褪黑素联合亚低温治疗新生儿缺氧缺血性脑病的研究进展

刘一勋; 夏世文

doi:10.7499/j.issn.1008-8830.2302099

PDF(962 KB)

HTML

中国当代儿科杂志 ›› 2023, Vol. 25 ›› Issue (8) : 864-869. DOI: 10.7499/j.issn.1008-8830.2302099

综述

褪黑素联合亚低温治疗新生儿缺氧缺血性脑病的研究进展

刘一勋^1,2, 夏世文²

作者信息 +

Research research on the use of melatonin in combination with therapeutic hypothermia for the treatment of neonatal hypoxic-ischemic encephalopathy

LIU Yi-Xun, XIA Shi-Wen

Author information +

文章历史 +

摘要

新生儿缺氧缺血性脑病（hypoxic-ischemic encephalopathy，HIE）是足月儿死亡和远期神经发育障碍的主要病因之一，尚无根治措施。亚低温治疗（therapeutic hypothermia，TH）是新生儿监护病房中HIE的标准疗法，但在偏远地区的安全性和有效性尚不确定。褪黑素（melatonin，MT）是一种主要由松果体分泌的吲哚类内分泌激素，能够轻易穿透血脑屏障。通过受体和非受体机制，MT发挥抗氧化、抗炎效果，参与调控细胞器功能、抑制细胞死亡。可靠的安全性及临床（前）结果使MT被认为是治疗HIE有前景的药物之一。该文就MT联合TH治疗HIE的研究进展进行综述。

Abstract

Neonatal hypoxic-ischemic encephalopathy (HIE) remains one of the leading causes of death and long-term neurodevelopmental disorders in full-term neonates, and there is currently no curative treatment. Therapeutic hypothermia is now a standard therapy for HIE in the neonatal intensive care unit, but its safety and efficacy in remote areas remains unclear. Melatonin is an indole endocrine hormone mainly produced by the pineal gland and it has the ability to easily penetrate the blood-brain barrier. Through receptor and non-receptor mechanisms, melatonin exerts anti-oxidative and anti-inflammatory effects and participates in the regulation of organelle function and the inhibition of cell death. Melatonin is considered one of the most promising drugs for the treatment of HIE based on its reliable safety profile and clinical/preclinical results. This article reviews the recent research on the use of melatonin in combination with therapeutic hypothermia for the treatment of neonatal HIE.

导出引用

刘一勋, 夏世文. 褪黑素联合亚低温治疗新生儿缺氧缺血性脑病的研究进展[J]. 中国当代儿科杂志. 2023, 25(8): 864-869 https://doi.org/10.7499/j.issn.1008-8830.2302099

LIU Yi-Xun, XIA Shi-Wen. Research research on the use of melatonin in combination with therapeutic hypothermia for the treatment of neonatal hypoxic-ischemic encephalopathy[J]. Chinese Journal of Contemporary Pediatrics. 2023, 25(8): 864-869 https://doi.org/10.7499/j.issn.1008-8830.2302099

参考文献

1 Papazian O. Neonatal hypoxic-ischemic encephalopathy[J]. Medicina (B Aires), 2018, 78 Suppl 2: 36-41. PMID: 30199363.
2 王睁, 王颖雯, 程国强, 等. 亚低温治疗中重度新生儿缺氧缺血性脑病系统评价/Meta分析[J]. 中国循证儿科杂志, 2022, 17(2): 81-89. DOI: 10.3969/j.issn.1673-5501.2022.02.001.
3 Wang Z, Zhang P, Zhou W, et al. Neonatal hypoxic-ischemic encephalopathy diagnosis and treatment: a national survey in China[J]. BMC Pediatr, 2021, 21(1): 261. PMID: 34090355. PMCID: PMC8178820. DOI: 10.1186/s12887-021-02737-6.
4 Pluta R, Furmaga-Jab?ońska W, Januszewski S, et al. Melatonin: a potential candidate for the treatment of experimental and clinical perinatal asphyxia[J]. Molecules, 2023, 28(3): 1105. PMID: 36770769. PMCID: PMC9919754. DOI: 10.3390/molecules28031105.
5 Sun Y, Ma L, Jin M, et al. Effects of melatonin on neurobehavior and cognition in a cerebral palsy model of plppr5-/- mice[J]. Front Endocrinol (Lausanne), 2021, 12: 598788. PMID: 33692754. PMCID: PMC7937640. DOI: 10.3389/fendo.2021.598788.
6 Ahmad QM, Chishti AL, Waseem N. Role of melatonin in management of hypoxic ischaemic encephalopathy in newborns: a randomized control trial[J]. J Pak Med Assoc, 2018, 68(8): 1233-1237. PMID: 30108392.
7 Aridas JDS, Yawno T, Sutherland AE, et al. Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs[J]. J Pineal Res, 2018, 64(4): e12479. PMID: 29464766. PMCID: PMC5947141. DOI: 10.1111/jpi.12479.
8 Martini S, Castellini L, Parladori R, et al. Free radicals and neonatal brain injury: from underlying pathophysiology to antioxidant treatment perspectives[J]. Antioxidants (Basel), 2021, 10(12): 2012. PMID: 34943115. PMCID: PMC8698308. DOI: 10.3390/antiox10122012.
9 陈亚敏, 文政芳, 王国霞. 褪黑素对缺氧缺血性脑损伤新生大鼠皮层氧化应激的影响[J]. 神经解剖学杂志, 2021, 37(3): 305-309. DOI: 10.16557/j.cnki.1000-7547.2021.03.009.
10 Fulia F, Gitto E, Cuzzocrea S, et al. Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin[J]. J Pineal Res, 2001, 31(4): 343-349. PMID: 11703564. DOI: 10.1034/j.1600-079x.2001.310409.x.
11 Sinha B, Wu Q, Li W, et al. Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor[J]. J Pineal Res, 2018, 64(1): e12443. PMID: 28796402. DOI: 10.1111/jpi.12443.
12 Martini S, Austin T, Aceti A, et al. Free radicals and neonatal encephalopathy: mechanisms of injury, biomarkers, and antioxidant treatment perspectives[J]. Pediatr Res, 2020, 87(5): 823-833. PMID: 31655487. DOI: 10.1038/s41390-019-0639-6.
13 Berger HR, Morken TS, Vettukattil R, et al. No improvement of neuronal metabolism in the reperfusion phase with melatonin treatment after hypoxic-ischemic brain injury in the neonatal rat[J]. J Neurochem, 2016, 136(2): 339-350. PMID: 26526584. DOI: 10.1111/jnc.13420.
14 Pang R, Advic-Belltheus A, Meehan C, et al. Melatonin for neonatal encephalopathy: from bench to bedside[J]. Int J Mol Sci, 2021, 22(11): 5481. PMID: 34067448. PMCID: PMC8196955. DOI: 10.3390/ijms22115481.
15 Yao L, Lu P, Ling EA. Melatonin suppresses toll like receptor 4-dependent caspase-3 signaling activation coupled with reduced production of proinflammatory mediators in hypoxic microglia[J]. PLoS One, 2016, 11(11): e0166010. PMID: 27812200. PMCID: PMC5094586. DOI: 10.1371/journal.pone.0166010.
16 Merlo S, Luaces JP, Spampinato SF, et al. SIRT1 mediates melatonin's effects on microglial activation in hypoxia: in vitro and in vivo evidence[J]. Biomolecules, 2020, 10(3): 364. PMID: 32120833. PMCID: PMC7175216. DOI: 10.3390/biom10030364.
17 Li W, He P, Huang Y, et al. Selective autophagy of intracellular organelles: recent research advances[J]. Theranostics, 2021, 11(1): 222-256. PMID: 33391472. PMCID: PMC7681076. DOI: 10.7150/thno.49860.
18 Carloni S, Riparini G, Buonocore G, et al. Rapid modulation of the silent information regulator 1 by melatonin after hypoxia-ischemia in the neonatal rat brain[J]. J Pineal Res, 2017, 63(3): e12434. PMID: 28708259. DOI: 10.1111/jpi.12434.
19 战美芹, 顾燕, 李梅, 等. 褪黑素在缺氧缺血性脑损伤新生大鼠线粒体自噬中的作用[J]. 中华新生儿科杂志, 2018, 33(6): 456-462. DOI: 10.3760/cma.j.issn.2096-2932.2018.06.014.
20 Gao Q, Guo X, Cao Y, et al. Melatonin protects HT22 hippocampal cells from H2O2-induced injury by increasing beclin1 and Atg protein levels to activate autophagy[J]. Curr Pharm Des, 2021, 27(3): 446-454. PMID: 32838711. DOI: 10.2174/1381612826666200824105835.
21 Singh-Mallah G, Nair S, Sandberg M, et al. The role of mitochondrial and endoplasmic reticulum reactive oxygen species production in models of perinatal brain injury[J]. Antioxid Redox Signal, 2019, 31(9): 643-663. PMID: 30957515. PMCID: PMC6657303. DOI: 10.1089/ars.2019.7779.
22 Carloni S, Albertini MC, Galluzzi L, et al. Melatonin reduces endoplasmic reticulum stress and preserves sirtuin 1 expression in neuronal cells of newborn rats after hypoxia-ischemia[J]. J Pineal Res, 2014, 57(2): 192-199. PMID: 24980917. DOI: 10.1111/jpi.12156.
23 苟知贤, 胡兴, 王幽梦, 等. 褪黑素对缺氧缺血性脑损伤新生大鼠海马区细胞焦亡的影响[J]. 中华实用儿科临床杂志, 2020, 35(18): 1416-1420. DOI: 10.3760/cma.j.cn101070-20190306-00162.
24 Pang R, Han HJ, Meehan C, et al. Efficacy of melatonin in term neonatal models of perinatal hypoxia-ischaemia[J]. Ann Clin Transl Neurol, 2022, 9(6): 795-809. PMID: 35413154. PMCID: PMC9186150. DOI: 10.1002/acn3.51559.
25 Robertson NJ, Faulkner S, Fleiss B, et al. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model[J]. Brain, 2013, 136(Pt 1): 90-105. PMID: 23183236. DOI: 10.1093/brain/aws285.
26 Robertson NJ, Martinello K, Lingam I, et al. Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: a translational study[J]. Neurobiol Dis, 2019, 121: 240-251. PMID: 30300675. DOI: 10.1016/j.nbd.2018.10.004.
27 Robertson NJ, Lingam I, Meehan C, et al. High-dose melatonin and ethanol excipient combined with therapeutic hypothermia in a newborn piglet asphyxia model[J]. Sci Rep, 2020, 10(1): 3898. PMID: 32127612. PMCID: PMC7054316. DOI: 10.1038/s41598-020-60858-x.
28 Aridas JD, Yawno T, Sutherland AE, et al. Melatonin augments the neuroprotective effects of hypothermia in lambs following perinatal asphyxia[J]. J Pineal Res, 2021, 71(1): e12744. PMID: 34032315. DOI: 10.1111/jpi.12744.
29 Aly H, Elmahdy H, El-Dib M, et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study[J]. J Perinatol, 2015, 35(3): 186-191. PMID: 25393080. DOI: 10.1038/jp.2014.186.
30 Jerez-Calero A, Salvatierra-Cuenca MT, Benitez-Feliponi á, et al. Hypothermia plus melatonin in asphyctic newborns: a randomized-controlled pilot study[J]. Pediatr Crit Care Med, 2020, 21(7): 647-655. PMID: 32168305. DOI: 10.1097/PCC.0000000000002346.
31 Azzopardi D, Chew AT, Deierl A, et al. Prospective qualification of early cerebral biomarkers in a randomised trial of treatment with xenon combined with moderate hypothermia after birth asphyxia[J]. EBioMedicine, 2019, 47: 484-491. PMID: 31451436. PMCID: PMC6796501. DOI: 10.1016/j.ebiom.2019.08.034.
32 Pang R, Avdic-Belltheus A, Meehan C, et al. Melatonin and/or erythropoietin combined with hypothermia in a piglet model of perinatal asphyxia[J]. Brain Commun, 2021, 3(1): fcaa211. PMID: 33604569. PMCID: PMC7876304. DOI: 10.1093/braincomms/fcaa211.
33 Filippi L, Fiorini P, Catarzi S, et al. Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI): a feasibility study[J]. J Matern Fetal Neonatal Med, 2018, 31(8): 973-980. PMID: 28274169. DOI: 10.1080/14767058.2017.1304536.
34 Jiang B, Li W, Stewart S, et al. Sand-mediated ice seeding enables serum-free low-cryoprotectant cryopreservation of human induced pluripotent stem cells[J]. Bioact Mater, 2021, 6(12): 4377-4388. PMID: 33997514. PMCID: PMC8111032. DOI: 10.1016/j.bioactmat.2021.04.025.
35 Balduini W, Weiss MD, Carloni S, et al. Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia[J]. J Pineal Res, 2019, 66(4): e12565. PMID: 30734962. DOI: 10.1111/jpi.12565.
36 Merchant NM, Azzopardi DV, Hawwa AF, et al. Pharmacokinetics of melatonin in preterm infants[J]. Br J Clin Pharmacol, 2013, 76(5): 725-733. PMID: 23432339. PMCID: PMC3853531. DOI: 10.1111/bcp.12092.
37 Carloni S, Proietti F, Rocchi M, et al. Melatonin pharmacokinetics following oral administration in preterm neonates[J]. Molecules, 2017, 22(12): 2115. PMID: 29194416. PMCID: PMC6149762. DOI: 10.3390/molecules22122115.