Melatonin attenuates white matter damage after focal brain ischemia in rats by regulating the TLR4/NF-κB pathway

Yansong Zhao; Haiyu Wang; Wei Chen; Lanfen Chen; Dianmei Liu; Xin Wang; Xiaoli Wang

doi:10.1016/j.brainresbull.2019.05.019

Melatonin attenuates white matter damage after focal brain ischemia in rats by regulating the TLR4/NF-κB pathway

Brain Res Bull. 2019 Aug:150:168-178. doi: 10.1016/j.brainresbull.2019.05.019. Epub 2019 May 31.

Authors

Yansong Zhao¹, Haiyu Wang², Wei Chen³, Lanfen Chen³, Dianmei Liu³, Xin Wang⁴, Xiaoli Wang⁵

Affiliations

¹ Department of Ophthalmology, Affiliated Hospital, Weifang Medical University, Weifang, Shandong 261031, China. Electronic address: zhaoyansong74@163.com.
² Department of Medical Imaging, Rizhao Traditional Chinese Hospital, Rizhao, Shandong 276800, China.
³ Department of Medical Imaging, Weifang Medical University, Weifang, Shandong 261053, China.
⁴ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Department of Medical Imaging, Weifang Medical University, Weifang, Shandong 261053, China. Electronic address: wxlpine@163.com.

PMID: 31158461
DOI: 10.1016/j.brainresbull.2019.05.019

Abstract

Objective: To assess the possible neuroprotective effects of melatonin against brain white matter damage via the Toll-like receptor 4 (TLR4)/ nuclear factor-kappa B (NF-κB) signaling pathway in focal cerebral ischemic rats.

Methods: Fifty-four Sprague-Dawley rats were randomly divided into the Sham, middle cerebral artery occlusion (MCAO), and melatonin groups. The successful MCAO models were evaluated by Laser Doppler flowmetry, magnetic resonance imaging (MRI) with T2-weighted imaging (T2WI) examination and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. White matter damage was assessed by myelin basic protein (MBP) immunohistochemical, Luxol Fast Blue (LFB) staining, and diffusion tensor imaging (DTI) examination. The proliferation of oligodendrocyte progenitor cells (OPCs) was examined by proliferating cell nuclear antigen (PCNA)/neural glial antigen 2 (NG2)/DAPI immunofluorescent staining. And the effects of melatonin therapy on the TLR4, NF-κB, and interleukin (IL)-1β proteins were examined by immunohistochemical staining. The correlation between the proliferating OPCs and TLR4 protein, IL-1β and TLR4 protein was respectively analyzed by linear regression analysis.

Results: The infarct volume was significantly reduced and white matter damage was also significantly alleviated in the melatonin group as compared with the MCAO group (P < 0.05), and there were more TLR4⁺, NF-κB⁺ and IL-1β⁺ cells in the MCAO group compared with the melatonin group (P < 0.01). Similarly, more PCNA⁺NG2⁺ cells were observed in the subventricular zone and white matter areas in the melatonin group compared with the MCAO group (P < 0.01). The number of TLR4⁺ cells was closely positively correlated with that of IL-1β⁺ cells, and negatively correlated with that of PCNA⁺NG2⁺ cells.

Conclusions: In summary, melatonin could promote the proliferation of endogenous OPCs and suppress the expression of IL-1β protein via inhibiting TLR4/NF-κB signaling, thus alleviate the white matter damage in focal cerebral ischemic rats.

Keywords: Brain ischemia; Diffusion tensor imaging; Melatonin; TLR4/NF-κB signaling; White matter.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / metabolism
Brain Ischemia / drug therapy*
Brain Ischemia / pathology
Diffusion Tensor Imaging
Disease Models, Animal
Infarction, Middle Cerebral Artery / pathology
Magnetic Resonance Imaging
Male
Melatonin / metabolism
Melatonin / pharmacology*
NF-kappa B / metabolism
Oligodendrocyte Precursor Cells / metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction / drug effects
Toll-Like Receptor 4 / metabolism
White Matter / drug effects*
White Matter / metabolism

Substances

NF-kappa B
Tlr4 protein, rat
Toll-Like Receptor 4
Melatonin