitative analysis of melatonin secretion by the sheep pineal gland revealed that far greater amounts were secreted into blood than into CSF, reflecting the much larger volume of blood compared to CSF (Rollag et al., 1978).
Night work effects on salivary cytokines TNF, IL-1β and IL-6
Published in Chronobiology International, 2019
Érica Lui Reinhardt, Pedro Augusto Carlos Magno Fernandes, Regina P. Markus, Frida Marina Fischer
Our results of salivary TNF and IL-1β are in agreement with their findings about cytokines, but not those regarding salivary IL-6. However, Cuesta et al. (2016) detected the presence of significant plasma melatonin rhythms following three simulated night shifts, without any significant phase shift or change in amplitude. In the present study, in contrast, a melatonin rhythm was absent and there were significant changes in melatonin amplitude among night workers. Recently, it was suggested a close relationship between melatonin and the synthesis of IL-6 by monocytes (Song et al. 2018). In addition, melatonin, at concentrations compatible to nocturnal plasma concentration (pM to nM), inhibits the rolling and adhesion of leukocytes (Lotufo et al. 2001; Markus et al. 2018). During the mounting of an inflammatory response the nocturnal melatonin peak is reduced or even absent, as the activation of the nuclear factor kappa B (NFκB) pathway in pinealocytes blocks the synthesis of melatonin in rodents and humans (Markus et al. 2018). Thus, the whole circadian system, including clocks and pineal gland, is involved in regulating cytokine profile in shift workers.
Pharmacotherapy and nutritional supplements for seasonal affective disorders: a systematic review
Published in Expert Opinion on Pharmacotherapy, 2018
Olivia Cools, Kaat Hebbrecht, Violette Coppens, Laurence Roosens, Andy De Witte, Manuel Morrens, Hugo Neels, Bernard Sabbe
Two beta-blockers have been shown to have certain positive effects on mood symptomatology and are hypothesized to suppress the nocturnal secretion of melatonin; melatonin is released in response to stimulation of the β-adrenergic receptors on the pinealocytes [66,67]. Atenolol, a long-acting beta-blocker, was compared with placebo [66]. Both groups significantly improved, but no significant differences were observed between them [66]. Schlager et al. [67] proposed that the failure of atenolol was due to its long-acting properties and hypothesized that a short-acting beta-blocker given before sunrise would be more beneficial [67]. Propranolol was investigated in a two-phase design with an introductory, open-label phase followed by a DB-RCT [67]. After the open-label phase (n = 33), depressive scores significantly decreased, with 24 out of 33 subjects being in remission. Only 12 subjects enrolled in the subsequent RCT. In the second phase, all subjects regained symptoms, although the severity of depressive symptomatology was significantly higher in the placebo group [67].
Revisiting the pineal gland: a review of calcification, masses, precocious puberty, and melatonin functions
Published in International Journal of Neuroscience, 2020
Shrey Patel, Benjamin Rahmani, Jason Gandhi, Omar Seyam, Gunjan Joshi, Inefta Reid, Noel L. Smith, Wayne C. Waltzer, Sardar Ali Khan
Parenchymal pinealocytes predominantly make up the pineal body. The term pinealocytes encompasses a large array of cell types; some which are photosensitive and some which are not. Scientists have observed the presence of photo-transduction molecules such as rod-opsin, recoverin, and arrestin (S-antigen), which is the basis of the widely accepted idea that the gland is photosensitive [9–11]. Although debate continues as to whether or not true photoreceptor pinealoctyes exist, physiologists concluded that astrocytes and phagocytes (microglia) exist within the pineal gland [2]. Although pinealocytes are the primary cells types, there are about 5 different cell types within the pineal gland which are described in Table 2 [12].