Research Papers:

Melatonin protects against blood-brain barrier damage by inhibiting the TLR4/ NF-κB signaling pathway after LPS treatment in neonatal rats

Yingying Hu, Zhouguang Wang, Shulin Pan, Hongyu Zhang, Mingchu Fang, Huai Jiang, Hao Zhang, Zhengzheng Gao, Kebin Xu, Zhenmao Li, Jian Xiao _ and Zhenlang Lin

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Oncotarget. 2017; 8:31638-31654. https://doi.org/10.18632/oncotarget.15780

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Yingying Hu1,*, Zhouguang Wang2,*, Shulin Pan1, Hongyu Zhang2, Mingchu Fang1, Huai Jiang1, Hao Zhang1, Zhengzheng Gao2, Kebin Xu2, Zhenmao Li2, Jian Xiao2 and Zhenlang Lin1

1Department of Neonatology, The Second Affiliated Hospital & Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China

2Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China

*These authors have contributed equally to this work

Correspondence to:

Jian Xiao, email: [email protected]

Zhenlang Lin, email: [email protected]

Zhouguang Wang, email: [email protected]

Keywords: blood-brain barrier, melatonin, TLR4/NF-κB, white matter injury, hypoxic-ischemic and inflammatory

Received: December 28, 2016     Accepted: January 25, 2017     Published: February 28, 2017


Hypoxic-ischemic and inflammatory (HII) induces the disruption of blood–brain barrier (BBB) which leads to inflammatory responses and neuronal cell death, resulting in brain secondary damage. Previous studies showed that melatonin produced potent neuroprotective effects in neonatal hypoxic-ischaemic models. However, the relationship between BBB disruption and melatonin in HII was still unclear. The present study therefore investigated the beneficial effects of melatonin on BBB after HII and the underlying mechanisms. HII animal model was conducted by receiving lipopolysaccharide followed by 90 min hypoxia-ischaemia in postnatal day 2 Sprague–Dawley rat pups. Melatonin was injected intraperitoneally 1 h before lipopolysaccharide injection and then once a day for 1 week to evaluate the long-term effects. In this study, we demonstrated that melatonin administration inhibited the disruption of BBB permeability and improved the white matter recovery in HII model rats. Melatonin significantly attenuated the degradation of junction proteins and the neuroprotective role was related to the inhibition of microglial toll-like receptor 4/ nuclear factor-kappa B signaling pathway both in vivo and in vitro. Taken together, our data demonstrated that therapeutic strategies targeting inflammation might be suitable for the therapy of preserving BBB integrity after HII.

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