Melatonin alleviates brain and peripheral tissue edema in a neonatal rat model of hypoxic-ischemic brain damage: the involvement of edema related proteins

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Abstract

Background

Previous studies have indicated edema may be involved in the pathophysiology following hypoxic-ischemic encephalopathy (HIE), and melatonin may exhibit neuro-protection against brain insults. However, little is known regarding the mechanisms that involve the protective effects of melatonin in the brain and peripheral tissues after HIE. The present study aimed to examine the effects of melatonin on multiple organs, and the expression of edema related proteins in a neonatal rat model of hypoxic-ischemic brain damage (HIBD).

Methods

One hundred ninety-two neonatal rats were randomly divided into three subgroups that underwent a sham surgery or HIBD. After the HIBD or sham-injury, the rats received an intraperitoneal injection of melatonin or an equal volume vehicle, respectively. We investigated the effects of melatonin on brain, kidney, and colon edema via histological examination and the expression of edema related proteins, including AQP-4, ZO-1 and occludin, via qPCR and western blot.

Results

Our data indicated (1) Melatonin reduced the histological injury in the brain and peripheral organs induced by HIBD as assessed via H-E staining and transmission electron microscopy. (2) Melatonin alleviated the HIBD-induced cerebral edema characterized by increased brain water content. (3) HIBD induced significant changes of edema related proteins, such as AQP-4, ZO-1 and occludin, and these changes were partially reversed by melatonin treatment.

Conclusions

These findings provide substantial evidence that melatonin treatment has protective effects on the brain and peripheral organs after HIBD, and the edema related proteins, AQP4, ZO-1, and occludin, may indirectly contribute tothe mechanism of the edema protection by melatonin.

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Most cited references 27

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Pathophysiology of acute kidney injury.

David P Basile, Melissa Anderson, Timothy A. Sutton (2012)

Acute kidney injury (AKI) is the leading cause of nephrology consultation and is associated with high mortality rates. The primary causes of AKI include ischemia, hypoxia, or nephrotoxicity. An underlying feature is a rapid decline in glomerular filtration rate (GFR) usually associated with decreases in renal blood flow. Inflammation represents an important additional component of AKI leading to the extension phase of injury, which may be associated with insensitivity to vasodilator therapy. It is suggested that targeting the extension phase represents an area potential of treatment with the greatest possible impact. The underlying basis of renal injury appears to be impaired energetics of the highly metabolically active nephron segments (i.e., proximal tubules and thick ascending limb) in the renal outer medulla, which can trigger conversion from transient hypoxia to intrinsic renal failure. Injury to kidney cells can be lethal or sublethal. Sublethal injury represents an important component in AKI, as it may profoundly influence GFR and renal blood flow. The nature of the recovery response is mediated by the degree to which sublethal cells can restore normal function and promote regeneration. The successful recovery from AKI depends on the degree to which these repair processes ensue and these may be compromised in elderly or chronic kidney disease (CKD) patients. Recent data suggest that AKI represents a potential link to CKD in surviving patients. Finally, earlier diagnosis of AKI represents an important area in treating patients with AKI that has spawned increased awareness of the potential that biomarkers of AKI may play in the future. © 2012 American Physiological Society. Compr Physiol 2:1303-1353, 2012.

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Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines.

Kei-Xian Tan, Rüdiger Hardeland, Russel Reiter (2009)

Kynuramines represent their own class of biogenic amines. They are formed either by decarboxylation of kynurenines or pyrrole ring cleavage of indoleamines. N(2)-formylated compounds formed in this last reaction can be deformylated either enzymatically by arylamine formamidases or hemoperoxidases, or photochemically. The earlier literature mainly focussed on cardiovascular effects of kynuramine, 5-hydroxykynuramine and their N(1),N(1)-dimethylated analogs, including indirect effects via release of catecholamines or acetylcholine and interference with serotonin receptors. After the discovery of N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) and N(1)-acetyl-5-methoxykynuramine (AMK) as major brain metabolites of melatonin, these compounds became of particular interest. They were shown to be produced enzymatically, pseudoenzymatically, by various free radical-mediated and via photochemical processes. In recent years, AFMK and AMK were shown to scavenge reactive oxygen and nitrogen species, thereby forming several newly discovered 3-indolinone, cinnolinone and quinazoline compounds, and to protect tissues from damage by reactive intermediates in various models. AMK is of special interest due to its properties as a potent cyclooxygenase inhibitor, NO scavenger forming a stable nitrosation product, inhibitor and/or downregulator of neuronal and inducible NO synthases, and a mitochondrial metabolism modulator. AMK easily interacts with aromates, forms adducts with tyrosyl and tryptophanyl residues, and may modify proteins.

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Hypoxic Ischemic Encephalopathy: Pathophysiology and Experimental Treatments.

Kimberly Allen, Debra Brandon (2011)

Hypoxic ischemic encephalopathy (HIE) is a serious birth complication affecting full term infants: 40-60% of affected infants die by 2 years of age or have severe disabilities. The majority of the underlying pathologic events of HIE are a result of impaired cerebral blood flow and oxygen delivery to the brain with resulting primary and secondary energy failure. In the past, treatment options were limited to supportive medical therapy. Currently, several experimental treatments are being explored in neonates and animal models to ameliorate the effects of secondary energy failure. This review discusses the underlying pathophysiologic effects of a hypoxic-ischemic event and experimental treatment modalities being explored to manage infants with HIE. Further research is needed to better understand if the long-term impact of the experimental treatments and whether the combinations of experimental treatments can improve outcomes in infants with HIE.

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Author and article information

Contributors

Bin Sun: (86)512-80693557 , sunyu0628@126.com

Xing Feng: xing_feng66@suda.edu.cn

Journal

Journal ID (nlm-ta): BMC Pediatr

Journal ID (iso-abbrev): BMC Pediatr

Title: BMC Pediatrics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2431

Publication date (Electronic): 28 March 2017

Publication date PMC-release: 28 March 2017

Publication date Collection: 2017

Volume: 17

Electronic Location Identifier: 90

Affiliations

[1 ]GRID grid.452253.7, Institute of Pediatric Research, , Children’s Hospital of Soochow University, ; Suzhou, 215006 China

[2 ]ISNI 0000 0004 1788 4869, GRID grid.452743.3, Department of Neonatology, , Northern Jiangsu People’s Hospital, ; Yangzhou, 225001 China

[3 ]GRID grid.452253.7, Department of Neonatology, , Children’s Hospital of Soochow University, ; Suzhou, 215006 China

Article

Publisher ID: 824

DOI: 10.1186/s12887-017-0824-x

PMC ID: 5371222

PubMed ID: 28351378

SO-VID: 486b16b4-56fb-47d0-b310-06aa4db68de3

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 30 October 2015

Date accepted : 2 March 2017

Funding

Funded by: National Natural Science Foundation

Award ID: 81471488

Award ID: 81271378

Award ID: 81502157

Award ID: 81501291

Award Recipient : Li-Xiao Xu Xin Ding Xing Feng

Funded by: FundRef http://dx.doi.org/10.13039/501100005066, Key medical subjects of Jiangsu province;

Award ID: XK201120

Award Recipient : Xing Feng

Funded by: Public health technology project of Suzhou

Award ID: SS201536

Award Recipient : Xing Feng

Funded by: Jiangsu Province key research and development of special funds

Award ID: BE2015644

Award Recipient : Bin Sun

Funded by: Science and Technology Project of Suzhou

Award ID: SYSD2013105

Award ID: SYS201446

Award ID: SYS201441

Award Recipient : Li-Xiao Xu Bin Sun

Funded by: Key Laboratory of Suzhou City

Award ID: SZS201108

Award Recipient : Xing Feng

Funded by: the Department of Pediatrics Clinical Center of Suzhou

Award ID: Szzx201504

Award Recipient : Xing Feng

Custom metadata

ScienceOpen disciplines: Pediatrics

Keywords: melatonin,hypoxic-ischemic encephalopathy,edema,aquaporin-4,zonula occludens-1,occludin

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ScienceOpen disciplines: Pediatrics

Keywords: melatonin, hypoxic-ischemic encephalopathy, edema, aquaporin-4, zonula occludens-1, occludin

Melatonin alleviates brain and peripheral tissue edema in a neonatal rat model of hypoxic-ischemic brain damage: the involvement of edema related proteins

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Pediatric Pulse: Advancing Neonatal and Child Health

Most cited references 27

Pathophysiology of acute kidney injury.

Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines.

Hypoxic Ischemic Encephalopathy: Pathophysiology and Experimental Treatments.

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