Melatonin As a Master Regulator of Cell Death and Inflammation: Molecular Mechanisms and Clinical Implications for Newborn Care

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2019 Apr 10

PMID 30962427

Citations 112

Authors

Anna Tarocco

Natascia Caroccia

Giampaolo Morciano

Mariusz R Wieckowski

Gina Ancora

Giampaolo Garani

Paolo Pinton

Affiliations

Soon will be listed here.

Abstract

Melatonin, more commonly known as the sleep hormone, is mainly secreted by the pineal gland in dark conditions and regulates the circadian rhythm of the organism. Its intrinsic properties, including high cell permeability, the ability to easily cross both the blood-brain and placenta barriers, and its role as an endogenous reservoir of free radical scavengers (with indirect extra activities), confer it beneficial uses as an adjuvant in the biomedical field. Melatonin can exert its effects by acting through specific cellular receptors on the plasma membrane, similar to other hormones, or through receptor-independent mechanisms that involve complex molecular cross talk with other players. There is increasing evidence regarding the extraordinary beneficial effects of melatonin, also via exogenous administration. Here, we summarize molecular pathways in which melatonin is considered a master regulator, with attention to cell death and inflammation mechanisms from basic, translational and clinical points of view in the context of newborn care.

Citing Articles

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References

Padilla-Gomes N, Enriquez G, Acosta-Rojas R, Perapoch J, Hernandez-Andrade E, Gratacos E . Prevalence of neonatal ultrasound brain lesions in premature infants with and without intrauterine growth restriction. Acta Paediatr. 2007; 96(11):1582-7. DOI: 10.1111/j.1651-2227.2007.00496.x. View

Katzer D, Mueller A, Welzing L, Reutter H, Reinsberg J, Bartmann P . Antioxidative status and oxidative stress in the fetal circulation at birth: the effects of time of delivery and presence of labor. Early Hum Dev. 2015; 91(2):119-24. DOI: 10.1016/j.earlhumdev.2014.12.012. View

Yu G, Kubota H, Okita M, Maeda T . The anti-inflammatory and antioxidant effects of melatonin on LPS-stimulated bovine mammary epithelial cells. PLoS One. 2017; 12(5):e0178525. PMC: 5444821. DOI: 10.1371/journal.pone.0178525. View

Mantovani M, Kaster M, Pertile R, Calixto J, Rodrigues A, Santos A . Mechanisms involved in the antinociception caused by melatonin in mice. J Pineal Res. 2006; 41(4):382-9. DOI: 10.1111/j.1600-079X.2006.00380.x. View

Koh P . Melatonin attenuates the focal cerebral ischemic injury by inhibiting the dissociation of pBad from 14-3-3. J Pineal Res. 2007; 44(1):101-6. DOI: 10.1111/j.1600-079X.2007.00495.x. View

Yu H, Dickson E, Jung S, Koh D, Hille B . High membrane permeability for melatonin. J Gen Physiol. 2015; 147(1):63-76. PMC: 4692493. DOI: 10.1085/jgp.201511526. View

Gitto E, Reiter R, Amodio A, Romeo C, Cuzzocrea E, Sabatino G . Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin. J Pineal Res. 2004; 36(4):250-5. DOI: 10.1111/j.1600-079X.2004.00124.x. View

Carloni S, Proietti F, Rocchi M, Longini M, Marseglia L, DAngelo G . Melatonin Pharmacokinetics Following Oral Administration in Preterm Neonates. Molecules. 2017; 22(12). PMC: 6149762. DOI: 10.3390/molecules22122115. View

Miller S, Yawno T, Alers N, Castillo-Melendez M, Supramaniam V, VanZyl N . Antenatal antioxidant treatment with melatonin to decrease newborn neurodevelopmental deficits and brain injury caused by fetal growth restriction. J Pineal Res. 2014; 56(3):283-94. DOI: 10.1111/jpi.12121. View

10.

Esposito E, Cuzzocrea S . Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol. 2011; 8(3):228-42. PMC: 3001216. DOI: 10.2174/157015910792246155. View

11.

Zhou H, Zhang Y, Hu S, Shi C, Zhu P, Ma Q . Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis. J Pineal Res. 2017; 63(1). PMC: 5518188. DOI: 10.1111/jpi.12413. View

12.

Areti A, Komirishetty P, Akuthota M, Malik R, Kumar A . Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy. J Pineal Res. 2017; 62(3). DOI: 10.1111/jpi.12393. View

13.

Olivier P, Fontaine R, Loron G, Steenwinckel J, Biran V, Massonneau V . Melatonin promotes oligodendroglial maturation of injured white matter in neonatal rats. PLoS One. 2009; 4(9):e7128. PMC: 2742165. DOI: 10.1371/journal.pone.0007128. View

14.

Shavali S, Ho B, Govitrapong P, Sawlom S, Ajjimaporn A, Klongpanichapak S . Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin an endogenous opioid. Brain Res Bull. 2005; 64(6):471-9. DOI: 10.1016/j.brainresbull.2004.09.008. View

15.

Andrabi S, Sayeed I, Siemen D, Wolf G, Horn T . Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB J. 2004; 18(7):869-71. DOI: 10.1096/fj.03-1031fje. View

16.

Jan J, Wasdell M, Freeman R, Bax M . Evidence supporting the use of melatonin in short gestation infants. J Pineal Res. 2007; 42(1):22-7. DOI: 10.1111/j.1600-079X.2006.00398.x. View

17.

Hu Y, Wang Z, Liu Y, Pan S, Zhang H, Fang M . Melatonin reduces hypoxic-ischaemic (HI) induced autophagy and apoptosis: An in vivo and in vitro investigation in experimental models of neonatal HI brain injury. Neurosci Lett. 2017; 653:105-112. DOI: 10.1016/j.neulet.2016.11.050. View

18.

Morciano G, Preti D, Pedriali G, Aquila G, Missiroli S, Fantinati A . Discovery of Novel 1,3,8-Triazaspiro[4.5]decane Derivatives That Target the c Subunit of F/F-Adenosine Triphosphate (ATP) Synthase for the Treatment of Reperfusion Damage in Myocardial Infarction. J Med Chem. 2018; 61(16):7131-7143. DOI: 10.1021/acs.jmedchem.8b00278. View

19.

Fineschi V, Viola R, La Russa R, Santurro A, Frati P . A Controversial Medicolegal Issue: Timing the Onset of Perinatal Hypoxic-Ischemic Brain Injury. Mediators Inflamm. 2017; 2017:6024959. PMC: 5572618. DOI: 10.1155/2017/6024959. View

20.

Petrosillo G, Moro N, Ruggiero F, Paradies G . Melatonin inhibits cardiolipin peroxidation in mitochondria and prevents the mitochondrial permeability transition and cytochrome c release. Free Radic Biol Med. 2009; 47(7):969-74. DOI: 10.1016/j.freeradbiomed.2009.06.032. View