Melatonin: the placental antioxidant and anti-inflammatory

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is an indolamine hormone with many physiological and biological roles. Melatonin is an antioxidant, anti-inflammatory, free radical scavenger, circadian rhythm regulator, and sleep hormone. However, its most popular role is the ability to regulate sleep through the circadian rhythm. Interestingly, recent studies have shown that melatonin is an important and essential hormone during pregnancy, specifically in the placenta. This is primarily due to the placenta's ability to synthesize its own melatonin rather than depending on the pineal gland. During pregnancy, melatonin acts as an antioxidant and anti-inflammatory, which is necessary to ensure a stable environment for both the mother and the fetus. It is an essential antioxidant in the placenta because it reduces oxidative stress by constantly scavenging for free radicals, i.e., maintain the placenta's integrity. In a healthy pregnancy, the maternal immune system is constantly altered to accommodate the needs of the growing fetus, and melatonin acts as a key anti-inflammatory by regulating immune homeostasis during early and late gestation. This literature review aims to identify and summarize melatonin's role as a powerful antioxidant and anti-inflammatory that reduces oxidative stress and inflammation to maintain a favorable homeostatic environment in the placenta throughout gestation.

Keywords: HCMV; NLRP3 inflammasome; anti-inflammatory; antioxidant; melatonin; oxidative stress; placenta; pregnancy.

Figure 1

Structure of the placenta. The placenta is a multifaceted organ with many biological functions that are endocrinologic and immunologic. This temporary organ provides nutrients and oxygen, removes harmful waste products and carbon dioxide, and envelops the fetus in a protective immunologic membrane throughout gestation. Furthermore, the placenta has two distinct sides, fetal and maternal, and several layers and sublayers. The chorion layer is an immensely vascular membrane layer that surrounds the fetus. The chorion has two sublayers: the extraembryonic mesoderm and the trophoblast (cytotrophoblast and syncytiotrophoblast). Both layers are located on the fetal side of the placenta. The extraembryonic mesoderm is a tissue that contributes to the epithelium of the yolk sac, amnion, and chorionic villi (chorion plate). The trophoblasts are specialized cells crucial for embryo implantation because they interact with the maternal uterine environment to limit fetal immune rejection and ensure an adequate blood supply. The two types of trophoblast cells are cytotrophoblast and syncytiotrophoblast. Both cells cover the outer surface of the chorionic villus. The cytotrophoblast is the innermost lining of the chorionic villus, while the syncytiotrophoblast is the outermost lining of the chorionic villus that is bathed in maternal blood. Because the syncytiotrophoblast is bathed in maternal blood, it has the vital role of transporting nutrients to the fetus and removing waste. Therefore, these cells must have ample blood supply and blood flow and undergo apoptosis regularly to maintain adequate blood circulation. The cytotrophoblast cells are progenitor stem cells of the syncytiotrophoblast. These cells differentiate into the syncytiotrophoblast cells. Therefore, the cytotrophoblast has the specialized role of ensuring that the placenta has ample blood supply with nutrients and oxygen. Adequate blood supply and blood flow by the cytotrophoblast and syncytiotrophoblast are essential in maintaining the integrity of the placenta. If the integrity of the placenta becomes compromised, then adverse pregnancy complications, such as pre-eclampsia, preterm birth, and intrauterine growth restriction, will occur. Created with Biorender.com.

Figure 2

Melatonin biosynthesis and its distribution in the human body during pregnancy. The synthesis of melatonin begins with the amino acid tryptophan, which subsequently transforms into 5-HTP. This intermediate is then converted into serotonin. The rate-limiting enzyme, AANAT, acts on serotonin, culminating in N-acetylserotonin production. ASMT then catalyzes the final step, yielding melatonin. Once synthesized, the SCN in the brain, which regulates circadian rhythms, signals the pineal gland to release melatonin into the maternal circulation. Notably, melatonin is also synthesized within the placenta by trophoblastic cells. This melatonin subsequently influences various processes in placental function, essential for fetal growth and development. 5-HTP, 5-hydroxytryptophan; AANAT, arylalkylamine N-acetyltransferase; ASMT, acetylserotonin O-methyltransferase; SCN, suprachiasmatic nucleus. Created with Biorender.com.

Figure 3

Signaling pathway of melatonin via G-protein-coupled receptors. Melatonin primarily signals through two G-protein-coupled receptors, MT1 and MT2. Upon melatonin binding, the MT1 homodimer receptor and MT2 homodimer receptor couples with Gi proteins, inhibiting adenylate cyclase. This results in decreased cAMP production and subsequent reduced activation of PKA. MT1 and MT2 heterodimer activation can also couple with Gq/11 proteins to stimulate PLC. This enzyme catalyzes the conversion of PIP2 into IP3 and DAG. IP3 subsequently promotes calcium release from intracellular stores, elevating intracellular calcium levels. Simultaneously, DAG and calcium can activate PKC, which influences a broad spectrum of cellular activities. PKC modulates numerous cellular processes by phosphorylating target proteins. The heterodimerization of MT1 and MT2 in the placenta has yet to be studied. However, the binding of melatonin on the MT1 homodimer and MT2 homodimer has been shown to elicit antioxidant and anti-inflammatory responses in placental cells by reducing oxidative stress and inflammation. Moreover, activating these receptors in these cells indicates autocrine and paracrine activity, imperative to placental homeostasis and fetal development. Gi and Gq, G-proteins; GDP and GTP, guanosine diphosphate and guanosine triphosphate, respectively; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; Ca²⁺, calcium ions; PKC, protein kinase C. Created with Biorender.com.

Figure 4

Role of melatonin in homeostasis and viral infection during pregnancy. Melatonin is pivotal in maintaining cellular homeostasis due to its antioxidant properties, which neutralize ROS. In the placenta, melatonin supports a healthy pregnancy through its antioxidant activity, anti-inflammatory actions, Nrf-2 upregulation to enhance cellular defense mechanisms, trophoblast cell protection essential for placental and fetal development, and hormone production regulation to balance the hormonal environment for fetal growth. In the context of viral infections such as HCMV, HIV, HSV, and ZIKV, melatonin levels drop significantly, leading to an increase in ROS. This surge in oxidative stress can cause complications, including free radicals/ROS production, NLRP3 activation, inflammation, TXNIP dissociation affecting cellular stress responses, and chronodisruption, which together elevate the risks of IUGR, preterm birth, pre-eclampsia, and other potential complications. ROS, reactive oxygen species; HCMV, human cytomegalovirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; ZIKV, Zika virus; IUGR, intrauterine growth restriction; NLRP3, NOD-, LRR-, and pyrin domain-containing protein 3; TXNIP, thioredoxin-interacting protein. Created with Biorender.com.